ABCMdb

ABCG2 p.Val12Met

ClinVar:	c.34G>A , p.Val12Met ? , association
Predicted by SNAP2:	A: D (66%), C: D (66%), D: D (80%), E: D (75%), F: D (66%), G: D (75%), H: D (80%), I: N (53%), K: D (80%), L: D (66%), M: N (72%), N: D (63%), P: D (85%), Q: D (75%), R: D (80%), S: D (63%), T: D (66%), W: D (80%), Y: D (63%),
Predicted by PROVEAN:	A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, M: N, N: N, P: N, Q: N, R: N, S: N, T: N, W: D, Y: N,

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[hide] C421A polymorphism in the human breast cancer resi... Mol Cancer Ther. 2002 Jun;1(8):611-6. Imai Y, Nakane M, Kage K, Tsukahara S, Ishikawa E, Tsuruo T, Miki Y, Sugimoto Y
C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance.
Mol Cancer Ther. 2002 Jun;1(8):611-6., [PMID:12479221]

Abstract [show]
Breast cancer resistance protein (BCRP) confers multidrug resistance to cancer cells against agents such as SN-38 (an active metabolite of irinotecan), mitoxantrone, and topotecan. Among 59 human tumor cell lines tested, 6 cell lines, A549, NCI-H460, KM-12, HT-29, OVCAR-5, and RPMI8226, showed high BCRP expression. BCRP cDNA was isolated from 11 cancer cell lines and three variant cDNAs [G34A substituting Met for Val-12 (V12M), C421A substituting Lys for Gln-141 (Q141K), and 944-949 deletion lacking Ala-315 and Thr-316 (delta315-6)] were identified. G34A and C421A variants were polymorphisms, and 944-949 deletion was a splicing variant. C421A BCRP-transfected PA317 cells showed markedly decreased protein expression and low-level drug resistance compared with wild-type BCRP-transfected cells when transfectants expressed similar levels of BCRP mRNA. G34A or 944-949-deleted BCRP-transfected PA317 cells showed similar or somewhat lower protein expression and drug resistance compared with wild-type BCRP-transfected cells. Of 124 healthy Japanese volunteers, 67 were wild-type, 48 were heterozygous, and 9 were homozygous for the C421A allele. These results suggest that some people possess the C421A polymorphic BCRP gene and express low amounts of Q141K BCRP. In addition to that, C376T polymorphism in exon 4 substituting stop codon for Gln-126 was found in 3 of the 124 general Japanese population. This C376T polymorphism may also have high impact because active BCRP protein will not be expressed from the C376T allele. Therefore, people with C376T and/or C421A polymorphisms may express low amounts of BCRP, and this low BCRP expression might result in hypersensitivity of normal cells to such anticancer drugs as irinotecan and mitoxantrone.

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5 BCRP cDNA was isolated from 11 cancer cell lines and three variant cDNAs [G34A substituting Met for Val-12 (V12M), C421A substituting Lys for Gln141 (Q141K), and 944-949 deletion lacking Ala-315 and Thr-316 (⌬315-6)] were identified. Login to comment
60 PA317 cells transfected with wild-type, G34A, C421A, and 944-949-deleted BCRP cDNAs were designated PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6 cells, respectively. Login to comment
83 G34A mutation that substitutes Met for Val-12 was found in MCF-7 cells. Login to comment
92 Western blotting of mutant BCRP-transfected PA317 cells demonstrated markedly low expression of Q141K BCRP in PA/Q141K cells compared with other BCRP-transfected cells. Login to comment
93 PA/WT, PA/V12M, and PA/⌬315-6 cells showed similar BCRP expression (Fig. 3A). Login to comment
96 In contrast, Northern blotting demonstrated similar levels of BCRP mRNA in PA/WT, PA/V12M, PA/ Q141K, and PA/⌬315-6 cells (Fig. 3B). Login to comment
104 Table 1 BCRP cDNA variants identified in this study Variant Amino acid change Cell line G34A Val-12 to Met MCF-7a C421A Gln-141 to Lys MDA-MB-231a A549a HCT-116a Deletion of 944-949 Deletion of Ala-315 and Thr-316 MCF-7 A549 HT-29 SK-OV-3 a Heterozygous allele. Login to comment
116 PA/WT and PA/V12M cells showed similar levels of resistance to the anticancer drugs (Table 2; Fig. 4A). Login to comment
125 In contrast, only a marginal shift occurred in PA/WT, PA/V12M, and PA/⌬315-6 cells (Fig. 5). Login to comment
126 Increases of mean fluorescence channel number in PA/ WT, PA/V12M, and PA/⌬315-6 cells were 1.5-, 1.6-, and 1.5-fold in the presence of topotecan, respectively. Login to comment
137 PA317 cells transfected with wild-type, G34A, C421A, and 944-949-deleted BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6, respectively. Login to comment
145 Table 2 IC50 a (ng/ml) of BCRP-transfected PA317 cells PA317 PA/WT PA/V12M PA/Q141K PA/⌬315-6 SN-38 2.5 98 98 30 55 Mitoxantrone 0.060 0.58 0.63 0.25 0.42 Topotecan 17 Ͼ200 Ͼ200 100 190 a IC50s (drug dose causing 50% inhibition of cell growth) were determined from cell growth curves in each experiment. Login to comment
148 PA317 cells transfected with wild-type, G34A, C421A, and 944-949- deleted BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6, respectively. Login to comment
149 A, sensitivity to SN-38 (A-1), mitoxantrone (A-2), and topotecan (A-3) of PA317, PA/WT, PA/V12M, and PA/Q141K cells. Login to comment
151 F, PA317; E, PA/WT; ‚, PA/V12M; Ⅺ, PA/Q141K; ᭛, PA/⌬315-6. Login to comment
165 By Western blotting, BCRP expression in PA/Q141K cells was markedly lower than that in the other BCRP transfectants. Login to comment
166 Another transfection experiment of mutant BCRP cDNAs in KB-3-1 human epidermoid carcinoma cells also revealed markedly lower expression of Q141K BCRP compared with wild-type and V12M BCRP (data not shown). Login to comment
186 PA317 cells transfected with wild-type, G34A, C421A, and 944-949- deleted BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6, respectively. Login to comment
188 In parental PA317 cells, a fluorescence peak shift to the right after the incubation with topotecan indicates cellular uptake of topotecan, whereas only marginal shifts occurred in PA/WT, PA/V12M, and PA/⌬315-6 cells. Login to comment
4 BCRP cDNA was isolated from 11 cancer cell lines and three variant cDNAs [G34A substituting Met for Val-12 (V12M), C421A substituting Lys for Gln-141 (Q141K), and 944-949 deletion lacking Ala-315 and Thr-316 (⌬315-6)] were identified. Login to comment
59 PA317 cells transfected with wild-type, G34A, C421A, and 944-949-deleted BCRP cDNAs were designated PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6 cells, respectively. Login to comment
82 G34A mutation that substitutes Met for Val-12 was found in MCF-7 cells. Login to comment
95 In contrast, Northern blotting demonstrated similar levels of BCRP mRNA in PA/WT, PA/V12M, PA/ Q141K, and PA/⌬315-6 cells (Fig. 3B). Login to comment
103 Table 1 BCRP cDNA variants identified in this study Variant Amino acid change Cell line G34A Val-12 to Met MCF-7a C421A Gln-141 to Lys MDA-MB-231a A549a HCT-116a Deletion of 944-949 Deletion of Ala-315 and Thr-316 MCF-7 A549 HT-29 SK-OV-3 a Heterozygous allele. Login to comment
115 PA/WT and PA/V12M cells showed similar levels of resistance to the anticancer drugs (Table 2; Fig. 4A). Login to comment
124 In contrast, only a marginal shift occurred in PA/WT, PA/V12M, and PA/⌬315-6 cells (Fig. 5). Login to comment
136 PA317 cells transfected with wild-type, G34A, C421A, and 944-949-deleted BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6, respectively. Login to comment
144 Table 2 IC50 a (ng/ml) of BCRP-transfected PA317 cells PA317 PA/WT PA/V12M PA/Q141K PA/⌬315-6 SN-38 2.5 98 98 30 55 Mitoxantrone 0.060 0.58 0.63 0.25 0.42 Topotecan 17 Ͼ200 Ͼ200 100 190 a IC50s (drug dose causing 50% inhibition of cell growth) were determined from cell growth curves in each experiment. Login to comment
147 PA317 cells transfected with wild-type, G34A, C421A, and 944-949- deleted BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6, respectively. Login to comment
150 F, PA317; E, PA/WT; ‚, PA/V12M; Ⅺ, PA/Q141K; ᭛, PA/⌬315-6. Login to comment
185 PA317 cells transfected with wild-type, G34A, C421A, and 944-949- deleted BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6, respectively. Login to comment
187 In parental PA317 cells, a fluorescence peak shift to the right after the incubation with topotecan indicates cellular uptake of topotecan, whereas only marginal shifts occurred in PA/WT, PA/V12M, and PA/⌬315-6 cells. Login to comment

[hide] Natural allelic variants of breast cancer resistan... Pharmacogenetics. 2003 Jan;13(1):19-28. Zamber CP, Lamba JK, Yasuda K, Farnum J, Thummel K, Schuetz JD, Schuetz EG
Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine.
Pharmacogenetics. 2003 Jan;13(1):19-28., [PMID:12544509]

Abstract [show]
The aim of this study was to identify the extent of genetic variability in breast cancer resistance protein (BCRP) in humans. We first analysed the sequence of BCRP cDNA from human livers and from human intestines phenotyped for expression of intestinal BCRP. We then determined the frequency of all known coding single nucleotide polymorphisms (cSNPs) using DNA from individuals representing 11 different ethnic populations. Nine SNPs including four non-synonymous and three synonymous cSNPs and two intronic SNPs were identified. Of the missense mutations, exon 2 SNP (G34A) resulted in a V12M change; exon 5 SNP (C421A) resulted in a Q141K substitution; exon 6 SNP (A616C) resulted in an I206L amino acid substitution; and exon 15 SNP (A1768T) resulted in a N590Y change in the BCRP protein. The two most frequent polymorphisms identified in the human population studied were the G34A and C421A transitions. There was marked variation in BCRP genotypes and allele frequencies in the different populations. BCRP mRNA was phenotyped in human small bowel intestinal samples by real-time polymerase chain reaction and BCRP protein was analysed on immunoblots of tissue from the same individuals. There was a 78-fold variation in expression of BCRP mRNA and significant variation in BCRP protein expression in human intestine. Expression of intestinal BCRP mRNA and protein was not different between persons expressing the common Gln141 allele compared to the Lys141 allele. Thus, common natural allelic variants of BCRP have been identified, and did not influence interindividual variation in expression of BCRP mRNA in human intestine, but remain to be tested for their effect on BCRP function.

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4 Of the missense mutations, exon 2 SNP (G34A) resulted in a V12M change; exon 5 SNP (C421A) resulted in a Q141K substitution; exon 6 SNP (A616C) resulted in an I206L amino acid substitution; and exon 15 SNP (A1768T) resulted in a N590Y change in the BCRP protein. Login to comment
92 Exon 2 A 34G.A transition results in a Val12 Met change (Fig. 1). Login to comment
119 Table 1 Frequencies of BCRP alleles in different ethnic groups Position in gene AC084732Ã Position in mRNA XM_032424Ã Sequence Region Caucasians African-Americans Japanese (n ¼ 20) Chinese (n ¼ 20) SE Asians (not Chinese or Japanese) (n ¼ 20) Pacific Islanders (n ¼ 14) À18398 À29 gctct(A/G)ttaag Exon 1 0.02 (1.5%)a 0 (0%)e ND ND ND ND 34 34 tccca(G/A)tgtca Exon 2 (V12M) 0.02 (4.7%)b 0.04 (8.3%)f 0.15 (30%) 0.20 (40%) 0.45 (70%) 0.64 (85.7%) 114 114 ttaag(T/C)tttca Exon 2 0.01 (1.2%)b 0 (0%)f 0 (0%) 0 (0%) 0 (0%) 0 (0%) 239 tttta (A/G)tttac Intron 2 0.03 (5.9%)c 0.05 (9.5%)g 0.15 (30%) 0.20 (40%) 0.45 (70%) 0.64 (85.7%) 8184 369 ggtta(C/T)gtggt Exon 4 0 (0%)a 0.07 (13.3%)e ND ND ND ND 8825 421 actta(C/A)agttc Exon 5 (Q141K) 0.14 (25.9%)d 0 (8%)f 0.35 (50%) 0.35 (60%) 0.15 (20%) 0.14 (28.6%) 18186 attat(A/G)atatt Intron 5 0 (0%)c 0 (8%)g 0 (0%) 0.05 (10%) 0 (0%) 0 (0%) 18286 616 cttcc(A/C)tcttg Exon 6 (I206L) 0 (0%)a 0 (8%)e 0 (0%) 0 (0%) 0 (0%) 0 (0%) 45073 1768 gacaa(A/T)acttc Exon 15 (N590Y) 0.01 (1.5%)a 0 (8%)e ND ND ND ND Position in gene AC084732Ã Position in mRNA XM_032424Ã Sequence Region Mexican-Indians (n ¼ 10) Mexicans (n ¼ 20) Hispanic Livers (n ¼ 10) Middle Eastern (n ¼ 40) Ashkenazi Jewish (n ¼ 20) Africans North of Sahara (n ¼ 14) À18398 À29 gctct(A/G)ttaag Exon 1 ND ND ND ND ND ND 34 34 tccca(G/A)tgtca Exon 2 (V12M) 0.90 (100%) 0.10 (20%) 0.40 (60%) 0.05 (10%) 0.10 (20%) 0.14 (14.3%) 114 114 ttaag(T/C)tttca Exon 2 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 239 tttta(A/G)tttac Intron 2 0.90 (100%) 0.10 (20%) 0.40 (60%) 0.05 (10%) 0.10 (20%) 0.14 (14.3%) 8184 369 ggtta(C/T)gtggt Exon 4 ND ND ND ND ND ND 8825 421 actta(C/A)agttc Exon 5 (Q141K) 0.10 (20%) 0.05 (10%) 0.10 (20%) 0.13 (25%) 0.05 (10%) 0 (0%) 18186 attat(A/G)atatt Intron 5 0 (0%) 0.10 (20%) 0 (0%) 0 (0%) 0.05 (10%) 0.07 (14.3%) 18286 616 cttcc(A/C)tcttg Exon 6 (I206L) 0 (0%) 0 (0%) 0.10 (20%) 0 (0%) 0 (0%) 0 (0%) 45073 1768 gacaa(A/T)acttc Exon 15 (N590Y) ND ND ND ND ND ND Data reported as: allele frequency (% individuals with at least one variant allele). Login to comment
125 Unauthorized reproduction of this article is prohibited. G34A V12M Exon 2 C71T1 A24V Exon 2 623C1 F208S Exon 6 A616C I206L Exon 6 C496G1 Q166E Exon 5 C421A Q141K Exon 5 A1444G2 R482G Exon 12 G1445C3 R482T Exon 12 A1768T N590Y Exon 15 Walker A motif: amino acids 80-89 Walker B motif: amino acids 206-210 SNPs found in human samples in this study Reported in ABCP1 Drug selected variants, MXR2 and BCRP3 MXR BCRP Fig. 1 BCRP protein topology and the positions of the identified SNPs resulting in missense mutations. Login to comment
173 The Val12 Met and the Gln141 Lys were the most frequent allelic variants. Login to comment
174 The Val12 Met was linked to an intron 2 A239G SNP in all populations. Login to comment
175 Marked population variation in the frequency of the BCRP Val12 Met SNP was found from as high as 100% in the Mexican-Indian population with at least one variant allele to as low as 4.7% in the Caucasian population. Login to comment

[hide] Single-nucleotide polymorphism (SNP) analysis in t... Cancer Biol Ther. 2002 Nov-Dec;1(6):696-702. Honjo Y, Morisaki K, Huff LM, Robey RW, Hung J, Dean M, Bates SE
Single-nucleotide polymorphism (SNP) analysis in the ABC half-transporter ABCG2 (MXR/BCRP/ABCP1).
Cancer Biol Ther. 2002 Nov-Dec;1(6):696-702., [PMID:12642696]

Abstract [show]
Variations in the amino acid sequence of ABC transporters have been shown to impact substrate specificity. We identified two acquired mutations in ABCG2, the ABC half-transporter overexpressed in mitoxantrone-resistant cell lines. These mutations confer differences in substrate specificity and suggest that naturally occurring variants could also affect substrate specificity. To search for the existence of single nucleotide polymorphisms (SNPs) in ABCG2, we sequenced 90 ethnically diverse DNAs from the Single Nucleotide Polymorphism Discovery Resource representing the spectrum of human genotypes. We identified 3 noncoding SNPs in the untranslated regions, 3 nonsynonymous and 2 synonymous SNPs in the coding region and 7 SNPs in the intron sequences adjacent to the sixteen ABCG2 exons. Nonsynonymous SNPs at nucleotide 238 (V12M; exon 2) and nucleotide 625 (Q141K; exon 5) showed a greater frequency of heterozygosity (22.2% and 10%) than the SNP at 2062 (D620N; exon 16). Heterozygous changes at nucleotide 238 are in linkage disequilibrium with an SNP observed 36 bases downstream from the end of exon 2. No polymorphism at amino acid 482 was identified to correspond to the R to G or R to T mutations previously found in two drug resistant cell lines. Among 23 drug resistant sublines for which sequence at position 482 was determined, no additional mutations were found. Heterozygosity at amino acid 12 allowed us to identify overexpression of a single allele in a subset of drug resistant cell lines, a feature that could be exploited clinically in evaluating the significance of ABCG2 expression in malignancy. We conclude that ABCG2 is well conserved and that described amino acid polymorphisms seem unlikely to alter transporter stability or function.

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6 Nonsynonymous SNPs at nucleotide 238 (V12M; exon 2) and nucleotide 625 (Q141K; exon 5) showed a greater frequency of heterozygosity (22.2% and 10%) than the SNP at 2062 (D620N; exon 16). Login to comment
104 Amplification in the MCF-7 SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) ANALYSIS IN THE ABC HALF-TRANSPORTER ABCG2 (MXR/BCRP/ABCP1) www.landesbioscience.com Cancer Biology & Therapy 699 Table 2 PRIMERS USED IN SEQUENCING 90 DNA SAMPLES Forward Primer (5`-> 3`) Reverse Primer (5`-> 3`) Exon 1 TGCCCACTCAAAAGGTTC CCAACCCACACTTAACACAC Exon 2 TGTCACCTAGTGTTTGCAATC GCCAGTTTCTTGGAAATAGCC Exon 3 AATCCTGCTTTGGTCTCC TCTCCCATTCTTTTTCCTC Exon 4 AGCATGTGTTGGAGGGAAAA ATCAGCCAAAGCACTTACCC Exon 5 GCAGGCTTTGCAGACATCTA TGCTGATCATGATGCTTTCA Exon 6 TCTTACAGGACTGGCACACG CCCCAAGAATATCTGGGACA Exon 7 TCAGGCTGAACTAGAGCAAACA CAAACAGCACTCCTGCAGAC Exon 8 CATGGGAAGAAGAGAGAAAG GTTGACTGGTATCAGAAGAC Exon 9 ACTCCTGACCTCGTAATCC GAAGCAGATGATAACAGAACC Exon 10 TCTAATTGAAACTCTTCCCC AGTTCGAAGCCAGTCTAGC Exon 11 TGAGTTGACTGCGGTGATTT GTAATCCTCCGGATCCCATC Exon 12 GTCTAGCCCTGAGGATGTGG TGCAAAATGGACAGGTGTTT Exon 13 CAGACACAACATTGGAGAC TAAGGGCAAAGAGGAAAG Exon 14 CTGCATGAAATTACTCAAGC CCATCCTCTCATTTACTTCC Exon 15 AAACTGTTTACCTTGCCC GCACCTCACTTCAATCTC Exon 16 GAGTAACATTTGACGGATG CTCTACTCTACCCACAGTTC Table 3 RESULTS OF SNP ANALYSIS OF 16 EXONS ENCODING ABCG2* Wild-type Frequency Frequency Frequency Amino Acid Exon Nucleotide+ allele SNP Wt/Wt Wt/Var Var/Var aa# 1 91 C T 98.9% 1.1% Noncoding 175 A G 97.8% 2.2% Noncoding 2 238 G A 76.7% 22.2% 1.1% 12 Val to Met 5 625 C A 88.9% 10% 1.1% 141 Gln to Lys 9 1302 G A 97.8% 2.2% 366 Glu to Glu 12 1629 A G 98.9% 1.1% 475 Leu to Leu 16 2062 G A 98.9% 1.1% 620 Asp to Asn 2597 C A 98.9% 1.1% Noncoding Intronic Variants 2 +36** A G 76.7% 22.2% 1.1% 6 -16 A G 88.9% 8.9% 2.2% 7 -20 T A 98.9% 1.1% +18 A G 93.3% 5.6% 1.1% 11 +20 A G 63.3% 27.8% 8.9% 12 +49 G T 75.6% 22.2% 2.2% 14 -21 C T 67.8% 28.9% 3.3% *Identified SNPs are recorded in the table with all 16 exons sequenced in 90 DNA samples. Login to comment

[hide] Genetic variation in the ATP-binding cassette tran... Eur J Pharm Sci. 2003 Apr;18(5):359-64. Backstrom G, Taipalensuu J, Melhus H, Brandstrom H, Svensson AC, Artursson P, Kindmark A
Genetic variation in the ATP-binding cassette transporter gene ABCG2 (BCRP) in a Swedish population.
Eur J Pharm Sci. 2003 Apr;18(5):359-64., [PMID:12694888]

Abstract [show]
The ATP-binding cassette transporter ABCG2 (also named breast cancer resistance protein, BCRP) functions as a drug efflux transporter and is expressed at high levels in the human small intestine. The aim of this study was to screen the human ABCG2 gene for genetic variation. The regions of the gene most likely to affect function, namely the coding parts, exon/intron boundaries, 5' untranslated region and 3' untranslated region and the proposed promoter region, were included in the screening. DNA was obtained from 60 Swedish individuals. The screening was performed using a polymerase chain reaction-denaturing high-performance liquid chromatography approach followed by sequence analysis. Eight sites of genetic variation were identified. The sequence variations considered to be most likely to affect transcription level or transport function were a CTCA deletion in the 5' flanking region, a single nucleotide polymorphism (SNP) in a 5' flanking CpG island, two non-synonymous SNPs, changing valine at amino acid position 12 to methionine and glutamine at position 141 to lysine, respectively. Genotyping of these sequence variations revealed linkage between the CTCA deletion and the SNP changing glutamine 141 for lysine. This information forms the basis for future association studies to investigate the genetic basis of differences of drug disposition due to sequence variation in the ABCG2 gene.

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62 Because To determine allele frequencies for the sequence varia- of the highly repetitive sequences surrounding exon 10, Table 2 Sequence variation in the human ABCG2 gene identified in the present study Sequence variant Nucleotide sequence (59 to 39) Affected Effect Identity to a ID DHPLC dbSNP b c Reference sequence Alteration pools g.-19572-19569 actcaCTCAcaaag actca caaag 15 59 Flanking deletion ss 4480605 ]] ]]]]d delCTCA g.-19202G.C gtactGatcag gtactCatcag 5 CpG island SNP rs 2231134 ] ] g.-18845T.C tgagcTcgtcc tgagcCcgtcc 8 59 UTR SNP rs 2231135 ] ] g.-18604delA cggcaAggagg cggca ggagg 1 59 UTR deletion ss 4480606 ] ]d g.34G.A tcccaGtgtca tcccaAtgtca 2 Missense SNP rs 2231137 ] ] Val12Met g.8007G.A ttggaGggaaa ttggaAggaaa 3 Intronic SNP ss 4480607 ] ]d g.8825C.A acttaCagttc acttaAagttc 4 Missense SNP rs 2231142 ] ] Gln141Lys d g.44997G.A ttcttAaaatt ttcttGaaatt 9 Intronic SNP rs 2231164 ] ] a Sequence variant ID in accordance with the nomenclature for sequence variation described at http://www.dmd.nl/mutnomen.html. Login to comment
80 The SNPs g.-19202G.C and g.34G.A (Val12Met) the CCAAT-box, a G/C single nucleotide polymorphism were less common, with frequencies of 0.05 and 0.02, (SNP), g.-19202G.C, was observed. Login to comment

[hide] Multidrug resistance mediated by the breast cancer... Oncogene. 2003 Oct 20;22(47):7340-58. Doyle LA, Ross DD
Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2).
Oncogene. 2003 Oct 20;22(47):7340-58., 2003-10-20 [PMID:14576842]

Abstract [show]
Observations of functional adenosine triphosphate (ATP)-dependent drug efflux in certain multidrug-resistant cancer cell lines without overexpression of P-glycoprotein or multidrug resistance protein (MRP) family members suggested the existence of another ATP-binding cassette (ABC) transporter capable of causing cancer drug resistance. In one such cell line (MCF-7/AdrVp), the overexpression of a novel member of the G subfamily of ABC transporters was found. The new transporter was termed the breast cancer resistance protein (BCRP), because of its identification in MCF-7 human breast carcinoma cells. BCRP is a 655 amino-acid polypeptide, formally designated as ABCG2. Like all members of the ABC G (white) subfamily, BCRP is a half transporter. Transfection and enforced overexpression of BCRP in drug-sensitive MCF-7 or MDA-MB-231 cells recapitulates the drug-resistance phenotype of MCF-7/AdrVp cells, consistent with current evidence suggesting that functional BCRP is a homodimer. BCRP maps to chromosome 4q22, downstream from a TATA-less promoter. The spectrum of anticancer drugs effluxed by BCRP includes mitoxantrone, camptothecin-derived and indolocarbazole topoisomerase I inhibitors, methotrexate, flavopiridol, and quinazoline ErbB1 inhibitors. Transport of anthracyclines is variable and appears to depend on the presence of a BCRP mutation at codon 482. Potent and specific inhibitors of BCRP are now being developed, opening the door to clinical applications of BCRP inhibition. Owing to tissue localization in the placenta, bile canaliculi, colon, small bowel, and brain microvessel endothelium, BCRP may play a role in protecting the organism from potentially harmful xenobiotics. BCRP expression has also been demonstrated in pluripotential "side population" stem cells, responsible for the characteristic ability of these cells to exclude Hoechst 33342 dye, and possibly for the maintenance of the stem cell phenotype. Studies are emerging on the role of BCRP expression in drug resistance in clinical cancers. More prospective studies are needed, preferably combining BCRP protein or mRNA quantification with functional assays, in order to determine the contribution of BCRP to drug resistance in human cancers.

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127 Allelic variation as a result of SNPs results in alterations of the BCRP protein at amino acids 12 (V12M), 141 (Q141K), 206 (I206L), and 590 (N590Y), with the most frequent polymorphisms being the exon 2 SNP (G34A) and the exon 5 SNP (C421A), which produce changes in amino acids 12 and 141 (Honjo et al., 2002; Imai et al., 2002a; Zamber et al., 2003). Login to comment

[hide] Single nucleotide polymorphisms result in impaired... Int J Cancer. 2004 Mar 20;109(2):238-46. Mizuarai S, Aozasa N, Kotani H
Single nucleotide polymorphisms result in impaired membrane localization and reduced atpase activity in multidrug transporter ABCG2.
Int J Cancer. 2004 Mar 20;109(2):238-46., 2004-03-20 [PMID:14750175]

Abstract [show]
ABCG2/MXR/ABCP1/BCRP is a member of the ATP-binding cassette membrane transporter, which consists of six transmembrane regions and one ATP-binding cassette. The transporter is known to be involved in the efflux of various anticancer compounds such as mitoxantrone, doxorubicin and topoisomerase I inhibitor. In this study, we analyzed the effects of polymorphisms in ABCG2, V12M and Q141K on transporter function. When polarized LLC-PK1 cells were transfected with variant ABCG2, drug-resistance to topoisomerase I inhibitor of cells expressing V12M or Q141K was less than 1/10 that of wild-type ABCG2 transfected cells, and was accompanied by increased drug accumulation and decreased drug efflux in the variant ABCG2-expressing cells. We further elucidated the molecular mechanisms of the transport dysfunction by investigating membrane localization and ATPase activity. Confocal microscopic analysis revealed that apical plasma membrane localization of V12M was disturbed, while the localization of wild-type transporters occurred specifically in the apical plasma membrane of polarized LLC-PK1 cells. Also, ATPase activities measured in the membrane of SF9 cells infected with variant ABCG2 showed that Q141K decreased activity by 1.3 below that of wild-type ABCG2. In addition, kinetic analysis of ATPase activity showed that the K(m) value in Q141K was 1.4-fold higher than that of wild-type ABCG2. These results indicated that naturally occurring SNPs alter transport functions of ABCG2 transporter and analysis of SNPs in ABCG2 may hold great importance in understanding the response/metabolism of chemotherapy compounds that act as substrates for ABCG2.

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2 In this study, we analyzed the effects of polymorphisms in ABCG2, V12M and Q141K on transporter function. Login to comment
3 When polarized LLC-PK1 cells were transfected with variant ABCG2, drug-resistance to topoisomerase I inhibitor of cells expressing V12M or Q141K was less than 1/10 that of wild-type ABCG2 transfected cells, and was accompanied by increased drug accumulation and decreased drug efflux in the variant ABCG2-expressing cells. Login to comment
5 Confocal microscopic analysis revealed that apical plasma membrane localization of V12M was disturbed, while the localization of wild-type transporters occurred specifically in the apical plasma membrane of polarized LLC-PK1 cells. Login to comment
15 Homozygous CC patients expressed lower P-gp in the intestine compared to TT patients, resulting in increased digoxin plasma concentration after orally administered digoxin.21 Another report showed that a naturally occurring mutation of R433S in MRP1 caused increased organic anion transport and decreased doxorubicin resistance.22 Several groups have reported naturally occurring ABCG2 SNPs in various ethnic populations, including Caucasian, Asian and African.23-27 In those reports, polymorphisms at V12M and Q141K occurred at high frequency in most of the ethnic populations. Login to comment
21 The previously reported polymorphisms,V12M and Q141K, had high frequencies of 10.3% and 9.0%, respectively. Login to comment
22 Drug resistance to the ABCG2 substrate, indolocarbazole topoisomerase I inhibitor, was reduced more than 10-fold in polarized cells that expressed variant ABCG2 with either V12M or Q141K compared Abbreviations: ABC, ATP-binding cassette; ABCP1, placenta-specific ABC transporter; BCRP, breast cancer-resistant protein; GFP, green fluorescent protein; in; HRP, horse radish peroxidase; MDR, multidrug resistance protein; MRP, multidrug resistance-associated prote; MXR, mitoxantrone resistance protein; P-gp, P-glycoprotein; PVDF, polyvinylidene difluoride; Sf9 cells, Spodoptera frugiperda ovarian cells; SNPs, single nucleotide polymorphisms. Login to comment
28 We concluded that the functional impairment of these 2 variants were due to disturbance of apical plasma membrane localization for V12M and reduced ATPase activity for Q141K, indicating ABCG2 gene SNPs may greatly influence resistance to ABCG2 substrate. Login to comment
43 Establishment of LLC-PK1 cells expressing wild-type and mutant ABCG2 Wild-type ABCG2 and mutated ABCG2 genes (G34A for V12M and C421A for Q141K), the point mutations of which were introduced by PCR mutagenesis, were cloned into HindIII and XhoI sites of pcDNA3.1(ϩ) (Invitrogen). Login to comment
61 Drug efflux assay LLC-PK1 cells were incubated with the indicated concentration of indolocarbazole compound for 120 min under energy-depleted TABLE I - SINGLE NUCLEOTIDE POLYMORPHISMS IN ABCG21 SNP Effect Region Domain Frequency in 30 cell lines Frequency in 150 clinical samples Hetero Home Hetero Homo Allele (%) G34A V12M Exon2 N-terminal 5 (16.7%) 0 27 (18.0%) 2 (1.3%) 10.3 Aϩ10G Intron3 ND ND 21 (14.0%) 4 (2.7%) 9.7 C369T Wobble Exon4 ABC 0 0 1 (0.67%) 0 0.3 C376T Q126Term Exon4 ABC 0 1 (3.3%) 0 0 0.0 C421A Q141K Exon5 ABC 5 (16.7%) 1 (3.3%) 22 (15.3%) 2 (1.3%) 9.0 C458T T153M Exon5 ABC 1 (3.3%) 0 0 0 0.0 C474T Wobble Exon5 ABC 0 0 1 (0.67%) 0 0.3 Aϩ20G Intron11 ND ND 34 (22.7%) 10 (6.7%) 18.0 A1444G R482G Exon12 TM3 0 0 0 0 0.0 G1445C R482T Exon12 TM3 0 0 0 0 0.0 C-21T Intron13 ND ND 32 (21.3%) 4 (2.7%) 13.3 A1768T N590Y Exon15 EC3 0 0 1 (0.67%) 0 0.3 G2237T Exon16 3ЈUTR 1 (3.3%) 0 0 0 0.0 G2393T Exon16 3ЈUTR 1 (3.3%) 0 0 0 0.0 The positions of the polymorphisms correspond to that of the ABCG2 cDNA (GenBank accession number AB051855) with the first base of the ATG start codon set to 1. Login to comment
89 Samples of 7 ␮g RNA extracted from HeLa, control C4, WT, V12M and Q141K cells (lanes 1, 2, 3, 4 and 5 respectively) were subjected to Northern hybridization and the blots were probed with a cDNA fragment of ABCG2. Login to comment
92 Vector transformant C4 (a) and stable clones expressing wild-type (b), V12M (c) and Q141K (d) were stained with monoclonal antibody BXP-34. Login to comment
102 Two polymorphisms, V12M and Q141K, had high frequency rates of 10.3% and 9.0%, respectively, in the 150 Caucasian subjects. Login to comment
103 V12M was located at the N-terminal intracellular region and Q141K at the ATP-binding cassette region. Login to comment
108 LLC-PK1 cells expressing WT, V12M and Q141K were incubated with opti-MEM with 50 ␮M (A) or 0.5 ␮M (B) of radiolabeled topoisomerase inhibitor for 180 min. Login to comment
119 TABLE II - RESISTANT PROFILE (IC50) OF ABCG2 TO ANTI-CANCER COMPOUNDS Anti-cancer compound IC50 (␮M)1 Control C4 Wild type V12M Q141K TopoI inhibitor2 0.12 Ͼ50 (420) 0.94 (7.8) 5.9 (49) Mitoxantrone 0.0015 0.029 (19) 0.00093 (0.62) 0.0053 (3.5) Topotecan 0.098 2.1 (22) 0.16 (1.7) 0.48 (4.9) Doxorubicin 0.010 0.039 (3.9) 0.0073 (0.73) 0.014 (1.4) Vincristine 0.0034 0.0053 (1.6) 0.0021 (0.62) 0.0058 (1.7) Camptothecin 0.0087 0.021 (2.4) 0.012 (1.4) 0.027 (3.1) 1 Relative resistances to control cells are described in parentheses.-2 TopoI inhibitor, Indolocarbazole topoisomerase I inhibitor. Login to comment
120 Resistance profile of variant ABCG2 transporters to anticancer compounds Among the polymorphisms detected, V12M and Q141K had a high frequency of amino acid substitutions. Login to comment
123 Northern blotting and immunocytochemical analysis with a monoclonal antibody revealed that approximately equal levels of ABCG2 were expressed in V12M and Q141K clones compared to the expression in the wild-type (WT) clone (Fig. 1). Login to comment
125 Wild-type cells conferred greater than 420-fold higher resistance to an indolocarbazole I topoisomerase inhibitor compared to that of control C4 cells as previously reported.10 In contrast, IC50 values of variant ABCG2 clones, V12M and Q141K, were less than 1/10 that of WT cells. Login to comment
127 The IC50 values of WT cells to mitoxantrone and topotecan increased 19- and 22-fold, respectively, over C4 cells, whereas in the variant V12M and Q141K cells, IC50 values to mitoxantrone and topotecan decreased as observed with the indolocarbazole compound. Login to comment
130 Accumulation and efflux assay of topoisomerase I inhibitor in ABCG2 variant-expressing cells Increased sensitivities of V12M and Q141K cells are thought to arise from changes in the intracellular drug concentration of topoisomerase I inhibitor. Login to comment
134 However, significantly higher indolocarbazole topoisomerase I inhibitor accumulation was observed in both V12M and Q141K cells compared to that in WT cells (2.7and 1.8-fold higher, respectively). Login to comment
135 A drug accumulation assay performed at a low dose (0.5 ␮M) of the compound confirmed that compound accumulations increased in variant cell lines (3.1and 2.8-fold increase for V12M and Q141K, respectively). Login to comment
141 Compared to WT cells, Vmax of V12M and Q141K cells decreased 2.5-and 1.8-fold, respectively, indicating that the increased drug accumulation and consequent reduction in drug resistance were due to the decreased efflux velocity. Login to comment
145 Vmax values of V12M and Q141K decreased 2.2- and 1.7-fold, respectively, which agrees well with the results of drug efflux assays using cell lines. Login to comment
146 Subcellular localization of wild-type and variant ABCG2 Experimental data described above indicate that the V12M polymorphism impaired function of the transporter, leading to increased drug accumulation and subsequent decreased drug resistance to anticancer compounds. Login to comment
152 In the V12M clone, however, ABCG2 staining was not specifically localized to the apical membrane and showed sparse staining in all basolateral, apical and cytosolic stains (Fig. 3c). Login to comment
154 These data indicate that the polymorphism at V12M impairs the specific apical membrane localization of this transporter. Login to comment
163 (A) Control C4 cells; (B) and E, WT cells; (C,F), V12M cells; (D,G), Q141K cells. Login to comment
164 Impairment of ABCG2 localization in V12M also was confirmed by double staining of cells with ABCG2 and F-actin (Fig. 3E-G). Login to comment
168 In V12M cells, specific apical localization was disturbed, and the staining of cytosolic and other membrane regions was observed (Fig. 3F). Login to comment
169 To further confirm disturbed membrane localization of ABCG2 in V12M stable cell lines, cells co-stained with E-cadherin (localized to the lateral-membrane) also were analyzed with confocal microscopy. Login to comment
170 The expected pattern of apical staining with anti-ABCG2 antibody was observed in wild-type and Q141K variant expressing cell lines, whereas dispersed staining was confirmed in V12M cells (data not shown). Login to comment
171 Presence of substrate did not restore the localization of V12M variant (data not shown). Login to comment
178 In the case of V12M, no significant difference in ATPase activity was observed. Login to comment
182 We concluded that Q141K and V12M polymorphisms did not restore drug stimulation, which was observed in R482 mutant. Login to comment
185 Unexpectedly, the Km value of Q141K also increased 1.4-fold compared to that of WT (0.64 mM; WT, 0.64 mM; V12M, 0.91 mM; Q141K). Login to comment
186 In the V12M membrane, the ATPase activity increased in almost same manner as in the WT membrane. Login to comment
187 No significant difference in either Vmax or Km between WT and V12M membranes was found, indicating that V12M does not affect any changes in ATPase activity. Login to comment
188 DISCUSSION In our study, we confirmed the locations and frequencies of SNPs in ABCG2 using 30 cancer cell lines and 150 Caucasian clinical samples, and then characterized the functional effects of the major SNPs, V12M and Q141K (Fig. 5). Login to comment
192 Membrane fractions isolated from Sf9 cells expressing wild-type, V12M and Q141K ABCG2 transporters were subjected to Western blotting with BXP-21 monoclonal antibody. Login to comment
203 the impaired function of ABCG2, membrane localization of transporter for V12M and ATPase activity for Q141K. Login to comment
204 The polymorphism at V12M impaired apical membrane localization of ABCG2 in polarized LLC-PK1 cells. Login to comment
208 Our observation of the deficiency of apical membrane localization of V12M implies that the N-terminal intracellular region may be critical for apical membrane localization of ABCG2 protein. Login to comment
209 It would be interesting to study the effect of V12M on vectorial transport because the transporters are expressed in polarized LLC-PK1 cells. Login to comment
221 Since V12M affected apical membrane localization of ABCG2, the variant V12M could have a more significant effect on polarized LLC-PK1 FIGURE 4 - CONTINUED. Login to comment
224 Three identified variants, which affect transporter function, were designated as V12M (1), Q126Term (2) and Q141K (3). Login to comment

[hide] Multidrug resistance in cancer chemotherapy and xe... Curr Med Chem Anticancer Agents. 2004 Jan;4(1):31-42. Han B, Zhang JT
Multidrug resistance in cancer chemotherapy and xenobiotic protection mediated by the half ATP-binding cassette transporter ABCG2.
Curr Med Chem Anticancer Agents. 2004 Jan;4(1):31-42., [PMID:14754410]

Abstract [show]
ABCG2, also termed BCRP/MXR/ABCP, is a half ATP-binding cassette (ABC) transporter expressed on plasma membranes. ABCG2 was independently cloned from placenta as well as cell lines selected for resistance to mitoxantrone or anthracyclines. ABCG2 consists of a nucleotide-binding domain (NBD) at the amino terminus and a transmembrane domain (TMD) at the carboxyl terminus and it is postulated to form a homodimer to perform its biological functions. Over-expression of ABCG2 in cell lines confers resistance on a wide variety of anticancer drugs including mitoxantrone, daunorubicin, doxorubicin, topotecan and epirubicin. The expression of ABCG2 has been implicated in multidrug resistance (MDR) of acute myeloid leukemia and some solid tumors. In addition, ABCG2 can transport several fluorescent dyes or toxins. ABCG2 is found to be expressed in epithelial cells of intestine and colon, liver canaliculi, and renal tubules, where it serves to eliminate the plasma level of orally administered anticancer drugs as well as ingested toxins. ABCG2 is found to be highly expressed in placenta and the luminal surface of microvessel endothelium blood-brain barrier where it may play a role in limiting the penetration of drugs, such as topotecan from the maternal plasma into the fetus and from blood to brain. A variety of inhibitors for ABCG2 including GF120918 may prove useful for sensitizing cancer cells to chemotherapy or altering the distribution of orally administered drug substrates of ABCG2. Interestingly, ABCG2 is also expressed highly in hematopoietic stem cells. However, the function of ABCG2 in stem cells is currently unknown, although it may provide protection to stem cells from a variety of xenobiotics.

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108 Nonsynonymous SNPs at nucleotide 238 (Val12 Met; exon 2) and nucleotide 625 (Gln141 Lys; exon 5) showed a greater frequency of heterozygosity (22.2% and 10%, respectively) than the SNP at 2062 (Asp620 Asn; exon 16). Login to comment
113 Two non-synonymous SNPs, Val12 Met and Gln141 Lys, were also identified, which are consistent with the study by Honjo et al. [25]. Login to comment

[hide] Breast cancer resistance protein (BCRP) in acute l... Leuk Lymphoma. 2004 Apr;45(4):649-54. Plasschaert SL, Van Der Kolk DM, De Bont ES, Vellenga E, Kamps WA, De Vries EG
Breast cancer resistance protein (BCRP) in acute leukemia.
Leuk Lymphoma. 2004 Apr;45(4):649-54., [PMID:15160935]

Abstract [show]
Multidrug resistance, cross-resistance to structurally and functionally unrelated drugs, is an important cause of treatment failure in acute leukemia. Multidrug resistance can result from the overexpression of ATP-dependent efflux pumps, such as P-glycoprotein and members of the multidrug resistance associated protein (MRP) family. Recently a novel transporter has been identified, which is called breast cancer resistance protein (BCRP), ABCG2 or mitoxantrone resistance protein. BCRP confers resistance to chemotherapeutic agents, such as mitoxantrone, doxorubicin and daunorubicin. This review describes BCRP detection techniques and the normal physiology of BCRP. The role of BCRP in the physiology of hematopoietic stem cells is addressed as well as the involvement of BCRP in multidrug resistance in acute leukemia. In AML and ALL, several studies showed that BCRP is expressed and functionally active at low, but variable levels. However, further studies are warranted to investigate its effect on clinical outcome, and explore whether patients could benefit from the combination of BCRP inhibitors and chemotherapy.

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80 Another polymorphism was the G34A, which causes the substitution of valine for methionine at amino acid position 12. Login to comment

[hide] ABCG2 -- a transporter for all seasons. FEBS Lett. 2004 Jun 1;567(1):116-20. Sarkadi B, Ozvegy-Laczka C, Nemet K, Varadi A
ABCG2 -- a transporter for all seasons.
FEBS Lett. 2004 Jun 1;567(1):116-20., 2004-06-01 [PMID:15165903]

Abstract [show]
The human ABCG2 (ABCP/MXR/BCRP) protein is a recently recognized ABC half-transporter, which forms homodimers in the plasma membrane and actively extrudes a wide variety of chemically unrelated compounds from the cells. This protein protects our cells and tissues against various xenobiotics, with a crucial role in the intestine, liver, placenta, and the blood-brain barrier. Moreover, ABCG2 seems to have a key function in stem cell protection/regulation, and also in hypoxic defense mechanisms. Widely occurring single nucleotide polymorphisms in ABCG2 may affect absorption and distribution, altering the effectiveness and toxicity of drugs in large populations. At the clinics, overexpression of ABCG2 in tumor cells confers cancer multidrug resistance to a variety of newly developed anticancer agents. On the other hand, specific substrate mutants of ABCG2 are advocated for use as selectable markers in stem-cell based gene therapy.

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127 These SNPs yield ABCG2 variants containing V12M and Q141K. Login to comment

[hide] Functional assessment of ABCG2 (BCRP) gene polymor... Drug Metab Dispos. 2005 Jan;33(1):94-101. Epub 2004 Oct 8. Kobayashi D, Ieiri I, Hirota T, Takane H, Maegawa S, Kigawa J, Suzuki H, Nanba E, Oshimura M, Terakawa N, Otsubo K, Mine K, Sugiyama Y
Functional assessment of ABCG2 (BCRP) gene polymorphisms to protein expression in human placenta.
Drug Metab Dispos. 2005 Jan;33(1):94-101. Epub 2004 Oct 8., [PMID:15475413]

Abstract [show]
The aim of the present study was to assess the contribution of polymorphisms in the breast cancer resistance protein/ATP-binding cassette transporter G2 (BCRP/ABCG2) gene to the placental expression from a new perspective, allelic imbalance. Polymorphisms were screened by polymerase chain reaction (PCR)-single-strand conformation polymorphism analysis followed by sequencing with DNA extracted from 100 placentas. To examine whether polymorphisms of the BCRP gene correlate with the placental BCRP expression, we determined mRNA and protein levels by quantitative real-time PCR and Western blotting, respectively. In placentas, G34A (Val(12)Met) and C421A (Gln(141)Lys) were frequently observed (18-36%), but C376T, which creates a stop codon (Gln(126) stop codon), was found with an allelic frequency of 1%. The mean of the BCRP protein level was significantly lower (p < 0.05) in homozygotes for the A421 allele than in those for the C421 allele, and heterozygotes had an intermediate value. To evaluate whether the C421A polymorphism acts as a cis-element in BCRP transcription, allelic imbalance was determined using informative lymphoblasts and 56 samples of placental cDNA. In most of the placental samples we tested, the difference in expression levels between the two alleles was small, and only two samples indicated a monoallelic expression (i.e., preferential expression of one allele). These results suggest that 1) the predominant allelic expression pattern of BCRP in placental samples is biallelic, and 2) the mutation C421A is not a genetic variant acting in cis, but is considered to influence the translation efficiency.

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3 In placentas, G34A (Val12 Met) and C421A (Gln141 Lys) were frequently observed (18-36%), but C376T, which creates a stop codon (Gln126 stop codon), was found with an allelic frequency of 1%. Login to comment
110 Of these, five SNPs resulted in the following amino acid substitutions: G34A (Val12Met), C376T (Gln126stop), C421A (Gln141Lys), G1322A (Ser441Asn), and T1465C (Phe489Leu). Login to comment
112 C376T, which is associated with an amino acid substitution from Gln to a stop codon at codon 126 (Gln126stop), was detected in only two placental samples (1.0%) as TABLE 1 Genetic polymorphism in the BCRP gene in Japanese placentas (n ϭ 100) Location Positiona Reference Alleleb Variant Allele Amino Acid Substitution Genotype Frequency of Variant Allele R/R R/V V/V 5Ј-Flanking region -20445 gtctCctcc gtctTctcc 98 2 0 0.010 -20296 agctAttaa agctGttaa 80 18 2 0.110 -19781 aaaaAttat aaaaGttat 99 1 0 -19572_-19569 ctcaCTCAcaaa ctca--caaa 60 33 7 0.235 Exon 2 34 cccaGtgtc cccaAtgtc Val12Met 70 24 6 0.180 Intron 2 203 ϩ 16 tttaAttta tttaGttta 70 24 6 0.180 Intron 3 263 ϩ 10 tataAgaga tataGgaga 85 14 1 0.080 263 ϩ 72 ttttGtgtg ttttTGtgtg 99 1 0 0.005 Exon 4 376 ggtaCaagt ggtaTaagt Gln126stop 98 2 0 0.010 Exon 5 421 cttaCagtt cttaAagtt Gln141Lys 42 45 13 0.355 Intron 5 532-16 ttatAatat ttatGatat 99 1 0 0.005 Exon 9 1098 aggaGatca aggaAatca Synonymous 98 2 0 0.010 Intron 10 1277 ϩ 95 atagTgtaa atagAgtaa 97 3 0 0.015 Exon 11 1322 agcaGtgtt agcaAtgtt Ser441Asn 99 1 0 0.005 Intron 11 1367 ϩ 20 ttctAggaa ttctGggaa 71 25 4 0.165 Exon 12 1465 tataTttac tataCttac Phe489Leu 99 1 0 0.005 Intron 12 1492 ϩ 49 ctatGggtg ctatCggtg 44 45 11 0.335 Exon 13 1515 atgcCttct atgc-ttct Phe506Ser 99 1 0 0.005 Phe507Leu Val508Leu Met509stop Intron 13 1648-42 tgaaAttac tgaaTttac 99 1 0 0.005 1648-21 gactCttag gactTttag 71 25 4 0.165 Intron 14 1738-46 tcttAaaat tcttGaaat 24 52 24 0.500 3Ј-UTR 2332 cttcAgtct cttcTAgtct 86 14 0 0.070 2364 tgccAttat tgccCttat 99 1 0 0.005 2512 agaaCttac agaaTttac 99 1 0 0.005 R, reference allele; V, variant allele. Login to comment
148 SNP Amino Acid Change Population Genotypes Frequency of Variant Allele R/R R/V V/V G34A Val12Met Japanese (n ϭ 120) 81 37 2 0.17 (0.12-0.22) Caucasian (n ϭ 150) 139 11 0 0.04 (0.02-0.06) African American (n ϭ 150) 132 17 1 0.06 (0.04-0.09) C376T Gln126stop Japanese (n ϭ 120) 118 2 0 0.01 (0.00-0.02) Caucasian (n ϭ 150) 150 0 0 0.00 African American (n ϭ 150) 150 0 0 0.00 C421A Gln141Lys Japanese (n ϭ 120) 61 45 14 0.30 (0.25-0.36) Caucasian (n ϭ 150) 121 25 4 0.11 (0.08-0.15) African American (n ϭ 150) 144 5 1 0.02 (0.01-0.04) R, reference allele; V, variant allele. Login to comment
169 Among the nonsynonymous polymorphisms, G34A (Val12Met) and C421A (Gln141Lys) appeared commonly in Japanese subjects, and allelic frequencies of these polymorphisms were in keeping with those of a previous report (Imai et al., 2002). Login to comment

[hide] Functional analysis of SNPs variants of BCRP/ABCG2... Pharm Res. 2004 Oct;21(10):1895-903. Kondo C, Suzuki H, Itoda M, Ozawa S, Sawada J, Kobayashi D, Ieiri I, Mine K, Ohtsubo K, Sugiyama Y
Functional analysis of SNPs variants of BCRP/ABCG2.
Pharm Res. 2004 Oct;21(10):1895-903., [PMID:15553238]

Abstract [show]
PURPOSE: The aim of the current study was to identify the effect of single nucleotide polymorphisms (SNPs) in breast cancer resistance protein (BCRP/ABCG2) on its localization, expression level, and transport activity. METHODS: The cellular localization was identified using the wild type and seven different SNP variants of BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S, and S441N BCRP) after transfection of their cDNAs in plasmid vector to LLC-PK1 cells. Their expression levels and transport activities were determined using the membrane vesicles from HEK293 cells infected with the recombinant adenoviruses containing these kinds of BCRP cDNAs. RESULTS: Wild type and six different SNP variants of BCRP other than S441N BCRP were expressed on the apical membrane, whereas S441N BCRP showed intracellular localization. The expression levels of Q141K and S441N BCRP proteins were significantly lower compared with the wild type and the other five variants. Furthermore, the transport activity of E1S, DHEAS, MTX, and PAH normalized by the expression level of BCRP protein was almost the same for the wild type, V12M, Q141K, A149P, R163K, Q166E, and P269S BCRP. CONCLUSIONS: These results suggest that Q141K SNPs may associate with a lower expression level, and S441N SNPs may affect both the expression level and cellular localization. It is possible that subjects with these polymorphisms may have lower expression level of BCRP protein and, consequently, a reduced ability to export these substrates.

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3 The cellular localization was identified using the wild type and seven different SNP variants of BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S, and S441N BCRP) after transfection of their cDNAs in plasmid vector to LLC-PK1 cells. Login to comment
8 Furthermore, the transport activity of E1S, DHEAS, MTX, and PAH normalized by the expression level of BCRP protein was almost the same for the wild type, V12M, Q141K, A149P, R163K, Q166E, and P269S BCRP. Login to comment
26 On analyzing the specimens from the 100 Japanese volunteers, 7 kinds of SNPs were identified for the BCRP gene: G34A (V12M), C376T (Q376Stop), C421A (Q141K), G1098A (E366E), G1322A (S441N), T1465C (F489L), and C1515- (AFFVM505-509ASSL Stop). Login to comment
27 The allele frequencies of these SNPs are 18, 1, 36, 1, 0.5, 0.5, and 0.5%, respectively. In the 84 cell lines, 7 kinds of SNPs were identified and their frequency for G34A (V12M), C376T (Q126Stop), C421A (Q141K), G445C (A149P), G488A (R163K), C805T (P269S), and G1098A (E366E) are 22, 3, 29, 1, 0.6, 0.6 and 2%, respectively. Login to comment
29 We constructed expression systems for the wild type and SNPs variants of BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S, S441N BCRP) and examined whether these SNPs variants of BCRP alter its localization, expression level, and transport activity. Login to comment
42 Using site-directed mutagenesis, SNP variants of BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S and S441N BCRP) were constructed on pcDNA3.1 vector (SNPs type BCRP/pcDNA3.1). Login to comment
43 V12M BCRP was amplified with 5Ј- GTCGAAGTTTTTATCCCAATGTCACAAGGAAA- CACCAATGGC-3Ј and `-GCCATTGGTGTTTCCTTGT- GACATTGGGATAAAAACTTCGAC-3Ј. Login to comment
52 For SNPs type BCRPs, viruses were prepared in the same way, resulting in the production of pAd-SNPs BCRP (pAd-V12M, Q141K, A149P, R163K, Q166E, P269S, and S441N BCRP). Login to comment
110 Except for two SNP variants of BCRP (Q141K and S441N BCRP), the ATP-dependent uptakes per mg membrane protein of SNP variants (V12M, A149P, R163K, Q166E, P269S BCRP) were similar to that of the wild-type BCRP (Fig. 3a). Login to comment
114 As shown in Fig. 3b, the transport activity of other SNP variants of BCRP (V12M, Q141K, A149P, R163K, Q166E, and P269S BCRP) was almost identical to that of the wild-type BCRP. Login to comment
115 As far as V12M and Q141K BCRP were concerned, these have a high allele frequency in Japanese and we determined the kinetic parameters for the transport of [3 H]E1S. Login to comment
116 As shown in Fig. 4, the ATP-dependent uptake of [3 H]E1S was saturable, and the Km values were 11.6 ± 4.79, 9.07 ± 1.52, and 14.0 ± 7.27 ␮M, and the Vmax values were 13.3 ± 3.3, 13.5 ± 1.29, and 4.57 ± 1.58 nmol min-1 mg-1 protein, for the wild type, V12M, and Q141K BCRP, respectively. In addition to [3 H]E1S, the transport of other BCRP substrates was examined. Login to comment
120 Figure 5a shows the ATP-dependent uptake of DHEAS, PAH, and MTX per mg membrane protein for the wild-type and SNPs BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S, and S441N BCRP). Login to comment
155 Concerning the cellular localization of SNPs variants of BCrP, Mizuarai et al. reported the intracellular localization of V12M BCRP in stably transfected LLC-PK1 cells very recently (23). Login to comment
156 The finding by Mizuarai et al. (23) was in marked contrast to the present finding that V12M BCRP is expressed on the apical membrane of transiently transfected LLC-PK1 cells (Fig. 1). Login to comment
158 It is possible that the cellular localization of V12M BCRP is affected by the culture conditions of LLC-PK1 cells. Login to comment
162 For these compounds, our results indicated that the transport activity per BCRP molecule for 6 kinds of SNP variants (V12M, A149P, R163K, Q166E, P269S, and also Q141K BCRP) is almost the same as that of the wild type BCRP (Figs. Login to comment
173 Saturation of [3 H]E1S transport was determined for the wild-type, V12M, and Q141K BCRP. Login to comment
180 Furthermore, the Km values for E1S were similar between the wild type, V12M and Q141K BCRP (Fig. 4). Login to comment

[hide] Linkage disequilibrium and haplotype architecture ... Ann Hum Genet. 2004 Nov;68(Pt 6):563-73. Wang H, Hao B, Zhou K, Chen X, Wu S, Zhou G, Zhu Y, He F
Linkage disequilibrium and haplotype architecture for two ABC transporter genes (ABCC1 and ABCG2) in Chinese population: implications for pharmacogenomic association studies.
Ann Hum Genet. 2004 Nov;68(Pt 6):563-73., [PMID:15598215]

Abstract [show]
Information about linkage disequilibrium (LD) patterns and haplotype structures for candidate genes is instructive for the design and analysis of genetic association studies for complex diseases and drug response. ABCC1 and ABCG2 are genes coding for two multidrug resistance (MDR) associated transporters; they are also related to some pathophysiological traits. To pinpoint the LD profiles of these MDR genes in Chinese, we systemically screened 27 unrelated individuals for single nucleotide polymorphisms (SNPs) in the coding and regulatory regions of these genes, and thereby characterized their haplotype structures. Despite marked variations in haplotype diversity, LD pattern and intragenic recombination intensity between the two genes, both loci could be partitioned into several LD blocks, in which a modest number of haplotypes accounted for a high fraction of the sampled chromosomes. We concluded that each locus has its own genomic LD profile, but that they still share a common segmental LD architecture with low haplotype diversity. Our data will benefit genetic association studies of complex traits and drug response possibly related to these genes.

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57 SNP Nucleotide sequence Minor allele dbSNP ID effect position (major/minor) frequency (%) ABCC1 1 5`FR/-1862 gacccG/Aggcca 44.4 2 5`FR/-1830 atcctA/Gtctac 1.9 3 5`FR/-1680 gaggaG/Aaaaag 1.9 4 5`FR/-471 cggatA/Gctgtc 7.4 5 E2/218 caaaaC/Tcaaaa 3.7 Thr73Ile 6 I2/-26 gttgtG/Aggggg 1.9 rs8187842 7 I3/-66 ctgggT/Cgacaa 37.0 rs4148337 8 I7/+54 ccactC/Actgtg 9.3 rs903880 9 I7/+64 ggcctC/Gaatcc 48.1 rs246232 10 E8/816 cagccG/Agtgaa 1.9 wobble 11 E8/825 aaggtT/Cgtgta 38.9 rs246221 wobble 12 E9/1062 gtgaaT/Cgacac 35.2 rs35587 wobble 13 I9/+8 aggggA/Gcgctg 37.0 rs35588 14 I12/-37 cactcA/Ggggca 20.4 rs35604 15 E13/1684 tggccT/Ctgtgc 20.4 rs35605 wobble 16 I13/+105 ccggtC/Tgggct 20.4 rs35606 17 I14/+105 ccagcC/Tgcttg 1.9 18 I15/+627 gctgtA/Gtttta 25.8 rs35628 19 I15/+669 aatctG/Ttagaa 7.4* rs4148353 20 I15/-967 ctttcT/Ggctgt 37.0 rs152029 21 E16/2007 atcccC/Tgaagg 3.7 rs2301666 wobble 22 E17/2168 tctccG/Aagaaa 5.6 rs4148356 Arg723Gln 23 I18/-30 gcactG/Cacgtg 16.7 rs2074087 24 I22/+62 aattaT/Ctccct 27.8 rs3887893 25 I22/-43 gtcagC/Ttccct 3.7 26 E27/3915 gaggaC/Tctgga 1.9 wobble 27 E28/4002 aagtcG/Atccct 11.1 rs2239330 wobble 28 I28/-35 tcagcA/Gtgaca 27.8 rs212087 29 I30/+30 gcacaG/Atggcc 29.6 rs212088 30 3`UTR/+801 accccC/Gactcc 33.3 rs129081 noncoding 31 3`UTR/+866 tactgT/Atccca 14.8 rs212090 noncoding 32 3`FR/+1513 gttctT/Ctaagg 27.8 ABCG2 1 5`UTR/-407 cgcagC/Tgcctc 1.9 2 5`UTR/-376 ggggaG/Acgctc 1.9 3 E2/34 tcccaG/Atgtca 20.4 rs2231137 Val12Met 4 I2/+36 ttttaA/Gtttac 25.9 rs4148152 5 I3/+10 gtataA/Ggagag 20.4 rs2231138 6 E5/421 acttaC/Agttct 22.2 rs2231142 Gln141Lys 7 E7/805 acgggC/Tctgct 3.7 Pro269Ser 8 I9/-126 agccaT/Gtgagt 7.4 9 I11/+20 gttctA/Gggaac 31.5 rs2231153 10 I12/+49 cctatG/Tggtga 16.7 rs2231156 11 I13/+40 tgtttT/Ctttcc 24.1 rs2231157 12 I13/-21 tgactC/Tttagt 29.6 rs2231162 13 I14/-46 ttcttG/Aaaatt 48.1 rs2725267 SNPs in specific regions, i.e. 5`flanking region (5`FR), 5`untranslated region (5`UTR), intron (I), exon (E), 3`UTR, and 3`FR, are presented as region/+(-): for 5`FR and 5`UTR, n nucleotides upstream (-) from the translation initiation site; for 3`UTR and 3`FR, n nt downstream (+) from the third base of stop codon; for coding regions, n corresponds to positions of their cDNA with the first base of start codon set to 1; and for introns, n nt upstream (-) from 3` site or downstream (+) from 5` site of introns. Login to comment

[hide] Eight novel single nucleotide polymorphisms in ABC... Drug Metab Pharmacokinet. 2003;18(3):212-7. Itoda M, Saito Y, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Suzuki H, Sugiyama Y, Ozawa S, Sawada J
Eight novel single nucleotide polymorphisms in ABCG2/BCRP in Japanese cancer patients administered irinotacan.
Drug Metab Pharmacokinet. 2003;18(3):212-7., [PMID:15618737]

Abstract [show]
Eight novel single nucleotide polymorphisms (SNPs) were found in the gene encoding the ATP-binding cassette transporter, ABCG2/BCRP, from 60 Japanese individuals administered the anti-cancer drug irinotecan. The detected SNPs were as follows: 1) SNP, MPJ6_AG2005 (IVS2-93T>C); Gene Name, ABCG2; Accession Number, NT_006204; 2) SNP, MPJ6_AG2007 (IVS3+71_72 insT); Gene Name, ABCG2; Accession Number, NT_006204; 3) SNP, MPJ6_AG2012 (IVS6-204C>T); Gene Name, ABCG2; Accession Number, NT_006204; 4) SNP, MPJ6_AG2015 (at nucleotide 1098G>A (exon 9) from the A of the translation initiation codon); Gene Name, ABCG2; Accession Number, NT_006204; 5) SNP, MPJ6_AG2017 (1291T>C (exon 11)); Gene Name, ABCG2; Accession Number, NT_006204; 6) SNP, MPJ6_AG2019 (IVS11-135G>A); Gene Name, ABCG2; Accession Number, NT_006204; 7) SNP, MPJ6_AG2020 (1465T>C (exon 12)); Gene Name, ABCG2; Accession Number, NT_006204; 8) SNP, MPJ6_AG2023 (IVS13+65T>G); Gene Name, ABCG2; Accession Number, NT_006204.MPJ6_AG2015 was a synonymous SNP (E366E). MPJ6_AG2017 and MPJ6_AG2020 resulted in amino acid alterations, F431L and F489L, respectively.

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46 Information on ABCG2WBCRP single nucleotide polymorphisms (SNPs) has been published.8-10) Five naturally occurring nonsynonymous SNPs have been reported in Japanese and Caucasians: V12M, Q126Stop, Q141K, I206L, and N590Y.8-10) SNP Q126Stop was found in 3 out of 124 healthy Japanese subjects.9) Since it may be possible that ABCG2WBCRP polymorphisms are associated with the eŠectiveness and adverse eŠects of irinotecan, ABCG2WBCRP exons and their ‰anking regions were sequenced to identify Japanese speciˆc SNPs. Login to comment
126 Masaya ITODA, et al.SNP18 (216) Novel ABCG2 SNPs SNP19 (217) tion of ABCG2WBCRP haplotypes in conjunction with other frequently found SNPs, including non-synonymous ones (34GÀA (V12M, SNP frequency 19z) and 421CÀA (Q141K, SNP frequency 33z)) in the Japanese population. Login to comment
128 MPJ6äAG2012 was closely associated with the known SNP, IVS1-99GÀA (rs1584481, ssj0001922), but not with the SNPs, 34GÀA (V12M) and 421CÀA (Q141K). Login to comment

[hide] Cytoplasmic confinement of breast cancer resistanc... Mol Pharmacol. 2005 Apr;67(4):1349-59. Epub 2005 Jan 18. Ifergan I, Jansen G, Assaraf YG
Cytoplasmic confinement of breast cancer resistance protein (BCRP/ABCG2) as a novel mechanism of adaptation to short-term folate deprivation.
Mol Pharmacol. 2005 Apr;67(4):1349-59. Epub 2005 Jan 18., [PMID:15657365]

Abstract [show]
The unique capability of breast cancer resistance protein (BCRP/ABCG2) to export mono-, di-, and triglutamates of folates should limit cellular proliferation under conditions of folate deprivation, particularly upon BCRP overexpression. Here, we explored the mode of adaptation of BCRP-overexpressing cells to short-term folate deprivation. MCF-7/MR cells grown in high folate medium (2.3 muM folic acid) containing mitoxantrone had 62% of their overexpressed BCRP in the plasma membrane and only 38% in the cytoplasm. In contrast, cells grown for 2 weeks in folic acid-free medium followed by an adaptation week in low folate medium (1 nM folic acid) had 86% of BCRP in the cytoplasm and only 14% in the plasma membrane. Unlike BCRP, various transmembrane proteins retained their normal plasma membrane localization in folate-deprived cells. Folate deprivation was also associated with a 3-fold decrease in BCRP and multidrug resistance protein 1 (MRP1/ABCC1) levels. Confocal microscopy with folate-deprived cells revealed that cytoplasmic BCRP colocalized with calnexin, an established endoplasmic reticulum resident. The loss of BCRP from the plasma membrane in folate-deprived cells consistently resulted in a 4.5-fold increase in [(3)H]folic acid accumulation relative to MCF-7/MR cells. Hence, cellular adaptation to shortterm folate deprivation results in a selective confinement of BCRP to the cytoplasm along with a moderate decrease in BCRP and MRP1 levels aimed at preserving the poor intracellular folate pools. These results constitute a novel mechanism of cellular adaptation to short-term folate deprivation and provide further support to the possible role of BCRP in the maintenance of cellular folate homeostasis.

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236 It was found that an N-terminal BCRP mutation (Val12Met) disrupted the apical plasma membrane localization of BCRP in polarized LLC-PK1 cells. Login to comment

[hide] Functional analysis of the human variants of breas... Drug Metab Dispos. 2005 Jun;33(6):697-705. Epub 2005 Mar 2. Vethanayagam RR, Wang H, Gupta A, Zhang Y, Lewis F, Unadkat JD, Mao Q
Functional analysis of the human variants of breast cancer resistance protein: I206L, N590Y, and D620N.
Drug Metab Dispos. 2005 Jun;33(6):697-705. Epub 2005 Mar 2., [PMID:15743976]

Abstract [show]
Previous studies have shown that the V12M and Q141K variants of breast cancer resistance protein (BCRP) can affect expression and function of the transporter. In this study, the effects of the I206L, N590Y, and D620N variants on protein expression, plasma membrane localization, and transport activity of BCRP were investigated. Wild-type BCRP and the three variants were stably expressed in human embryonic kidney (HEK) cells. Confocal microscopy analysis showed that the three variants were predominantly routed to the plasma membrane of HEK cells. The expression level of I206L in the plasma membrane was approximately 45% of that of wild-type protein, whereas the N590Y and D620N levels were increased approximately 3.6-fold and 2.4-fold, respectively, as determined by immunoblotting. All three variants transported mitoxantrone, pheophorbide a, and BODIPY FL-prazosin. After normalization for differences in BCRP expression, I206L, N590Y, and D620N exhibited approximately 2-fold, 0.3-fold, and 0.5-fold wild-type efflux activities, respectively. The variants also conferred resistance to mitoxantrone and topotecan. Mitoxantrone and topotecan resistance by I206L and N590Y was approximately 2-fold and 0.3-fold of the wild-type BCRP resistance levels, respectively. Although D620N conferred a topotecan resistance similar to that of the wild-type protein, its level of mitoxantrone resistance was decreased by 50%. After normalization to BCRP expression levels, ATPase activities of I206L were not significantly different from those of wild-type protein, whereas N590Y and D620N exhibited approximately 30% and 50% of wild-type ATPase activities, respectively. These results suggest that I206L has the lowest protein expression and the highest activity, whereas N590Y and D620N display higher expression and lower activity, relative to wild-type BCRP.

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20 Two variants, V12M and Q141K, occurred at particularly high allele frequencies in Chinese and Japanese populations (30-60%) and at relatively lower allele frequencies in white people and African-Americans (5-26%) (Zamber et al., 2003). Login to comment
207 Imai et al. (2002) demonstrated that Q141K was expressed at a lower level in transfected murine fibroblast PA317 cells and conferred lower levels of drug resistance compared with wild-type BCRP, whereas V12M exhibited an expression level and drug resistance profiles very similar to those of wild-type protein (Imai et al., 2002). Login to comment
208 Another study (Mizuarai et al., 2004) showed that V12M and Q141K were expressed in the polarized LLC-PK1 porcine kidney cells at levels comparable to that of wild-type protein; however, both V12M and Q141K conferred significantly lower drug resistance than wild-type protein, accompanied with increased drug accumulation and decreased drug efflux. Login to comment
209 Further analysis of the mechanism of transport dysfunction revealed that the apical membrane localization of V12M was disrupted, whereas the expression and apical membrane localization of Q141K were not affected; however, the ATPase activity of Q141K was decreased. Login to comment
210 A recent study illustrated that V12M was expressed in HEK cells at levels similar to that of wild-type BCRP, whereas the Q141K level was significantly decreased compared with wild-type protein; however, the transport activity normalized by the BCRP expression was almost the same for V12M, Q141K and wild-type BCRP (Kondo et al., 2004). Login to comment

[hide] Single nucleotide polymorphisms modify the transpo... Cancer Chemother Pharmacol. 2005 Aug;56(2):161-72. Epub 2005 Apr 19. Morisaki K, Robey RW, Ozvegy-Laczka C, Honjo Y, Polgar O, Steadman K, Sarkadi B, Bates SE
Single nucleotide polymorphisms modify the transporter activity of ABCG2.
Cancer Chemother Pharmacol. 2005 Aug;56(2):161-72. Epub 2005 Apr 19., [PMID:15838659]

Abstract [show]
Single nucleotide polymorphism (SNP) analyses of the ABCG2 gene have revealed three nonsynonymous SNPs resulting in the amino acid changes at V12M, Q141K and D620N. To determine whether the SNPs have an effect on drug transport, human embryonic kidney cells (HEK-293) were stably transfected with full length ABCG2 coding wild-type or SNP variants of ABCG2. In 4-day cytotoxicity assays with mitoxantrone, topotecan, SN-38 or diflomotecan, cells transfected with wild-type R482 ABCG2 showed IC50 values up to 1.2-fold to 5-fold higher than cells expressing comparable levels of Q141K ABCG2, suggesting that the Q141K SNP affects drug transport. FTC-inhibitable mitoxantrone efflux normalized to ABCG2 surface expression as assayed by the anti-ABCG2 antibody 5D3 was significantly lower in cells transfected with Q141K ABCG2 than in those transfected with wild-type R482 ABCG2 (P = 0.0048). Values for V12M and D620N ABCG2 were comparable to those for wild-type R482 ABCG2. The vanadate-sensitive ATPase activity of ABCG2 was assayed in Sf9 insect cells infected with wild-type or SNP variants of ABCG2. Basal ATPase activity in cells transfected with Q141K ABCG2 was 1.8-fold lower than in cells transfected with wild-type ABCG2, but was comparable among cells expressing wild-type, V12M or D620N ABCG2. Confocal studies of ABCG2 localization revealed higher intracellular staining in the Q141K transfectants than in cells transfected with wild-type or V12M ABCG2. Decreased transport of Hoechst 33342 was observed in Sf9 cells expressing V12M ABCG2; however, this was not true in HEK-293 cells expressing V12M ABCG2. These results suggest that the Q141K SNP affects the transport efficiency of ABCG2 and may result in altered pharmacokinetics or drug-resistance profiles in clinical oncology.

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0 ORIGINAL ARTICLE Kuniaki Morisaki Æ Robert W. Robey Csilla O¨ zvegy-Laczka Æ Yasumasa Honjo Orsolya Polgar Æ Kenneth Steadman Bala´ zs Sarkadi Æ Susan E. Bates Single nucleotide polymorphisms modify the transporter activity of ABCG2 Received: 21 July 2004 / Accepted: 1 October 2004 / Published online: 19 April 2005 Ó Springer-Verlag 2005 Abstract Single nucleotide polymorphism (SNP) analyses of the ABCG2 gene have revealed three nonsynonymous SNPs resulting in the amino acid changes at V12M, Q141K and D620N. Login to comment
4 Values for V12M and D620N ABCG2 were comparable to those for wild-type R482 ABCG2. Login to comment
6 Basal ATPase activity in cells transfected with Q141K ABCG2 was 1.8-fold lower than in cells transfected with wild-type ABCG2, but was comparable among cells expressing wild-type, V12M or D620N ABCG2. Login to comment
7 Confocal studies of ABCG2 localization revealed higher intracellular staining in the Q141K transfectants than in cells transfected with wild-type or V12M ABCG2. Login to comment
8 Decreased transport of Hoechst 33342 was observed in Sf9 cells expressing V12M ABCG2; however, this was not true in HEK-293 cells expressing V12M ABCG2. Login to comment
30 We previously sequenced the ABCG2 gene in 90 genomic DNA samples representing a global genetic diversity and identified three nonsynonymous SNPs -34G fi A, substituting a valine for methionine (V12M); 421C fi A, substituting a glutamine for lysine (Q141K); and 1858C fi A, substituting an aspartic acid for asparagine (D620N)-in the coding region of ABCG2 [18]. Login to comment
33 In a study of SNPs in ABCG2 in the general Japanese population, the V12M and Q141K SNPs were observed at higher allelic frequencies (17.2% and 26.6%, respectively) [19]. Login to comment
34 Similarly, in other studies, the V12M and Q141K SNPs have also been found to be the most frequent polymorphisms in various ethnic and racial groups including Caucasian, Asian, and Swedish populations [3, 48]. Login to comment
37 containing full-length ABCG2 encoding wild-type (R482), mutant (R482T, R482G), or SNP variants (V12M, Q141K, or D620N) of ABCG2. Login to comment
97 Additionally, we generated an ABCG2 transfectant with the first 11 amino acids deleted and the V12M SNP (1_33del34G fi A, 1_11delV12M) in order to examine whether the substituted methionine at amino acid 12 can serve as the first codon for a functional ABCG2. Login to comment
98 Clones were initially screened using the anti-ABCG2 antibody 5D3 and, from the positive clones obtained, 12 clones transfected with V12M, Q141K, D620N, or 1_11delV12M were selected for further study: V12M-12, -13 and -14; Q141K-5, -8, -13 and -16; D620N-2, -3 and -23; and 1_11delV12M-2 and -8. Login to comment
101 Although Northern blot analysis demonstrated higher expression of ABCG2 mRNA in wild-type (482R) ABCG2-transfected clones than in V12M-13 and Q141K-8 clones, immunoblot analysis showed generally comparable (within two- to threefold) ABCG2 protein expression in 482R, V12M-13, and Q141K-8 transfectants. Login to comment
103 Differential resistance among cells transfected with wild-type, V12M and Q141K ABCG2 To determine whether the SNPs affected the transport activity of ABCG2, 4-day cytotoxicity assays were performed with the ABCG2 substrates mitoxantrone, topotecan, SN-38, and diflomotecan (BN80915) on ABCG2-transfected HEK-293 cells expressing comparable amounts of ABCG2. Login to comment
105 Comparable surface expression of ABCG2 in the 482R-2, Q141K-5, Q141K-8 and V12M-13 clones was confirmed using the 5D3 antibody, as shown in Fig. 2a. Login to comment
106 This is in contrast to the immunoblot data that showed somewhat higher levels of ABCG2 in the V12M-13 clone. Login to comment
108 a Northern blot analysis of ABCG2 expression in representative HEK-293 cells transfected with wild-type, V12M, Q141K, or D620N ABCG2. Login to comment
116 The V12M-13 and 482R-2 clones were comparably resistant to mitoxantrone, topotecan, SN-38 and diflomotecan, whereas the Q141K-5 and -8 clones had IC50 values that were 3-fold to 5-fold lower for mitoxantrone and topotecan, 2-fold to 3.4-fold lower for SN-38, and 1.2-fold to 2.3-fold lower for diflomotecan. Login to comment
121 b Cytotoxicity assays were performed with mitoxantrone, topotecan, SN-38, or diflomotecan on HEK-293 cells transfected with empty vector (filled circles), or the 482R-2 (open circles), V12M-13 (filled triangles), Q141K-5 (open squares), and Q141K-8 (hatched squares) clones from a. Login to comment
122 Representative results are shown clones each of ABCG2-transfected cells expressing R482, R482T, R482G, V12M, Q141K or D620N ABCG2. Login to comment
133 Efflux and expression values for cells transfected with V12M and D620N ABCG2 fell close to the line, while values for cells transfected with Q141K ABCG2 fell predominantly below the line. Login to comment
135 Among the transfectants, Q141K variants showed significantly lower values compared to the transfectants with wild-type ABCG2 and the other SNP variants, V12M and D620N (P=0.0048, 0.0005, and 0.0126, respectively), suggesting that Q141K ABCG2 transports mitoxantrone less efficiently than wild-type ABCG2. Login to comment
136 Although V12M and D620N variants showed somewhat higher efficiency of mitoxantrone transport than 482R, no statistically significant difference was found. Login to comment
140 We next examined the ATPase activity of V12M, Q141K, and D620N variants using this system. Login to comment
148 At 1 lM Clone Mitoxantrone Topotecan SN-38 Diflomotecan IC50 RR IC50 RR IC50 RR IC50 RR pcDNA3-10 0.6±0.3 - 8.7±1.2 - 1.2±0.7 - 0.3±0.2 - 482R-2 34±5.4 57 275±150 32 123±68 103 1.4±0.6 5 V12M-13 44±15 73 250±71 29 100±1 83 1±0.1 3 Q141K-5 7.4±1.8 12 55±7 6 36±11 30 0.6±0.07 2 Q141K-8 10.8±5.3 18 90±14 10 66±11 55 0.9±0.1 3 Table 1 Relative resistance (RR) of ABCG2-transfected cells to ABCG2 substrates. Login to comment
157 Effect of SNPs on cellular localization of ABCG2 To determine if the SNPs affected membrane localization of ABCG2, we performed immunofluorescence studies on HEK-293 cells stably transfected with wild-type, V12M or Q141K ABCG2. Login to comment
159 Similarly, cells expressing V12M ABCG2 also had ABCG2 localized primarily to the cell surface (Fig. 6b). Login to comment
163 To examine whether the nonsynonymous SNPs in ABCG2 affect the transport of this compound, Hoechst 33342 dye transport was measured in intact Sf9 cells expressing wild-type, V12M, Q141K, or D620N ABCG2, as well as the nonfunctional mutant, R482G/K86M. Login to comment
165 In contrast, Hoechst 33342 transport was significantly lower in cells expressing V12M ABCG2 following normalization to the higher ABCG2 expression in these cells, suggesting less efficient Hoechst 33342 transport by V12M ABCG2 (Fig. 7b). Login to comment
168 To evaluate the possibility that Hoechst 33342 transport was impaired in human cells expressing V12M ABCG2, we performed Hoechst accumulation studies with HEK-293 cells transfected with the wild-type or SNP variants of ABCG2. Login to comment
172 Representative histograms for 482R-9, 482G-1, V12M-13, D620N-2, Q141K-5, and 1_11delV12M-8 are shown substrate-free medium for 60 min continuing with or without FTC. Login to comment
174 No significant difference in FTC-inhibitable Hoechst efflux was observed between cells expressing wild-type (R482), V12M or Q141K ABCG2 (Fig. 7c, right column). Login to comment
175 Cytotoxicity assays with Hoechst 33342 confirmed marked resistance conferred by ABCG2, with an IC50 for the 482R-2 clone of 16.3±15.8 lM and for the V12M-13 clone of 56.7±5.8 lM. Login to comment
176 Since the IC50 for empty vector-transfected cells was 26.3±15.8 n M, this translates to a relative resistance of 621 for 482R-2 and 2155 for V12M-13. Login to comment
177 These data are not consistent with impaired transport of Hoechst 33342 by V12M ABCG2 and are in contrast to the results obtained with intact Sf9 insect cells. Login to comment
178 Discussion We and others have recently identified several polymorphisms in ABCG2, including three nonsynonymous SNPs resulting in amino acid substitution in the coding region of ABCG2: V12M, Q141K, D620N [4, 19, 20, 50]. Login to comment
189 Values from the experiment in a were obtained for ABCG2-transfected HEK-293 clones expressing varying levels of 482R, R482G, R482T, V12M, Q141K, and D620N ABCG2 and a box plot was generated. Login to comment
204 Four-day cytotoxicity assays demonstrated that, among HEK-293 cells transfected with wild-type, V12M, or Q141K ABCG2, those expressing Q141K ABCG2 had IC50 values for mitoxantrone, topotecan, SN-38 and diflomotecan that were as much as fivefold lower than those for cells expressing comparable levels Fig. 5 ATPase activity in Sf9 insect cells infected with ABCG2-bearing baculovirus. Login to comment
205 a Immunoblot detection of human wild-type, D620N, Q141K and V12M ABCG2 expressed in Sf9 insect cells. Login to comment
206 Membranes of Sf9 cells (1.5 lg total protein from V12M/Sf9, Q141K/Sf9 and D620N/Sf9, 1.0 lg from wild-type ABCG2/Sf9, and 1.2 lg from b-galactosidase/Sf9) dissolved in disaggregation buffer were subjected to electrophoresis on 7.5% Laemmli-type gels and blotted onto PVDF membranes, followed by immunodetection with the BXP-21 antibody. b ATPase activity measured in membranes of Sf9 cells expressing the wild-type, V12M, Q141K, and D620N variants of human ABCG2. Login to comment
210 HEK-293 cells transfected with wild-type (482R-2) (a), V12M (V12M-13) (b), or Q141K (Q141K-8) (c) ABCG2 were fixed, permeabilized, and then incubated with the mouse monoclonal anti-ABCG2 antibody, BXP-21. Login to comment
211 After washing, cells were incubated with Alexa Fluor 488-labeled secondary antibody and subjected to confocal laser scanning microscopy of wild-type or V12M ABCG2. Login to comment
212 When surface ABCG2 expression was used to normalize the FTC-inhibitable mitoxantrone efflux, we found that HEK-293 cells expressing Q141K ABCG2 transported mitoxantrone less efficiently than cells expressing wild-type, V12M or D620N ABCG2. Login to comment
214 However, in contrast to the results of Mizuarai et al., we did not observe enhanced sensitivity to ABCG2 substrate drugs in cells transfected with V12M ABCG2. Login to comment
217 Indeed, we noted impaired Hoechst 33342 transport in Sf9 cells expressing V12M ABCG2. Login to comment
218 This was in contrast to cytotoxicity assays with transfected human cells that displayed comparable resistance to Hoechst 33342 in cells expressing wild-type or V12M ABCG2. Login to comment
219 It is of note that Imai et al., using a human expression system, did not find increased sensitivity to mitoxantrone in PC3 cells transfected with V12M ABCG2 compared to cells transfected with wild-type [20]. Login to comment
220 These contrasting results suggest that the glycosylation status of the protein may be significant for the V12M SNP. Login to comment
243 In contrast to results in non-mammalian systems, no impairment of the V12M variant was observed in the HEK-293 transfectants. Login to comment

[hide] Mechanisms of resistance to anticancer drugs: the ... Pharmacogenomics. 2005 Mar;6(2):115-38. Lepper ER, Nooter K, Verweij J, Acharya MR, Figg WD, Sparreboom A
Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2.
Pharmacogenomics. 2005 Mar;6(2):115-38., [PMID:15882131]

Abstract [show]
ATP-binding cassette (ABC) genes play a role in the resistance of malignant cells to anticancer agents. The ABC gene products, including ABCB1 (P-glycoprotein) and ABCG2 (breast cancer-resistance protein [BCRP], mitoxantrone-resistance protein [MXR], or ABC transporter in placenta [ABCP]), are also known to influence oral absorption and disposition of a wide variety of drugs. As a result, the expression levels of these proteins in humans have important consequences for an individual's susceptibility to certain drug-induced side effects, interactions, and treatment efficacy. Naturally occurring variants in ABC transporter genes have been identified that might affect the function and expression of the protein. This review focuses on recent advances in the pharmacogenetics of the ABC transporters ABCB1 and ABCG2, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.

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134 An additional potentially functional polymorphism has been identified in the ABCG2 gene at nucleotide position 34, resulting in a Val12Met amino acid change. Login to comment
157 Position in gene* Nucleotide‡ Region Wild-type allele Variant allele Amino acid Change -19572 to -19569 5`-Flanking region CTCA - CTCA deletion -19202 5` UTR G C -18845 5` UTR T C -18604 5` UTR A - Deletion -18482 -113 Exon 1 C T Non-coding -18398 -29 Exon 1 A G Non-coding 34 34 Exon 2 G A 12 Val to Met 71 71 Exon 2 C T 24 Ala to Val 114 114 Exon 2 T C 38 Synonymous 239 Intron 2 A G 7268 Intron 2 T C 7420 Intron 3 - T Insertion 8007 Intron 3 G A 8184 369 Exon 4 C T 123 Synonymous 8191 376 Exon 4 C T 126 Gln to Term 8825 421 Exon 5 C A 141 Gln to Lys 8862 458 Exon 5 C T 153 Thr to Met 8878 474 Exon 5 C T 158 Synonymous 8900 496 Exon 5 C G 166 Gln to Glu 18186 Intron 5 A G 18286 616 Exon 6 A C 206 Ile to Leu 18293 623 Exon 6 T C 208 Phe to Ser 21530 Intron 6 C T 21718 Intron 6 A G 21903 Intron 7 A G 24618 Intron 7 T A 26297 1098 Exon 9 G A 366 Synonymous 38389 1291 Exon 11 T C 431 Phe to Leu 38485 Intron 11 A G 40111 Intron 11 G A 40303 1425 Exon 12 A G 475 Synonymous 40322 1444 Exon 12 A G 482 Arg to Gly 40323 1445 Exon 12 G C 482 Arg to Thr 40343 1465 Exon 12 T C 489 Phe to Leu 40419 Intron 12 G T 42314 Intron 13 T G 44997 Intron 14 A G 45022 Intron 14 C T 45073 1768 Exon 15 A T 590 Asn to Tyr 47355 1858 Exon 16 G A 620 Asp to Asn 47734 2237 Exon 16 G T Non-coding 47890 2393 Exon 16 G T Non-coding 47891 2394 Exon 16 C A Non-coding ABC: ATP-binding cassette; UTR: Untranslated region. Login to comment
174 Outside of cell Cell membrane C terminus ATP-binding site N terminus Inside of cellGln141Lys Walker A Walker B Signature motif Arg482Thr Val12Met Table 5. Login to comment

[hide] Breast cancer resistance protein: molecular target... Cancer Sci. 2005 Aug;96(8):457-65. Sugimoto Y, Tsukahara S, Ishikawa E, Mitsuhashi J
Breast cancer resistance protein: molecular target for anticancer drug resistance and pharmacokinetics/pharmacodynamics.
Cancer Sci. 2005 Aug;96(8):457-65., [PMID:16108826]

Abstract [show]
Breast cancer resistance protein (BCRP) is a half-molecule ATP-binding cassette transporter that forms a functional homodimer and pumps out various anticancer agents, such as 7-ethyl-10-hydroxycamptothecin, topotecan, mitoxantrone and flavopiridol, from cells. Estrogens, such as estrone and 17beta-estradiol, have been found to restore drug sensitivity levels in BCRP-transduced cells by increasing the cellular accumulation of such agents. Furthermore, synthetic estrogens, tamoxifen derivatives and phytoestrogens/flavonoids have now been identified that can effectively circumvent BCRP-mediated drug resistance. Transcellular transport experiments have shown that BCRP transports sulfated estrogens and various sulfated steroidal compounds, but not free estrogens. The kinase inhibitor gefitinib inhibited the transporter function of BCRP and reversed BCRP-mediated drug resistance both in vitro and in vivo. BCRP-transduced human epidermoid carcinoma A431 (A431/BCRP) and BCRP-transduced human non-small cell lung cancer PC-9 (PC-9/BCRP) cells showed gefitinib resistance. Physiological concentrations of estrogens (10-100 pM) reduced BCRP protein expression without affecting its mRNA levels. Two functional polymorphisms of the BCRP gene have been identified. The C376T (Q126Stop) polymorphism has a dramatic phenotype as active BCRP protein cannot be expressed from a C376T allele. The C421A (Q141K) polymorphism is also significant as Q141K-BCRP-transfected cells show markedly low protein expression levels and low-level drug resistance. Hence, individuals with C376T or C421A polymorphisms may express low levels of BCRP or none at all, resulting in hypersensitivity of normal cells to BCRP-substrate anticancer agents. In summary, both modulators of BCRP and functional single nucleotide polymorphisms within the BCRP gene affect the transporter function of the protein and thus can modulate drug sensitivity and substrate pharmacokinetics and pharmacodynamics in affected cells and individuals.

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165 From these analyses, we identified three BCRP coding SNP, G34A (V12M), C376T (Q126Stop) and C421A (Q141K), and a splicing variant, ∆315-6, that lacked nucleotides 944-949 (deletion of A315 and T316) (Fig. Login to comment
176 V12M-BCRP-transfected and ∆315-6-BCRP-transfected PA317 cells showed similar and somewhat lower BCRP protein expression and drug resistance levels compared with wild-type BCRP-transfected cells. Among the normal subjects in our analysis, 67 were wild type, 48 were heterozygous and nine were homozygous for the C421A allele. Login to comment
216 PA317 cells transfected with wild-type, G34A, C421A and ∆944-949 BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K and PA/∆315-6, respectively. Login to comment

[hide] The ATP-binding cassette transporter ABCG2 (BCRP),... J Histochem Cytochem. 2006 Feb;54(2):215-21. Epub 2005 Aug 22. Meissner K, Heydrich B, Jedlitschky G, Meyer Zu Schwabedissen H, Mosyagin I, Dazert P, Eckel L, Vogelgesang S, Warzok RW, Bohm M, Lehmann C, Wendt M, Cascorbi I, Kroemer HK
The ATP-binding cassette transporter ABCG2 (BCRP), a marker for side population stem cells, is expressed in human heart.
J Histochem Cytochem. 2006 Feb;54(2):215-21. Epub 2005 Aug 22., [PMID:16116030]

Abstract [show]
Efforts to improve severely impaired myocardial function include transplantation of autologous hematopoietic side population (SP) stem cells. The transmembrane ABC-type (ATP binding cassette) half-transporter ABCG2 (BCRP) serves as a marker protein for SP cell selection. We have recently shown that other ABC transport proteins such as ABCB1 and ABCC5 are differentially expressed in normal and diseased human heart. Here we investigated localization and individual ABCG2 expression in 15 ventricular (including 10 cardiomyopathic) and 51 auricular heart tissue samples using immunohistochemistry, confocal laser scanning fluorescence microscopy, and real-time RT-PCR. Individual genotypes were assigned using PCR-restriction fragment length polymorphism (RFLP) analysis and subsequently correlated to ABCG2 mRNA levels. ABCG2 was localized in endothelial cells of capillaries and arterioles of all samples. Ventricular samples from cardiomyopathic hearts exhibited significantly increased levels of ABCG2 mRNA (ABCG2/18S rRNA: 1.08 +/- 0.30 x 10(-7); p=0.028 (dilative cardiomyopathy) and 1.16 +/- 0.46 x 10(-7); p=0.009 (ischemic cardiomyopathy) compared with 0.44 +/- 0.26 x 10(-7) in nonfailing hearts). The individual haplotypes were not associated with altered mRNA expression. ABCG2 is variably expressed in endothelial cells of human heart, where it may function as a protective barrier against cardiotoxic drugs such as anthracyclines or mitoxantrone. ABCG2 expression is induced in dilative and ischemic cardiomyopathies.

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126 Among the four identified naturally occurring single nucleotide polymorphisms, 34G.A (V12M) and 421C.A (Q141K) were most common in diverse populations of different ethnic origin in North America (Zamber et al. 2003). Login to comment
127 Among the four identified naturally occurring single nucleotide polymorphisms, 34G.A (V12M) and 421C.A (Q141K) were most common in diverse populations of different ethnic origin in North America (Zamber et al. 2003). Login to comment

[hide] Role of the breast cancer resistance protein (ABCG... AAPS J. 2005 May 11;7(1):E118-33. Mao Q, Unadkat JD
Role of the breast cancer resistance protein (ABCG2) in drug transport.
AAPS J. 2005 May 11;7(1):E118-33., [PMID:16146333]

Abstract [show]
The 72-kDa breast cancer resistance protein (BCRP) is the second member of the subfamily G of the human ATP binding cassette (ABC) transporter superfamily and thus also designated as ABCG2. Unlike P-glycoprotein and MRP1, which are arranged in 2 repeated halves, BCRP is a half-transporter consisting of only 1 nucleotide binding domain followed by 1 membrane-spanning domain. Current experimental evidence suggests that BCRP may function as a homodimer or homotetramer. Overexpression of BCRP is associated with high levels of resistance to a variety of anticancer agents, including anthracyclines, mitoxantrone, and the camptothecins, by enhancing drug efflux. BCRP expression has been detected in a large number of hematological malignancies and solid tumors, indicating that this transporter may play an important role in clinical drug resistance of cancers. In addition to its role to confer resistance against chemotherapeutic agents, BCRP actively transports structurally diverse organic molecules, conjugated or unconjugated, such as estrone-3-sulfate, 17beta-estradiol 17-(beta-D-glucuronide), and methotrexate. BCRP is highly expressed in the placental syncytiotrophoblasts, in the apical membrane of the epithelium in the small intestine, in the liver canalicular membrane, and at the luminal surface of the endothelial cells of human brain microvessels. This strategic and substantial tissue localization indicates that BCRP also plays an important role in absorption, distribution, and elimination of drugs that are BCRP substrates. This review summarizes current knowledge of BCRP and its relevance to multidrug resistance and drug disposition.

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160 A variety of naturally occurring variants of BCRP have been identified in DNA samples of ethnically diverse origins.95-98 Notably, the alterations of BCRP protein at position 12 (V12M) and 141 (Q141K) occur frequently in Asia populations (~30%-60%) and relatively low frequencies in Caucasians and African-Americans (~5%-10%). Login to comment
161 For example, in a Japanese population studied, 39% to 50% are heterozygous and 7% are homozygous for the variant Q141K.95,96 In a Chinese population, 60% are heterozygous for Q141K.95 Several other variants such as I206L, N590Y, and D620N are much less frequent with allele frequencies of ~1%.95,97 For instance, N590Y is present in ~1.5% of Caucasians.95 I206L is found only in Hispanic populations so far.95 D620N is detected in 1.1% of all DNA samples examined with unknown genetic origin.97 In addition, a polymorphism in exon 4 that results in a substitution of stop codon for Gln at position 126 has also been identified.96 Amino acid changes at position 482 that were found in some drug-selected resistant cell lines have so far not been identified in normal populations or in DNA samples from cancer patients.49 In vitro functional characterization of the variants V12M and Q141K produced contradicting results. Login to comment
162 One study reported that Q141K was expressed at lower levels in transfected cells and therefore conferred lower drug resistance compared with the wild-type protein.96 The variant V12M displayed expression levels and drug-resistance properties similar to the wild-type protein.96 Another study reported that V12M and Q141K were expressed at levels comparable to the wild-type protein; however, both V12M and Q141K conferred significantly lower levels of drug resistance relative to the wild-type protein as compared with increased drug accumulation and decreased drug efflux.98 Further analysis of the mechanism of the transport dysfunction revealed that the apical membrane localization of V12M was disrupted and that ATPase activity of Q141K was decreased.98 A recent clinical study by Sparreboom et al73 has shown that the Q141K polymorphism is associated with significant changes of pharmacokinetic properties of diflomotecan, a substrate of BCRP. Login to comment

[hide] The ABC transporter Abcg2/Bcrp: role in hypoxia me... Biometals. 2005 Aug;18(4):349-58. Krishnamurthy P, Schuetz JD
The ABC transporter Abcg2/Bcrp: role in hypoxia mediated survival.
Biometals. 2005 Aug;18(4):349-58., [PMID:16158227]

Abstract [show]
ABC (ATP-binding cassette) transporters have diverse roles in many cellular processes. These diverse roles require the presence of conserved membrane spanning domains and nucleotide binding domains. Bcrp (Abcg2) is a member of the ATP binding cassette family of plasma membrane transporters that was originally discovered for its ability to confer drug resistance in tumor cells. Subsequent studies showed Bcrp expression in normal tissues and high expression in primitive stem cells. Bcrp expression is induced under low oxygen conditions consistent with its high expression in tissues exposed to low oxygen environments. Moreover, Bcrp interacts with heme and other porphyrins. This finding and its regulation by hypoxia suggests it may play a role in protecting cells/tissue from protoporphyrin accumulation under hypoxia. These observations are strengthened by the fact that porphyrins accumulate in tissues of the Bcrp knockout mouse. It is possible that humans with loss of function Bcrp alleles may be more susceptible to porphyrin-induced phototoxicity. We propose that Bcrp plays a role in porphyrin homoeostasis and regulates survival under low oxygen conditions.

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127 The SNPs in Bcrp that produce non-synonymous changes (i.e., amino acid substitutions) are at amino acids 12 (V12M), 141 (Q141K), 206 (I206L), and 590 (N590Y). Login to comment
128 The most frequent polymorphisms being the exon 2 SNP (G34A/ V12M) and the exon 5 SNP (C421A/Q141K), which produce changes in amino acids 12 and 141 (Imai et al. 2002; Mizuarai et al. 2004). Login to comment

[hide] Pharmacogenomics of the human ABC transporter ABCG... Naturwissenschaften. 2005 Oct;92(10):451-63. Ishikawa T, Tamura A, Saito H, Wakabayashi K, Nakagawa H
Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design.
Naturwissenschaften. 2005 Oct;92(10):451-63., [PMID:16160819]

Abstract [show]
In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug-drug interactions. We recently developed methods for high-speed functional screening and quantitative structure-activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.

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87 Non-synonymous SNPs are located at nucleotides 238 (exon 2) and 625, resulting in amino acid substitutions: V12M and Q141K. Login to comment
89 The V12M polymorphism in exon 2 (c.34G>A) affects the N-terminal intracellular region of the protein. Login to comment
91 The V12M polymorphism was found in all ethnic groups tested, with the highest allele frequency in Mexican-Indians (90% of only 5 individuals tested), but only 1.7% in a Swedish population (B¨ackstr¨om et al. 2003). Login to comment
93 Thus, there is a large difference in the allele frequency of the V12M polymorphism among different ethnic groups (Table 2). Login to comment
109 Imai et al. (2002) reported that the Q141K variant of ABCG2, stably expressed in PA317 cells, had a markedly lower expression level than the wild-type ABCG2 or the V12M variant. Login to comment
111 On the other hand, Mizuarai et al. (2004) expressed ABCG2 in polarized LLC-PK1 cells, and by using confocal microscopy demonstrated that the wild-type and the Q141K variant of ABCG2 mainly showed apical staining, while the V12M variant showed intracellular localization. Login to comment
112 However, Kondo et al. (2004) demonstrated that both V12M and Q141K variants were localized at the apical membrane in LLC-PK1 cells. Login to comment
113 These contradictory expression and localization data for ABCG2 variants indicate that differences in transfection conditions (transient or stable expression), the copy number of cDNA incorporated in genomic DNA or other cellular determinants may variably Table 2 Frequencies of ABCG2 alleles in different ethnic groups Position Ethnic group Variant allele Allele Reference Amino acid cDNA N Hetero Homo Frequency (%) V12M c.34G>A Japanese 29 9 1 19.0 Imai et al. (2002) Japanese 10 - - 15.0 Zamber et al. (2003) Japanese 220 61 8 17.5 Kobayashi et al. (2005) Chinese 10 - - 20.0 Zamber et al. (2003) Southeast Asians 10 - - 45.0 Zamber et al. (2003) Pacific Islanders 7 - - 64.0 Zamber et al. (2003) Swedish 60 2 0 1.7 B¨ackstr¨om et al. (2003) Dutch 100 11 1 6.5 Bosch et al. (2005) Caucasian 86 - - 2.0 Zamber et al. (2003) Caucasian 150 27 2 10.3 Mizuarai et al. (2004) Caucasian 150 11 0 3.7 Kobayashi et al. (2005) Ashkenazi Jewish 10 - - 10.0 Zamber et al. (2003) Middle Eastern 20 - - 5.0 Zamber et al. (2003) Africans North of Sahara 7 - - 14.0 Zamber et al. (2003) African American 150 17 1 6.3 Kobayashi et al. (2005) Mexicans 10 - - 10.0 Zamber et al. (2003) Hispanic Livers 5 - - 40.0 Zamber et al. (2003) Mexican Indians 5 - - 90.0 Zamber et al. (2003) Q126Stop c.376C>T Japanese 124 3 0 1.2 Imai et al. (2002) Japanese 60 2 0 1.7 Itoda et al. (2003) Japanese 220 4 0 0.9 Kobayashi et al. (2005) Caucasian 150 0 0 0.0 Mizuarai et al. (2004) Caucasian 150 0 0 0.0 Kobayashi et al. (2005) African American 150 0 0 0.0 Kobayashi et al. (2005) Q141K c.421C>A Japanese 124 48 9 26.6 Imai et al. (2002) Japanese 10 - - 35.0 Zamber et al. (2003) Japanese 220 90 27 32.7 Kobayashi et al. (2005) Chinese 95 43 11 34.2 de Jong et al. (2004) Chinese 10 - - 35.0 Zamber et al. (2003) Southeast Asians 10 - - 15.0 Zamber et al. (2003) Pacific Islanders 7 - - 14.0 Zamber et al. (2003) Swedish 60 10 1 10.0 B¨ackstr¨om et al. (2003) Dutch 100 20 2 12.0 Bosch et al. (2005) Caucasian 85 - - 14.0 Zamber et al. (2003) Caucasian 172 33 3 11.3 de Jong et al. (2004) Caucasian 150 22 2 8.7 Mizuarai et al. (2004) Caucasian 150 25 4 11.0 Kobayashi et al. (2005) Ashkenazi Jewish 10 - - 5.0 Zamber et al. (2003) Middle Eastern 20 - - 13.0 Zamber et al. (2003) Africans North of Sahara 7 - - 0.0 Zamber et al. (2003) African, Sub-Saharan 938 14 1 0.9 de Jong et al. (2004) African American 24 - - 0.0 Zamber et al. (2003) African American 150 5 1 2.3 Kobayashi et al. (2005) African American 94 8 1 5.3 de Jong et al. (2004) Mexicans 10 - - 5.0 Zamber et al. (2003) Hispanic Livers 5 - - 10.0 Zamber et al. (2003) Mexican Indians 5 - - 10.0 Zamber et al. (2003) R160Q c.479G>A Dutch 100 1 0 0.5 Bosch et al. (2005) I206L c.616A>C Japanese 10 - - 0.0 Zamber et al. (2003) Chinese 10 - - 0.0 Zamber et al. (2003) Southeast Asians 10 - - 0.0 Zamber et al. (2003) Pacific Islanders 7 - - 0.0 Zamber et al. (2003) Caucasian 65 - - 0.0 Zamber et al. (2003) Table 2 Continued Position Ethnic group Variant allele Allele Reference Amino acid cDNA N Hetero Homo Frequency (%) Ashkenazi Jewish 10 - - 0.0 Zamber et al. (2003) Middle Eastern 20 - - 0.0 Zamber et al. (2003) Africans North of Sahara 7 - - 0.0 Zamber et al. (2003) African American 15 - - 0.0 Zamber et al. (2003) Mexicans 10 - - 0.0 Zamber et al. (2003) Hispanic Livers 5 - - 10.0 Zamber et al. (2003) Mexican Indians 5 - - 0.0 Zamber et al. (2003) F431L c.1291T>C Japanese 60 1 0 0.8 Itoda et al. (2003) S441N c.1322G>A Japanese 100 1 0 0.5 Kobayashi et al. (2005) F489L c.1465T>C Japanese 60 1 0 0.8 Itoda et al. (2003) Japanese 100 1 0 0.5 Kobayashi et al. (2005) R575Stop c.1723C>T Dutch 100 1 0 0.5 Bosch et al. (2005) N590Y c.1768A>T Caucasian 65 - - 1.0 Zamber et al. (2003) Caucasian 150 1 0 0.3 Mizuarai et al. (2004) African Americans 15 - - 0.0 Zamber et al. (2003) D620N c.1858G>A Dutch 100 1 0 0.5 Bosch et al. (2005) affect the cellular processing and sorting of these proteins. Login to comment
114 Detailed studies are needed to clarify the mechanism of a reduced protein expression for Q141K and the altered cellular localization of V12M and Q141K variants. Login to comment
118 For this purpose, we have created variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, E334stop, N590Y, D620N, R482G, and R482T) by site-directed mutagenesis. Login to comment
130 After the normalization of expression levels, the V12M and T153M variants showed increased levels of MTX transport activity, whereas the I206L, N590Y, and D620N variants had lower transport activities. Login to comment

[hide] Membrane transporters and channels in chemoresista... Cancer Lett. 2006 Aug 8;239(2):168-82. Epub 2005 Oct 5. Huang Y, Sadee W
Membrane transporters and channels in chemoresistance and -sensitivity of tumor cells.
Cancer Lett. 2006 Aug 8;239(2):168-82. Epub 2005 Oct 5., 2006-08-08 [PMID:16169662]

Abstract [show]
Membrane transporters play important roles in mediating chemosensitivity and -resistance of tumor cells. ABC transporters, such as ABCB1/MDR1, ABCC1/MRP1 and ABCG2/BCRP, are frequently associated with decreased cellular accumulation of anticancer drugs and multidrug resistance of tumors. SLC transporters, such as folate, nucleoside, and amino acid transporters, commonly increase chemosensitivity by mediating the cellular uptake of hydrophilic drugs. Ion channels and pumps variably affect sensitivity to anticancer therapy by modulating viability of tumor cells. A pharmacogenomic approach, using correlations between drug potency and transporter gene expression in multiple cancer cell lines, has shown promise for identifying potential drug-transporter relationships and predicting anticancer drug response, in an effort to optimize chemotherapy for individual patients.

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79 Two additional SNPs, i.e. V12M and Q141K, also affect substrate specificity and transport capacity of ABCG2 [26]. Login to comment

[hide] Genetic polymorphisms of ATP-binding cassette tran... Expert Opin Pharmacother. 2005 Nov;6(14):2455-73. Sakurai A, Tamura A, Onishi Y, Ishikawa T
Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications.
Expert Opin Pharmacother. 2005 Nov;6(14):2455-73., [PMID:16259577]

Abstract [show]
Pharmacogenomics, the study of the influence of genetic factors on drug action, is increasingly important for predicting pharmacokinetics profiles and/or adverse reactions to drugs. Drug transporters, as well as drug metabolism play pivotal roles in determining the pharmacokinetic profiles of drugs and their overall pharmacological effects. There is an increasing number of reports addressing genetic polymorphisms of drug transporters. However, information regarding the functional impact of genetic polymorphisms in drug transporter genes is still limited. Detailed functional analysis in vitro may provide clear insight into the biochemical and therapeutic significance of genetic polymorphisms. This review addresses functional aspects of the genetic polymorphisms of human ATP-binding cassette transporters, ABCB1 and ABCG2, which are critically involved in the pharmacokinetics of drugs.

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210 In different ethnic groups, seven naturally-occurring non-synonymous SNPs have been reported: V12M, Q126Stop, Q141K, I206L, F431L, S441N, F489L, N590Y and D620N. Login to comment
211 Among the above variations, two alterations (c.34G > A [V12M], c.421C > A [Q141K]) affecting the protein structure have been reported to be polymorphic in several populations. Login to comment
215 Non-synonymous SNPs are located at nucleotides 238 (exon 2) and 625 (exon 5), resulting in the amino acid substitutions V12M and Q141K. Login to comment
217 The V12M polymorphism in exon 2 (c.34G > A) affects the N-terminal intracellular region of the protein. Login to comment
219 The V12M polymorphism was found in all ethnic groups tested, with the highest allele frequency in Mexican-Indians (90%, but only 10 individuals were tested), but only 2% in a Swedish population [130,132]. Login to comment
220 Upon the combination of several population studies, a consistent and significant (p < 0.0001) difference can be observed between the overall allele frequencies of V12M in Caucasian/African-American and Japanese populations (Table 4). Login to comment
225 Location Position Allele Amino acid Allele frequency in Caucasian populations Allele frequency in Japanese populatins Allele frequency in African populations n % n % n % Exon 2 34 G A 12 Val 12 Met 546 94.4 5.6 259 82.4 17.6 181 93.7 6.3 Exon 4 376 C T 126 Gln 126 stop 300 100 0 404 98.9 1.1 150 100 0 Exon 5 421 C A 141 Gln 141 Lys 717 89.0 11.0 354 69.4 30.6 1213 98.6 1.4 Exon 5 479 G A 160 Arg 160 Gln 100 99.5 0.5 ND ND ND ND ND ND Exon 11 1291 T C 431 Phe 431 Leu ND ND ND 60 99.2 0.8 ND ND ND Exon 11 1322 G A 441 Ser 441 Asn ND ND ND 100 99.5 0.5 ND ND ND Exon 12 1465 T C 489 Phe 489 Leu ND ND ND 160 99.4 0.6 ND ND ND Exon 14 1723 C T 575 Arg 575 stop 100 99.5 0.5 ND ND ND ND ND ND Exon 15 1768 A T 590 Asn 590 Tyr 215 99.5 0.5 ND ND ND 15 100 0 Exon 16 1858 T A 620 Asp 620 Asp 100 99.5 0.5 ND ND ND ND ND ND Data are from [129-135,137]. Login to comment
228 Similar to V12M, substantial and significant (p < 0.0001) allele frequency differences can be observed among the three major ethnic groups tested, potentially reflecting different population admixtures and unequal effects of environmental selection factors. Login to comment
242 Imai et al. [129] reported that the Q141K variant of ABCG2 stably expressed in PA317 cells had a markedly lower expression level than the wild-type ABCG2 or the V12M variant. Login to comment
244 On the other hand, Mizuarai et al. [135] expressed ABCG2 in polarised LLC-PK1 cells, and by using confocal microscopy demonstrated that the wild-type and the Q141K variant of ABCG2 showed mainly apical staining, and the V12M variant showed intracellular localisation. Login to comment
245 However, Kondo et al. [138] demonstrated that both V12M and Q141K variants were localised at the apical membrane in LLC-PK1 cells. Login to comment
250 COOH H2N N590Y V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L F489L D620N R482G R482T S441N F571I EXTRACELLULAR INTRACELLULAR R160Q R575stop ATP-binding site (transient or stable expression), the copy number of cDNA incorporated in genomic DNA or other cellular determinants may variably affect the cellular processing and sorting of these proteins. Login to comment
251 Detailed studies are needed to clarify the mechanism of a reduced protein expression for Q141K and the altered cellular localisation of V12M and Q141K variants. Login to comment
255 For this purpose, variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, E334stop, N590Y, D620N, R482G and R482T) were created by site-directed mutagenesis (Figure 3). Login to comment
267 The V12M and T153M variants showed increased levels of MTX transport activity, whereas the I206L, N590Y and D620N variants had lower transport activities. Login to comment
318 W T G 51C D 620N R 482G R 482T N 590Y E334stop I206L Q 166E T153M Q 141K Q 126stop V12M ATP-dependentMTXtransport (nmol/min/mgprotein) 2.0 1.5 1.0 0.5 0.0 5. Login to comment

[hide] Functional SNPs of the breast cancer resistance pr... Cancer Lett. 2006 Mar 8;234(1):73-80. Epub 2005 Nov 21. Yanase K, Tsukahara S, Mitsuhashi J, Sugimoto Y
Functional SNPs of the breast cancer resistance protein-therapeutic effects and inhibitor development.
Cancer Lett. 2006 Mar 8;234(1):73-80. Epub 2005 Nov 21., 2006-03-08 [PMID:16303243]

Abstract [show]
Breast cancer resistance protein (BCRP) is a half-molecule ATP-binding cassette transporter that pumps out various anticancer agents such as 7-ethyl-10-hydroxycamptothecin, topotecan and mitoxantrone. We have previously identified three polymorphisms within the BCRP gene, G34A (substituting Met for Val-12), C376T (substituting a stop codon for Gln-126) and C421A (substituting Lys for Gln-141). C421A BCRP-transfected murine fibroblast PA317 cells showed markedly decreased protein expression and low-level drug resistance when compared with wild-type BCRP-transfected cells. In contrast, G34A BCRP-transfected PA317 cells showed a similar protein expression and drug resistance profile to wild-type. The C376T polymorphism would be expected to have a considerable impact as active BCRP protein will not be expressed from a T376 allele. Hence, people with C376T and/or C421A polymorphisms may express low levels of BCRP, resulting in hypersensitivity of normal cells to BCRP-substrate anticancer agents. Estrogens, estrone and 17beta-estradiol, were previously found to restore drug sensitivity levels in BCRP-transduced cells by increasing the cellular accumulation of anticancer agents. BCRP transports sulfated estrogens but not free estrogens and in a series of screening experiments for synthesized and natural estrogenic compounds, several tamoxifen derivatives and phytoestrogens/flavonoids were identified that effectively circumvent BCRP-mediated drug resistance. The kinase inhibitors gefitinib and imatinib mesylate also interact with BCRP. Gefitinib, an inhibitor of epidermal growth factor receptor-tyrosine kinase, inhibits its transporter function and reverses BCRP-mediated drug resistance both in vitro and in vivo. BCRP-transfected human epidermoid carcinoma A431 cells and BCRP-transfected human non-small cell lung cancer PC-9 cells show gefitinib resistance. Imatinib, an inhibitor of BCR-ABL tyrosine kinase, also inhibits BCRP-mediated drug transport. Hence, both functional SNPs and inhibitors of BCRP reduce its transporter function and thus modulate substrate pharmacokinetics and pharmacodynamics.

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1 We have previously identified three polymorphisms within the BCRP gene, G34A (substituting Met for Val-12), C376T (substituting a stop codon for Gln-126) and C421A (substituting Lys for Gln-141). Login to comment
42 C421A (Q141K) BCRP SNP We have previously identified three variant BCRP cDNAs, containing the substitutions G34A (V12M), C421A (Q141K) and a 944-949 deletion lacking Ala-315 and Thr-316 (D315-6) [23]. Login to comment
45 In addition, both G34A BCRP-transfected PA317 (PA/ V12M) cells and 944-949-deleted BCRP-transfected PA317 (PA/D315-6) cells showed either similar or marginally lower protein expression and drug resistance levels compared to PA/WT cells (Fig. 1 and Table 1). Login to comment
74 However, in our Table 1 Drug sensitivities of BCRP-transfected PA317 cells Cells IC50 (ng/ml) SN-38 Topotecan MXR PA317 2.5 0.060 17 PA/WT 98 0.58 O200 PA/V12M 98 0.63 O200 PA/Q141K 30 0.25 100 PA/D315-6 55 0.42 190 Cells were cultured for 5 days in the absence or presence of increasing concentrations of the indicated anticancer agents. Login to comment
92 Therefore, we first Table 3 SNPs within the BCRP gene Variation Region Effect Domain A-1379G 50 -flanking (promoter) - D-654-651 50 -flanking (promoter) - G-286C 50 -flanking (promoter) - T-476C Exon 1 (50 - UTR) - D-235A Exon 1 (50 - UTR) - A-113G Exon 1 (50 - UTR) - A-29G Exon 1 (50 - UTR) - G34A Exon 2 V12M N-terminal T114C Exon 2 No change N-terminal G151T Exon 2 G51C N-terminal C369T Exon 4 No change NBD C376T Exon 4 Q126stop NBD C421A Exon 5 Q141K NBD C458T Exon 5 T153M NBD C474T Exon 5 No change NBD C496G Exon 5 Q166E NBD A564G Exon 6 No change NBD A616C Exon 6 I206L NBD T623C Exon 6 F208S NBD T742C Exon 7 S248P Linker G1000T Exon 9 E334stop Linker G1098A Exon 9 No change Linker T1291C Exon 11 F431L TMD A1425G Exon 12 No change TMD T1465C Exon 12 F489L TMD A1768T Exon 15 N590Y TMD G1858A Exon 16 D620N TMD G2237T Exon 16 (30 - UTR) - G2393T Exon 16 (30 - UTR) - Abbreviations: UTR, untranslated region; NBD, nucleotide-binding domain; TMD, transmembrane domain. Login to comment

[hide] The role of the human ABCG2 multidrug transporter ... Cancer Lett. 2006 Mar 8;234(1):62-72. Epub 2005 Dec 7. Cervenak J, Andrikovics H, Ozvegy-Laczka C, Tordai A, Nemet K, Varadi A, Sarkadi B
The role of the human ABCG2 multidrug transporter and its variants in cancer therapy and toxicology.
Cancer Lett. 2006 Mar 8;234(1):62-72. Epub 2005 Dec 7., 2006-03-08 [PMID:16337740]

Abstract [show]
The human multidrug resistance ABC transporters provide a protective function in our body against a large number of toxic compounds. These proteins, residing in the plasma membrane, perform an active, ATP-dependent extrusion of such xenobiotics. However, the same proteins are also used by the tumor cells to fight various anticancer agents. ABCG2 is an important member of the multidrug resistance proteins, an 'ABC half transporter', which functions as a homodimer in the cell membrane. In this review, we provide a basic overview of ABCG2 function in physiology and drug metabolism, but concentrate on the discussion of mutations and polymorphisms discovered in this protein. Interestingly, a single nucleotide mutation, changing amino acid 482 from arginine to threonine or glycine in ABCG2, results in a major increase in the catalytic activity and a wider drug recognition by this protein. Still, this mutation proved to be an in vitro artifact, produced only in heavily drug-selected cell lines. In contrast, at least two, but possibly more polymorphic variants of ABCG2 were found to be present in large human populations with different ethnic background. However, currently available experimental data regarding the cellular expression, localization and function of these ABCG2 variants are strongly contradictory. Since, the proteins produced by these variant alleles may differently modulate cancer treatment, general drug absorption and toxicity, may represent risk factors in fetal toxicity, or alter the differentiation of stem cells, their exact characterization is a major challenge in this field.

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109 To date, altogether eight non-synonymous (V12M, Q141K, I206L, F431L, S441N, F489L, N590Y, D620N), five synonymous (silent) (c.114TOC, c.369COT, c.474COT, c.1098GOA, c.1425AOG) missense mutations, one nonsense (Q126X), and one frameshift (c.1515delC) mutations were identified in the coding region of ABCG2 in healthy individuals or in patients [43-46,49,63-65]. Login to comment
110 Among the above variations, affecting the protein structure, two alterations [c.34GOA (V12M), c.421CO A (Q141K)] have been reported to be polymorphic in several populations. Login to comment
114 The V12M polymorphism in exon 2 (c.34GOA) affects the N-terminal intracellular region of the protein. Login to comment
116 The V12M polymorphism was found in all ethnic groups tested, with the highest allele frequency in Mexican-Indians (90%, but only 10 individuals were tested), while only 2% in a Swedish population [43,49]. Login to comment
117 Upon the combination of several population studies, a consistent and significant (P!0.0001) difference can be observed between the overall allele frequencies of V12M in Caucasian/African American and Japanese populations (Table 1). Login to comment
122 Similarly to V12M, substantial and significant (P!0.0001) allele frequency differences can be observed between the three major ethnic groups tested, potentially reflecting different population admixture and unequal effects of environmental selection factors. Login to comment
123 On the basis of definitive molecular haplotype analyses (PCR-RFLP) for the three major variants [c.34GOA (V12M), c.376COT (Q126X), c.421COA (Q141K)] in a Japanese population, four haplotypes were identified G-C-C (V-Q-Q), G-C-A (V-Q-K), A-CC (M-Q-Q), and G-T-C (V-X-Q). Login to comment
127 The above results collectively suggest that the V12M, Q126X, and Q141K variants are likely to occur on separate chromosomes. Login to comment
130 Mainly the two major non-synonymous polymorphisms, V12M and Q141K, were investigated. Login to comment
132 Imai et al. [64] and Morisaki et al. [66] in stable mammalian expression systems found that in PA317 or HEK-293 cells the expressed Q141K ABCG2 protein had a lower expression level than the wild-type ABCG2, or the V12M variant. Login to comment
133 Morisaki et al. demonstrated that both the V12M and Q141K ABCG2 could reach the plasma membrane in the HEK-293 cells, while a significant portion of Table 1 Summary of population genetics data on naturally occurring sequence variations, affecting the coding region of the human ABCG2 gene Position in the ABCG2 genea Position in the ABCG2 cDNAb Amino acid substitution Population n C/K C/C AF (%G 95%CI) Ref. Login to comment
134 g.34GOA (exon 2) c.34GOA V12M Caucasian 150 27 2 10.3G3.5 [47] Caucasian 150 11 0 3.7G2.2 [46] Caucasian 86 n.a n.a 2.0Gn.a [49] Swedish 60 2 0 1.7G2.3 [43] Total Caucasian 360 40 2 6.1G1.8 Japanese 220 61 8 17.5G3.6 [46] Japanese 29 9 1 19.0G10.3 [64] Total Japanese 249 70 9 17.7G3.4 African-American 150 17 1 6.3G2.8 [46] g.8191COT (exon 4) c.376COT Q126X Caucasian 150 0 0 0.0 [46] Caucasian 150 0 0 0.0 [47] Total Caucasian 300 0 0 0.0 Japanese 220 4 0 0.9G0.9 [46] Japanese 124 3 0 1.2G1.4 [64] Japanese 60 2 0 1.7G2.3 [45] Total Japanese 404 9 0 1.1G0.7 African-American 150 0 0 0.0 [46] g.8825CO A (exon 5) c.421COA Q141K Caucasian 172 33 3 11.3G3.4 [63] Caucasian 150 25 4 11.0G3.6 [46] Caucasian 150 22 2 8.7G3.2 [47] Caucasian 85 n.a n.a 14.0Gn.a [49] Swedish 60 10 1 10.0G5.5 [43] Total Caucasian 532 90 10 10.3G1.9 Japanese 220 90 27 32.7G4.5 [46] Japanese 124 48 9 26.6G5.6 [64] Chinese 95 43 11 34.2G6.9 [63] Total Asian 439 181 47 31.3G3.1 African, Sub-Saharan 938 14 1 0.9G0.4 [63] African-American 150 5 1 2.3G1.7 [46] African-American 94 8 1 5.3G3.3 [63] Total Africanc 1182 27 3 1.4G0.5 g.40645AO T (exon 12) c.1465TOC F489L Japanese 100 1 0 0.5G1.0 [46] Japanese 60 1 0 0.8G1.7 [45] Total Japanese 160 2 0 0.6G0.9 g.45367AO T (exon 15) c.1768AOT N590Y Caucasian 150 1 0 0.3G0.7 [47] Caucasian 65 1 0 0.8G1.5 [49] Total Caucasian 215 2 0 0.5G0.7 Only those cDNA SNPs were listed that were detected in at least two independent studies. Login to comment
146 Mizuarai et al. expressed ABCG2 in polarized LLC-PKI cells, and by using confocal microscopy demonstrated that the wtABCG2 and Q141K showed mainly apical staining, while the V12M variant showed intracellular localization [47]. Login to comment
147 In a recent study, similarly LLC-PKI cells where used to express the V12M and Q141K variants and additionally five other polymorphisms (A149P, R163K, Q166E, P269S and S441N [55]). Login to comment
148 Interestingly, they found that all polymorphisms, including V12M and Q141K, had an apical localization, and only the S441N variant showed intracellular staining. Login to comment
151 Clearly, more detailed studies are required to clarify the mechanism of a reduced protein expression for Q141K, and the altered cellular localization found for the V12M and Q141K variants under certain conditions. Login to comment
153 When the functions of the ABCG2 variants were examined in cytotoxicity assays, a 10-fold decrease in drug resistance, as compared to the wild-type ABCG2, was reported by Mizuarai et al., when the V12M or Q141K-transfected LLC-PKI cells were challenged by mitoxantrone, topotecan, or an indolocarbazole topoisomerase I inhibitor [47]. Login to comment
162 Two studies compared the vanadate-sensitive ATPase activity of ABCG2 V12M and Q141K variants, using Sf9 (Spodoptera frugiperda) cell membranes [47,66]. Login to comment
164 On the other hand, the V12M (and D620N) ABCG2 showed a similar ATPase activity as the wild-type protein. Login to comment

[hide] High-speed screening of human ATP-binding cassette... Methods Enzymol. 2005;400:485-510. Ishikawa T, Sakurai A, Kanamori Y, Nagakura M, Hirano H, Takarada Y, Yamada K, Fukushima K, Kitajima M
High-speed screening of human ATP-binding cassette transporter function and genetic polymorphisms: new strategies in pharmacogenomics.
Methods Enzymol. 2005;400:485-510., [PMID:16399366]

Abstract [show]
Drug transporters represent an important mechanism in cellular uptake and efflux of drugs and their metabolites. Hitherto a variety of drug transporter genes have been cloned and classified into either solute carriers or ATP-binding cassette (ABC) transporters. Such drug transporters are expressed in various tissues such as the intestine, brain, liver, kidney, and, importantly, cancer cells, where they play critical roles in the absorption, distribution, and excretion of drugs. We developed high-speed functional screening and quantitative structure-activity relationship analysis methods to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide powerful and practical tools for screening synthetic and natural compounds, and the deduced data can be applied to the molecular design of new drugs. Furthermore, we demonstrate a new "SNP array" method to detect genetic polymorphisms of ABC transporters in human samples.

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115 For this purpose, variant forms (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, E334stop, N590Y, D620N, R482G, and R482T) have been created by site‐ directed mutagenesis with the QuikChange site‐directed mutagensis kit (Stratagene, La Jolla, CA). Login to comment
235 Imai et al. (2002) identified three allelic variants in the ABCG2 gene, of which two were nonsynonymous SNPs (V12M and Q141K) and the third was a splice variant with deletion of nucleotides 944-949 that lacks Ala‐315 and Thr‐316 (Á315‐6). Login to comment

[hide] Role of ABCG2/BCRP in biology and medicine. Annu Rev Pharmacol Toxicol. 2006;46:381-410. Krishnamurthy P, Schuetz JD
Role of ABCG2/BCRP in biology and medicine.
Annu Rev Pharmacol Toxicol. 2006;46:381-410., [PMID:16402910]

Abstract [show]
The protein variously named ABCG2/BCRP/MXR/ABCP is a recently described ATP-binding cassette (ABC) transporter originally identified by its ability to confer drug resistance that is independent of Mrp1 (multidrug-resistance protein 1) and Pgp (P-glycoprotein). Unlike Mrp1 and Pgp, ABCG2 is a half-transporter that must homodimerize to acquire transport activity. ABCG2 is found in a variety of stem cells and may protect them from exogenous and endogenous toxins. ABCG2 expression is upregulated under low-oxygen conditions, consistent with its high expression in tissues exposed to low-oxygen environments. ABCG2 interacts with heme and other porphyrins and protects cells and/or tissues from protoporphyrin accumulation under hypoxic conditions. Individuals who carry ABCG2 alleles that have impaired function may be more susceptible to porphyrin-induced toxicity. Abcg2 knock-out models have allowed in vivo studies of Abcg2 function in host and cellular defense. In combination with immunohistochemical analyses, these studies have revealed how ABCG2 influences the absorption, distribution, and excretion of drugs and cytotoxins.

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186 Interestingly, some human variants of ABCG2 (ABCG2-V12M) have impaired membrane localization (98). Login to comment
296 The two SNPs most frequently identified were in exon 2 (G34A, resulting in a V12M change) and exon 5 (C421A, resulting in a Q141K substitution). Login to comment

[hide] Topotecan is a substrate for multidrug resistance ... Curr Drug Metab. 2006 Jan;7(1):105-18. Tian Q, Zhang J, Chan SY, Tan TM, Duan W, Huang M, Zhu YZ, Chan E, Yu Q, Nie YQ, Ho PC, Li Q, Ng KY, Yang HY, Wei H, Bian JS, Zhou SF
Topotecan is a substrate for multidrug resistance associated protein 4.
Curr Drug Metab. 2006 Jan;7(1):105-18., [PMID:16454695]

Abstract [show]
Topotecan (TPT) is a semisynthetic water-soluble derivative of camptothecin (CPT) used as second-line therapy in patients with metastatic ovarian carcinoma, small cell lung cancer, and other malignancies. However, both dose-limiting toxicity and tumor resistance hinder the clinical use of TPT. The mechanisms for resistance to TPT are not fully defined, but increased efflux of the drug by multiple drug transporters including P-glycoprotein (PgP), multidrug resistance associated protein 1 (MRP1) and breast cancer resistance protein (BCRP) from tumor cells has been highly implicated. This study aimed to investigate whether overexpression of human MRP4 rendered resistance to TPT by examining the cytotoxicity profiles using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazonium bromide (MTT) assay and cellular accumulation of TPT in HepG2 cells stably overexpressing MRP4. Two kinds of cell lines, HepG2 with insertion of an empty vector plasmid (V/HepG2), HepG2 cells stably expressing MRP4 (MRP4/HepG2), were exposed to TPT for 4 or 48 hr in the absence or presence of various MRP4 inhibitors including DL-buthionine-(S,R)-sulphoximine (BSO), diclofenac, celecoxib, or MK-571. The intracellular accumulation of TPT and paclitaxel (a PgP substrate) by V/HepG2 and MRP4/HepG2 cells was determined by incubation of TPT with the cells and the amounts of the drug in cells were determined by validated HPLC methods. The study demonstrated that MRP4 conferred a 12.03- and 6.86-fold resistance to TPT in the 4- and 48-hr drug-exposure MTT assay, respectively. BSO, MK-571, celecoxib, or diclofenac sensitised MRP4/HepG2 cells to TPT cytotoxicity and partially reversed MRP4-mediated resistance to TPT. In addition, the accumulation of TPT was significantly reduced in MRP4/HepG2 cells compared to V/HepG2 cells, and one-binding site model was found the best fit for the MRP4-mediated efflux of TPT, with an estimated K(m) of 1.66 microM and V(max) of 0.341 ng/min/106 cells. Preincubation of MRP4/HepG2 cells with BSO (200 microM) for 24 hr, celecoxib (50 microM), or MK-571 (100 microM) for 2 hr significantly increased the accumulation of TPT over 10 min in MRP4/HepG2 cells by 28.0%, 37.3% and 32.5% (P < 0.05), respectively. By contrast, there was no significant difference in intracellular accumulation of paclitaxel in V/HepG2 and MRP4/HepG2 cells over 120 min. MRP4 also rendered resistance to adefovir dipivoxil (bis-POM-PMEA) and methotrexate, two reported MRP4 substrates. MRP4 did not exhibit any significant resistance to other model drugs including vinblastine, vincristine, etoposide, carboplatin, cyclosporine and paclitaxel in both long (48 hr) and short (4 hr) drug-exposure MTT assays. These findings indicate that MRP4 confers resistance to TPT and TPT is the substrate for MRP4. Further studies are needed to explore the role of MRP4 in resistance to, toxicity and pharmacokinetics of TPT in cancer patients.

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47 However, resistance levels of TPT are inconsistent in different BCRP overexpressing cell lines [51-59], probably due to the existence of three mutant variants of BCRP resulting in the amino acid changes at V12M, Q141K and D620N [63-67]. Login to comment

[hide] Functional validation of the genetic polymorphisms... Mol Pharmacol. 2006 Jul;70(1):287-96. Epub 2006 Apr 11. Tamura A, Watanabe M, Saito H, Nakagawa H, Kamachi T, Okura I, Ishikawa T
Functional validation of the genetic polymorphisms of human ATP-binding cassette (ABC) transporter ABCG2: identification of alleles that are defective in porphyrin transport.
Mol Pharmacol. 2006 Jul;70(1):287-96. Epub 2006 Apr 11., [PMID:16608919]

Abstract [show]
The ATP-binding cassette (ABC) transporter ABCG2 has been implicated to play a significant role in the response of patients to medication and/or the risk of diseases. To clarify the possible physiological or pathological relevance of ABCG2 polymorphisms, we have functionally validated single nucleotide polymorphisms (SNP) of ABCG2. In the present study, based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells. Because porphyrins are considered to be endogenous substrates for ABCG2, we have investigated the porphyrin transport activity of those variant forms in vitro. We herein provide evidence that the variants Q126stop, F208S, S248P, E334stop, and S441N are defective in porphyrin transport, whereas F489L exhibited impaired transport, approximately 10% of the activity observed for the wild type. Furthermore, Flp-In-293 cells expressing those variants were photosensitive. Thus, among those genetic polymorphisms of ABCG2, at least the hitherto validated alleles of Q126stop, S441N, and F489L are suggested to be of clinical importance related to the potential risk of porphyria.

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2 In the present study, based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells. Login to comment
82 GC indicates the percentage of guanine and cytosine contents in the PCR primer set. Tm shows the melting temperature (Tm) for each PCR primer set. Variant and Primers Primer Sequence (5Ј 3 3Ј) Primer Length GC Tm bases % °C V12M 33 39 55 Forward CGAAGTTTTTATCCCAATGTCACAAGGAAACAC Reverse GTGTTTCCTTGTGACATTGGGATAAAAACTTCG G51C 42 35 59 Forward ATCGAGTAAAACTGAAGAGTTGCTTTCTACCTTGTAGAAAAC Reverse GTTTTCGACAAGGTAGAAAGCAACTCTTCAGTTTTACTCGAT Q126stop 40 40 62 Forward GTAATTCAGGTTACGTGGTATAAGATGATGTTGTGATGGG Reverse CCCATCACAACATCATCTTATACCACGTAACCTGAATTAC Q141K 35 42 55 Forward CGGTGAGAGAAAACTTAAAGTTCTCAGCAGCTCTT Reverse AAGAGCTGCTGAGAACTTTAAGTTTTCTCTCACCG T153M 42 40 60 Forward CGGCTTGCAACAACTATGATGAATCATGAAAAAAACGAACGG Reverse CCGTTCGTTTTTTTCATGATTCATCATAGTTGTTGCAAGCCG Q166E 35 42 55 Forward GGATTAACAGGGTCATTGAAGAGTTAGGTCTGGAT Reverse ATCCAGACCTAACTCTTCAATGACCCTGTTAATCC I206L 36 44 59 Forward CTTATCACTGATCCTTCCCTCTTGTTCTTGGATGAG Reverse CTCATCCAAGAACAAGAGGGAAGGATCAGTGATAAG F208S 35 45 55 Forward TGATCCTTCCATCTTGTCCTTGGATGAGCCTACAA Reverse TTGTAGGCTCATCCAAGGACAAGATGGAAGGATCA S248P 35 40 55 Forward TTCATCAGCCTCGATATCCCATCTTCAAGTTGTTT Reverse AAACAACTTGAAGATGGGATATCGAGGCTGATGAA E334stop 35 31 55 Forward TCATAGAAAAATTAGCGTAGATTTATGTCAACTCC Reverse GGAGTTGACATAAATCTACGCTAATTTTTCTATGA F431L 28 60 62 Forward AGCTGGGGTTCTCCTCTTCCTGACGACC Reverse GGTCGTCAGGAAGAGGAGAACCCCAGCT S441N 34 47 59 Forward AACCAGTGTTTCAGCAATGTTTCAGCCGTGGAAC Reverse GTTCCACGGCTGAAACATTGCTGAAACACTGGTT F489L 46 34 62 Forward GAGGATGTTACCAAGTATTATACTTACCTGTATAGTGTACTTCATG Reverse CATGAAGTACACTATACAGGTAAGTATAATACTTGGTAACATCCTC F571I 36 47 61 Forward GTCATGGCTTCAGTACATCAGCATTCCACGATATGG Reverse CCATATCGTGGAATGCTGATGTACTGAAGCCATGAC N590Y 42 38 62 Forward CATAATGAATTTTTGGGACAATACTTCTGCCCAGGACTCAAT Reverse ATTGAGTCCTGGGCAGAAGTATTGTCCCAAAAATTCATTATG D620N 32 56 62 Forward GGTAAAGCAGGGCATCAATCTCTCACCCTGGG Reverse CCCAGGGTGAGAGATTGATGCCCTGCTTTACC veloped by using Western Lighting Chemiluminescent Reagent Plus (PerkinElmer Life and Analytical Sciences, Boston, MA) and detected by Lumino Imaging Analyzer FAS-1000 (Toyobo Engineering, Osaka, Japan). Login to comment
144 For this purpose, based on the currently available data on SNPs and acquired mutations, we generated variant forms (i.e., V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis. Login to comment
214 In the present study, based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells. Login to comment
219 The frequencies of the Q126stop, S441N, and F489L alleles are relatively low (less than 2%) compared with those of the V12M and Q141K alleles. Login to comment
224 Potential Risk Amino Acid Transport Allele Frequency cDNA Position Located on Exon Allele Data Sourcea Hemato MTX Wild-Type Allele % V12M ϩϩ ϩϩ 2.0-90.0 34 2 G A 1, 2, 4, 5, 7, 8 ૽૽ Q126stop - - 0.0-1.7 376 4 C T 1, 3, 5, 7 Q141K ϩϩ ϩϩ 0.0-35.5 421 5 C A 1, 2, 4, 5, 6, 7, 8 T153M ϩϩ ϩϩ 3.3 458 5 C T 5 R160Q N.D. N.D. 0.5 479 5 G A 8 Q166E ϩϩ ϩϩ N.D. 496 5 C G NCBI dbSNP rs1061017 I206L ϩϩ ϩϩ 10.0 616 6 A C 2 ૽૽ F208S - - N.D. 623 6 T C NCBI dbSNP rs1061018 ૽૽ S248P - - N.D. 742 7 T C NCBI dbSNP rs3116448 ૽૽ E334stop - - N.D. 1000 9 G T NCBI dbSNP rs3201997 F431L ϩϩ - 0.8 1291 11 T C 3 ૽૽ S441N - - 0.5 1322 11 G A 7 ૽ F489L ϩ - 0.5-0.8 1465 12 T C 3, 7 F571L ϩϩ ϩϩ 0.5 1711 14 T A NCBI dbSNP rs9282571 (૽૽) R575stop N.D. N.D. 0.5 1723 14 C T 8 N590Y ϩϩ ϩϩ 0.0-1.0 1768 15 A T 2, 5 D620N ϩϩ ϩϩ 0.5 1858 16 G A 8 Hemato, hematoporphyrin; NCBI, National Center for Biotechnology Information; N.D., not determined; ૽, risk of porphyria; (૽), potential risk is assumed as the lack of transport activity being as a result of a truncated protein. Login to comment

[hide] Genetic variation and haplotype structure of the A... Drug Metab Pharmacokinet. 2006 Apr;21(2):109-21. Maekawa K, Itoda M, Sai K, Saito Y, Kaniwa N, Shirao K, Hamaguchi T, Kunitoh H, Yamamoto N, Tamura T, Minami H, Kubota K, Ohtsu A, Yoshida T, Saijo N, Kamatani N, Ozawa S, Sawada J
Genetic variation and haplotype structure of the ABC transporter gene ABCG2 in a Japanese population.
Drug Metab Pharmacokinet. 2006 Apr;21(2):109-21., [PMID:16702730]

Abstract [show]
The ATP-binding cassette transporter, ABCG2, which is expressed at high levels in the intestine and liver, functions as an efflux transporter for many drugs, including clinically used anticancer agents such as topotecan and the active metabolite of irinotecan (SN-38). In this study, to elucidate the linkage disequilibrium (LD) profiles and haplotype structures of ABCG2, we have comprehensively searched for genetic variations in the putative promoter region, all the exons, and their flanking introns of ABCG2 from 177 Japanese cancer patients treated with irinotecan. Forty-three genetic variations, including 11 novel ones, were found: 5 in the 5'-flanking region, 13 in the coding exons, and 25 in the introns. In addition to 9 previously reported nonsynonymous single nucleotide polymorphisms (SNPs), 2 novel nonsynonymous SNPs, 38C>T (Ser13Leu) and 1060G>A (Gly354Arg), were found with minor allele frequencies of 0.3%. Based on the LD profiles between the SNPs and the estimated past recombination events, the region analyzed was divided into three blocks (Block -1, 1, and 2), each of which spans at least 0.2 kb, 46 kb, and 13 kb and contains 2, 24, and 17 variations, respectively. The two, eight, and five common haplotypes detected in 10 or more patients accounted for most (>90%) of the haplotypes inferred in Block -1, Block 1, and Block 2, respectively. The SNP and haplotype distributions in Japanese were different from those reported previously in Caucasians. This study provides fundamental information for the pharmacogenetic studies investigating the relationship between the genetic variations in ABCG2 and pharmacokinetic/pharmacodynamic parameters.

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17 In vitro studies have also indicated that a number of anticancer drugs are good substrates for ABCG2: e.g. topotecan, an irinotecan metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), and its glucuronide conjugate, SN-38G.810) Indeed, inhibition of the murine ABCG2 homologue, Bcrp 1, increases the bioavailability of topotecan when orally administered to mdr1aW1b- decient mice.11) In a clinical study, coadministration of topotecan with GF120918, a dual inhibitor for ABCG2 and P-glycoprotein, was shown to markedly increase the bioavailability and systemic exposure of topotecan.12) The cloning of ABCG2 from drug-selected cell lines revealed that acquired amino acid substitutions at residue 482 (Arg482Gly and Arg482Thr) of ABCG2 resulted in marked alterations in substrate recognition and transport ability.13) Thereafter, naturally occurring genetic variations in ABCG2 have been extensively examined in various ethnic populations1421) because they were expected to explain interindividual dierences in oral bioavailability and clearance of ABCG2 substrate drugs.22) Two nonsynonymous polymorphisms, 34GÀA (Val12Met) and 421CÀA (Gln141Lys), were detected at relatively high frequencies in most ethnic groups including Caucasians, Asians, and Africans.1416,1821,23) Both polymorphisms were reported to be associated with reduced protein expression in vitro andWor the increased sensitivity of the expressed cells toward several anticancer drugs although conicting data were also reported.16,2426) The expression of ABCG2 protein in placenta was signicantly lower in homozygotes with the 421A alleles than in those with the 421C alleles, while 34GÀA (Val12Met) did not aect ABCG2 protein expression.23) However, in intestinal samples, no association was found between the ABCG2 protein levels and the 421CÀA (Gln141Lys) genotype.18) A pharmacokinetic study showed that 421A (Gln141Lys) was unlikely to inuence the in vivo disposition of irinotecan in European Caucasian cancer patients.27) On the other hand, diomotecan pharmacokinetics were signicantly aected by the 421A genotype.28) To explain these inconsistencies, the elucidation of the haplotype structure of ABCG2 would be helpful; however, only limited information is available for the linkage disequilibrium (LD) prole and haplotype structure of this gene.20,21) Also, to facilitate future pharmacogenetic studies on ABCG2 genetic variations, haplotype analysis using its high-density SNPs found in a large number of samples is warranted. Login to comment
70 The observed allele frequencies were all in Hardy-Weinberg equilibrium (pÀ0.05) except for 34GÀA (Val12Met) and IVS2 {36AÀG (p0.028 for both variations). Login to comment
80 However, marked ethnic dierences in the allele frequencies were observed with |1203ä |1200delCTCA, 34GÀA (Val12Met), 421CÀA (Gln141Lys), and some intronic variations. Login to comment
85 115Haplotype Structure in Human ABCG2 (from |1836 to |1175 bp upstream of the translational start site) of the basal promoter,30) and was suggested to inuence irinotecan pharmacokinetics.31) The frequencies of two well-known nonsynonymous SNPs, 34GÀA (Val12Met) and 421CÀA (Gln141Lys), were 0.192 and 0.319 in our study, which were comparable to those in Chinese (0.204 and 0.2220.350, respectively).20,27) However, the frequencies were much higher than those in Caucasians (0.020.065 and 0.080.15), African-Americans (00.09 and 00.05), and a Swedish population (0.02 and 0.1).18,19,21,23,27) Of other relatively rare nonsynonymous SNPs, 376CÀT (Gln126X), 1291TÀC (Phe431Leu), 1322GÀA (Ser441Asn), 1465TÀC (Phe489Leu), and 1515delC (Phe506SerfsX4) were already detected in a Japanese population by Itoda et al.17) andWor Kobayashi et al.,23) but not found in other ethnic groups. Login to comment
98 As previously reported in various ethnic groups,14,18) perfect LD (r2 1.0) was observed between 34GÀA (Val12Met) and IVS2{ 36AÀG. Login to comment
130 In Block 1, seven haplotype groups (*1 to *7) were inferred, and the groups of *2 to *7 harbored non-synonymous SNPs, 421CÀA (Gln141Lys) (*2), 34GÀA (Val12Met) (*3), 376CÀT (Gln126X) (*4), 38CÀT (Ser13Leu) (*5), 479GÀA (Arg160Gln) (*6), and 1060GÀA (Gly354Arg) (*7). Login to comment
134 The haplotype-tagging SNPs (htSNPs) that were able to resolve the 8 common haplotypes were the following 7 variations: IVS199GÀA, 34GÀA (Val12Met), IVS293TÀC, 376CÀT (Gln126X), 421CÀA (Gln141Lys), IVS6217AÀG, and IVS6204CÀT. Login to comment
154 Mizuarai et al. showed that 34GÀA (Val12Met) was associated with reduced drug resistance in polarized LLC-PK1 cells, which might be caused by its impaired apical membrane localization.25) In contrast, several groups did not nd any signicant eects of Val12Met on the protein expression levels as well as drug resistance using stable and transient mammalian expression systems.16,24,26) According to Imai et al. and Kondo et al.,16,24) the Gln141Lys substitution resulted in decreased protein expression and reduced drug resistance. Login to comment
162 Except for Val12Met, Gln126X, and Gln141Lys, the allele frequencies of eight nonsynonymous SNPs were less than 0.01, and these low frequency variations do not largely contribute to the overall heterozygosity of ABCG2; however, they might have clinical importance. Login to comment
188 In a Swedish population, |1203ä |1200delCTCA was reported to be linked with 34GÀA (Val12Met), the representative SNP in the Block1 *3 group.19) Due to the high (0.54) and low (0.02) allele frequencies of |1203ä|1200delCTCA and 34GÀA (Val12Met), respectively, the Block |1 *1bBlock 1 *3 combination is not predominant in the Swedish population. Login to comment
189 Zhou et al. suggested that |1203ä |1200delCTCA might inuence pharmacokinetic parameters of irinotecan.31) On the other hand, the functional signicance of 34GÀA (Val12Met) is not fully elucidated as described above.16,2426) In this context, the major combination in Japanese, Block |1 *1bBlock 1 *3a, should be carefully considered in pharmacogenetic studies in Japanese. Login to comment

[hide] Role of pharmacogenetics of ATP-binding cassette t... Pharmacol Ther. 2006 Nov;112(2):457-73. Cascorbi I
Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs.
Pharmacol Ther. 2006 Nov;112(2):457-73., [PMID:16766035]

Abstract [show]
Interindividual differences of drug response are an important cause of treatment failures and adverse drug reactions. The identification of polymorphisms explaining distinct phenotypes of drug metabolizing enzymes contributed in part to the understanding of individual variations of drug plasma levels. However, bioavailability also depends on a major extent from the expression and activity of drug transport across biomembranes. In particular efflux transporters of the ATP-binding cassette (ABC) family such as ABCB1 (P-glycoprotein, P-gp), the ABCC (multidrug resistance-related protein, MRP) family and ABCG2 (breast cancer resistance protein, BCRP) have been identified as major determinants of chemoresistance in tumor cells. They are expressed in the apical membranes of many barrier tissue such as the intestine, liver, blood-brain barrier, kidney, placenta, testis and in lymphocytes, thus contributing to plasma, liquor, but also intracellular drug disposition. Since expression and function exhibit a broad variability, it was hypothesized that hereditary variances in the genes of membrane transporters could explain at least in part interindividual differences of pharmacokinetics and clinical outcome of a variety of drugs. This review focuses on the functional significance of single nucleotide polymorphisms (SNP) of ABCB1, ABCC1, ABCC2, and ABCG2 in in vitro systems, in vivo tissues and drug disposition, as well as on the clinical outcome of major indications.

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901 Both identified 34G>A (V12M) and 421C>A (Q141K). Login to comment
914 0.235 Exon 2 c. 34 G>A V12M 0.17 0.04a 0.06b IVS 2+16 A>G ? Login to comment
929 Moreover, decreased transport rates were found in Sf9 insect cells, transfected with the V12M variant (Morisaki et al., 2005). Login to comment
934 Interestingly, V12M was associated with elevated activity compared to the wild-type, whereas ABCG2 with premature stop-codon lacked any activity as expected (Ishikawa et al., 2005). Login to comment

[hide] Role of BCRP 421C>A polymorphism on rosuvastatin p... Clin Chim Acta. 2006 Nov;373(1-2):99-103. Epub 2006 May 13. Zhang W, Yu BN, He YJ, Fan L, Li Q, Liu ZQ, Wang A, Liu YL, Tan ZR, Fen-Jiang, Huang YF, Zhou HH
Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males.
Clin Chim Acta. 2006 Nov;373(1-2):99-103. Epub 2006 May 13., [PMID:16784736]

Abstract [show]
BACKGROUND: Rosuvastatin, a novel potent HMG-CoA reductase inhibitor, is excreted into bile mediated by breast cancer resistance protein (BCRP). Our objective was to determine the association between the most frequent single nucleotide polymorphisms (SNPs) of the BCRP (421C>A) and the pharmacokinetics of rosuvastatin. METHOD: Pre-screening of SLCO1B1 521TC and CYP2C9*1/*3 were performed before this pharmacokinetic study. Fourteen healthy volunteers who are SLCO1B1 521TT and CYP2C9*1/*1 wild-type homozygotes were selected to participate in this study. Seven were 421CC wild-type of BCRP, the others were carriers with at least one 421C>A mutant allele (five subjects had a genotype of 421CA and two were homozygotes of 421AA). Each was given a single oral dose of 20 mg rosuvastatin. The plasma concentrations of rosuvastatin were measured for up to 72 h by LC-MS. RESULTS: The pharmacokinetic parameters of rosuvastatin showed a significantly difference between the two genotyped groups. The AUC(0-72) and AUC(0-infinity) of rosuvastatin were lower in the 421CC group than in the 421CA+421AA group (33.8+/-11.4 vs. 59.6+/-22.2 ng.h/ml, P=0.018; 34.9+/-11.9 vs. 62.2+/-23.5 ng.h/ml, P=0.018), respectively. The C(max) value was higher in the 421CA+421AA group than that in the 421CC group (9.9+/-5.4 vs. 5.1+/-2.4 ng/ml, P=0.048). The CL/F value was lower in the 421CA+421AA group than that in the 421CC group (384.7+/-161.2 vs. 674.0+/-297.6 l/h, P=0.043). The T(1/2) and T(max) values showed no difference between these groups. CONCLUSIONS: The BCRP 421C>A polymorphism may play an important role in the pharmacokinetics of rosuvastatin in healthy Chinese males after the exclusion of impact of SLCO1B1 and CYP2C9 genetic polymorphism.

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109 In addition, the G34A (V12M) mutation causes disturbance of membrane localization and happens relatively high in Asians. Login to comment

[hide] Pharmacogenetic characteristics of indinavir, zido... J Acquir Immune Defic Syndr. 2006 Aug 1;42(4):441-9. Anderson PL, Lamba J, Aquilante CL, Schuetz E, Fletcher CV
Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study.
J Acquir Immune Defic Syndr. 2006 Aug 1;42(4):441-9., 2006-08-01 [PMID:16791115]

Abstract [show]
OBJECTIVE: The aim of the study was to investigate relationships among indinavir, lamivudine-triphosphate, and zidovudine-triphosphate pharmacokinetics and pharmacodynamics with polymorphisms in CYP3A5, MDR1, MRP2, MRP4, BCRP, and UGT1A1 genes. STUDY DESIGN: Retrospective pilot investigation among 33 subjects who participated in a randomized pharmacological study of indinavir, lamivudine, and zidovudine. Subjects were defined as genetic variant carriers or not. Relationships were investigated with multivariable regression. Indinavir clearance was adjusted for African American race; triphosphates for sex; and HIV-response for study arm, drug exposure, and baseline HIV-RNA. RESULTS: Genetically determined CYP3A5 expressors had 44% faster indinavir oral clearance versus nonexpressors (P = 0.002). MRP2-24C/T variant carriers had 24% faster indinavir oral clearance (P = 0.05). Lamivudine-triphosphate concentrations were elevated 20% in MRP4 T4131G variant carriers (P = 0.004). A trend for elevated zidovudine-triphosphates was observed in MRP4 G3724A variant carriers (P = 0.06). The log10 changes in HIV-RNA from baseline to week 52 were -3.7 for MDR1 2677 TT, -3.2 for GT, and -2.2 for GG (P < 0.05). Bilirubin increases were 2-fold higher in UGT1A1 [TA]7/[TA]7 genotypes. No relationships were identified with BCRP. DISCUSSION: Novel relationships were identified among genetic variants in drug transporters and indinavir, lamivudine-triphosphate, and zidovudine-triphosphate concentrations. CYP3A5 expression was associated with faster indinavir oral clearance. These pilot data provide a scientific basis for more rational utilization of antiretroviral drugs.

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165 For example, intracellular ZDV-phosphate concentrations (mono-, di-, tri-) were dependent on the cellular expression of MRP4,23,24 and the pharmacological activity of ZDV and 3TC was dependent on the expression of BCRP.25 Two relatively common functional polymorphisms have been identified in the BCRP gene, one a G-to-A change at nucleotide 34 in exon 2 (Val to Met at codon 12) and a C-to-A change at nucleotide 421 in exon 5 (Glu to Lys at codon 141).26 However, we did not observe relationships between these polymorphisms and ZDV-triphosphate or 3TC-triphosphate concentrations. Login to comment

[hide] Multidrug resistance: retrospect and prospects in ... Curr Med Chem. 2006;13(16):1859-76. Perez-Tomas R
Multidrug resistance: retrospect and prospects in anti-cancer drug treatment.
Curr Med Chem. 2006;13(16):1859-76., [PMID:16842198]

Abstract [show]
Conventional cancer chemotherapy is seriously limited by the multidrug resistance (MDR) commonly exhibited by tumour cells. One mechanism by which a living cell can achieve multiple resistances is via the active efflux of a broad range of anticancer drugs through the cellular membrane by MDR proteins. Such drugs are exported in both ATP-dependent and -independent manners, and can occur despite considerable concentration gradients. To the ATP-dependent group belongs the ATP-binding cassette (ABC) transporter family, which includes P-gp, MRP, BCRP, etc. Another protein related to MDR, though not belonging to the ABC transporter family, is lung resistance-related protein (LRP). All of these proteins are involved in diverse physiological processes, and are responsible for the uptake and efflux of a multitude of substances from cancer cells. Many inhibitors of MDR transporters have been identified over the years. Firstly, MDR drugs were not specifically developed for inhibiting MDR; in fact, they had other pharmacological properties, as well as a relatively low affinity for MDR transporters. They included compounds of diverse structure and function, such as verapamil and cyclosporine, and caused side effects. Secondly, the new drugs were more inhibitor-specific, in terms of MDR transport, and were designed to reduce such side effects (e.g., R-verapamil, dexniguldipine, etc.). Unfortunately, they displayed poor response in clinical studies. Recently, new compounds obtained from drug development programs conducted by the pharmaceutical industry are characterized by a high affinity to MDR transporters and are efficient at nanomolar concentrations. Some of these compounds (e.g., MS-209) are currently under clinical trials for specific forms of advanced cancers. We aim to provide an overview of the properties associated with those mammalian MDR transporters known to mediate significant transport of relevant drugs in cancer treatments. We also summarize recent advances concerning resistance to cancer drug therapies with respect to the function and overexpression of ABC and LRP multidrug transporters.

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219 The results showed three BCRP-coding SNPs [G34A (V12M), C376T (Q126stop) and C421A (Q141K)] (Fig. 6). Login to comment
220 The V12M and the Q141K SNPs greatly Fig. (6). Login to comment
227 V12M- and 315-6-BCRP transfected cells showed similar and somewhat lower BCRP protein and drug resistance levels than did wild-type BCRP-transfected cells [137, 138]. Login to comment

[hide] Breast cancer resistance protein in pharmacokineti... Expert Opin Drug Metab Toxicol. 2005 Dec;1(4):595-611. Xia CQ, Yang JJ, Gan LS
Breast cancer resistance protein in pharmacokinetics and drug-drug interactions.
Expert Opin Drug Metab Toxicol. 2005 Dec;1(4):595-611., [PMID:16863427]

Abstract [show]
Breast cancer resistance protein (BCRP), also known as ABCG2, ABCP and MXR, is a member of the ATP-binding cassette transporter G family. BCRP functions as a biological barrier that extrudes xenobiotics out of cells. The broad substrate specificity and tissue distributions of BCRP in the body make this transporter one of the major efflux transporters in chemotherapy. Recent studies have demonstrated that BCRP exerts a great impact on drug absorption and disposition. This review focuses on the role of BCRP in pharmacokinetics as well as in vitro and in vivo strategies to evaluate hepatic/intestinal BCRP-mediated drug transports and drug-drug interactions. The impacts of polymorphism and gender difference of BCRP are also discussed.

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170 The G34A variant in exon 2, resulting in a Val12Met amino acid change, has been associated with a low BCRP protein expression and an altered efflux function in cancer cells [73-74]. Login to comment

[hide] Human ABC transporter ABCG2 in xenobiotic protecti... Drug Metab Rev. 2006;38(3):371-91. Wakabayashi K, Tamura A, Saito H, Onishi Y, Ishikawa T
Human ABC transporter ABCG2 in xenobiotic protection and redox biology.
Drug Metab Rev. 2006;38(3):371-91., [PMID:16877258]

Abstract [show]
Human ATP-binding cassette (ABC) transporter ABCG2 (BCRP/MXR/ABCP) is regarded as a member of the phase III system of xenobiotic metabolism. This efflux pump is suggested to be responsible for protecting the body from toxic xenobiotics and for removing toxic metabolites. The aim of this review article is to address new aspects of ABCG2 related to redox biology, namely the posttranslational modification (intra- and intermolecular disulfide bond formation) of ABCG2 protein and the transport of porphyrin and chlorophyll metabolites, as well as the high-speed screening and QSAR analysis method to evaluate ABCG2-drug interactions.

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176 Based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in Sf9 insect cells. Login to comment

[hide] Human multidrug resistance ABCB and ABCG transport... Physiol Rev. 2006 Oct;86(4):1179-236. Sarkadi B, Homolya L, Szakacs G, Varadi A
Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system.
Physiol Rev. 2006 Oct;86(4):1179-236., [PMID:17015488]

Abstract [show]
In this review we give an overview of the physiological functions of a group of ATP binding cassette (ABC) transporter proteins, which were discovered, and still referred to, as multidrug resistance (MDR) transporters. Although they indeed play an important role in cancer drug resistance, their major physiological function is to provide general protection against hydrophobic xenobiotics. With a highly conserved structure, membrane topology, and mechanism of action, these essential transporters are preserved throughout all living systems, from bacteria to human. We describe the general structural and mechanistic features of the human MDR-ABC transporters and introduce some of the basic methods that can be applied for the analysis of their expression, function, regulation, and modulation. We treat in detail the biochemistry, cell biology, and physiology of the ABCB1 (MDR1/P-glycoprotein) and the ABCG2 (MXR/BCRP) proteins and describe emerging information related to additional ABCB- and ABCG-type transporters with a potential role in drug and xenobiotic resistance. Throughout this review we demonstrate and emphasize the general network characteristics of the MDR-ABC transporters, functioning at the cellular and physiological tissue barriers. In addition, we suggest that multidrug transporters are essential parts of an innate defense system, the "chemoimmunity" network, which has a number of features reminiscent of classical immunology.

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997 In healthy individuals or patients, altogether eight nonsynonymous (V12M, Q141K, I206L, F431L, S441N, F489L, N590Y, D620N), five synonymous (silent) (c. Login to comment
1006 From these numerous reported alterations, two protein variants, V12M, and Q141K, were found in relatively high frequencies, with significant differences in allele frequencies in different areas of the world (Fig. 11). Login to comment
1007 The V12M polymorphism affects the NH2-terminal intracellular region of the protein. Login to comment
1009 The V12M polymorphism was found in all ethnic groups tested, with the highest allele frequency in Mexican-Indians (90%), while only 2% in a Swedish population (18, 418), and also with a significant difference in allele frequencies in Caucasian and Japanese populations. Login to comment
1016 (251), by using stable mammalian expression systems, found that in PA317 or HEK-293 cells the expressed Q141K ABCG2 protein had a lower expression level than the wild-type ABCG2, or the V12M variant. Login to comment
1018 (251) demonstrated that both the V12M and Q141K ABCG2 could reach the plasma membrane in the HEK-293 cells, while a significant portion of Q141K remained intracellular. Login to comment
1023 (247) expressed ABCG2 in polarized LLC-PK1 cells, and by using confocal microscopy, the authors observed that the wild-type ABCG2 and Q141K showed mainly apical staining, while the V12M variant 1210 SARKADI, HOMOLYA, SZAKA´ CS, AND VA´ RADI Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org showed mostly intracellular localization. Login to comment
1025 (188) also used LLC-PK1 cells to express the V12M and Q141K variants and found that all polymorphisms, including V12M and Q141K, had an apical localization. Login to comment
1028 (247), when the V12M or Q141K-transfected LLC-PK1 cells were challenged by mitoxantrone, topotecan, or an indolocarbazole topoisomerase I inhibitor. Login to comment
1033 Two studies compared the vanadate-sensitive ATPase activity of ABCG2 V12M and Q141K variants, using Sf9 (Spodoptera frugiperda) cell membranes (247, 251). Login to comment
1035 On the other hand, the V12M ABCG2 showed a similar ATPase activity as the wild-type protein. Login to comment
1038 Clearly, more detailed studies are required to clarify the mechanism of a reduced protein expression for Q141K, and the altered cellular localization found for the V12M and Q141K variants under certain conditions. Login to comment

[hide] Towards understanding the mechanism of action of t... J Mol Graph Model. 2007 Mar;25(6):837-51. Epub 2006 Aug 30. Li YF, Polgar O, Okada M, Esser L, Bates SE, Xia D
Towards understanding the mechanism of action of the multidrug resistance-linked half-ABC transporter ABCG2: a molecular modeling study.
J Mol Graph Model. 2007 Mar;25(6):837-51. Epub 2006 Aug 30., [PMID:17027309]

Abstract [show]
The ATP-binding cassette protein ABCG2 is a member of a broad family of ABC transporters with potential clinical importance as a mediator of multidrug resistance. We carried out a homology and knowledge-based, and mutationally improved molecular modeling study to establish a much needed structural framework for the protein, which could serve as guidance for further genetic, biochemical, and structural analyses. Based on homology with known structures of both full-length and nucleotide-binding domains (NBD) of ABC transporters and structural knowledge of integral membrane proteins, an initial model of ABCG2 was established. Subsequent refinement to conform to the lipophilic index distributions in the transmembrane domain (TMD) and to the results of site-directed mutagenesis experiments led to an improved model. The complete ABCG2 model consists of two identical subunits facing each other in a closed conformation. The dimeric interface in the nucleotide-binding domain (NBD) involves a characteristic nucleotide sandwich and the interface in the TMD consists of the TM helices 1-3 of one subunit and the helices 5 and 6 of the other. The interface between the NBD and the TMD is bridged by the conserved structural motif between TM2 and TM3, the intracellular domain 1 (ICD1), and the terminal beta-strand (S6) of the central beta-sheet in the NBD. The apparent flexibility of the ICD1 may play a role in transmitting conformational changes from the NBD to the TMD or from the TMD to the NBD.

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174 Subsequently, a symmetric dimer Y.-F Li et al. / Journal of Molecular Graphics and Modelling 25 (2007) 837-851844 Table 4 Locations of mutations as predicted by the ABCG2 model and functional correlation Mutation Position in ABCG2 Phenotype Reference V12M N-terminal Membrane localization, SNP, and somewhat lower expression and lower resistance [22] S25Pa N-terminal Low drug resistance for the cell line due to lower expression at cell surface [42] T82Aa NBD, Walker A Low drug resistance for the cell line due to lower expression at cell surface [42] K86M NBD, Walker A No expression at cell surface, retained in the Golgi [43] K86I NBD, Walker A No expressed at cell surface [43] Q141K NBD SNP with lower protein expression and low drug resistance [22,23] T237V NBD Fully functional b I239K,R NBD Loss of expression may be due to structural disruption b R309G Linkerc Low drug resistance [42] D315-6 Linker Deletion mutant for A315 and T316. Login to comment

[hide] Toward individualized treatment: prediction of ant... Anticancer Drugs. 2007 Feb;18(2):111-26. Deeken JF, Figg WD, Bates SE, Sparreboom A
Toward individualized treatment: prediction of anticancer drug disposition and toxicity with pharmacogenetics.
Anticancer Drugs. 2007 Feb;18(2):111-26., [PMID:17159598]

Abstract [show]
A great deal of effort has been spent in defining the pharmacokinetics and pharmacodynamics of investigational and registered anticancer agents. Often, there is a marked variability in drug handling between individual patients, which contributes to variability in the pharmacodynamic effects of a given dose of a drug. A combination of physiological variables, genetic characteristics (pharmacogenetics) and environmental factors is known to alter the relationship between the absolute dose and the concentration-time profile in plasma. A variety of strategies are now being evaluated in patients with cancer to improve the therapeutic index of anticancer drugs by implementation of pharmacogenetic imprinting through genotyping or phenotyping individual patients. The efforts have mainly focused on variants in genes encoding the drug-metabolizing enzymes thiopurine S-methyltransferase, dihydropyrimidine dehydrogenase, members of the cytochrome P450 family, including the CYP2B, 2C, 2D and 3A subfamilies, members of the UDP glucuronosyltransferase family, as well as the ATP-binding cassette transporters ABCB1 (P-glycoprotein) and ABCG2 (breast cancer resistance protein). Several of these genotyping strategies have been shown to have substantial impact on therapeutic outcome and should eventually lead to improved anticancer chemotherapy.

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326 These SNPs occur at mRNA positions 34 (V12M; exon 2), 421 (Q141K, exon 16), 616 (I206L, exon 6) and 1768 (N590Y, exon 15). Login to comment
328 The SNPs of V12M, I206L and N590Y have not to date been found to confer an alteration in protein expression or function. Login to comment
331 Table 12 Ethnic frequencies (%) of allelic variants in ABCG2 gene Allelic variant Caucasians African-Americans Asians Hispanics Africans Middle Easterns V12M 2 4 20-45 40 5 Q141K 11-14 2.3-5.0 15-35 10 1.0 13 I206L 0 0 0 10 0 N590Y 1 Sources: [150-153]. Login to comment

[hide] Genetic polymorphisms of human ABC transporter ABC... J Exp Ther Oncol. 2006;6(1):1-11. Tamura A, Wakabayashi K, Onishi Y, Nakagawa H, Tsuji M, Matsuda Y, Ishikawa T
Genetic polymorphisms of human ABC transporter ABCG2: development of the standard method for functional validation of SNPs by using the Flp recombinase system.
J Exp Ther Oncol. 2006;6(1):1-11., [PMID:17228519]

Abstract [show]
The vector-mediated introduction of cDNA into mammalian cells by calcium phosphate co-precipitation or permeation with lipofectamine is widely used for the integration of cDNA into genomic DNA. However, integration of cDNA into the host's chromosomal DNA occurs randomly at unpredictable sites, and the number of integrated recombinant DNAs is not controllable. To investigate the effect of genetic polymorphisms of ABCG2 on the protein expression and the drug resistance profile, we developed the Flp-In method to integrate one single copy of ABCG2 variant-cDNA into FRT-tagged genomic DNA. More than 20 metaphase spreads were examined for both fluorescence in situ hybridization (FISH) mapping and multicolor-FISH analysis, and it has been revealed that ABCG2 cDNA was incorporated into the telomeric region of the short arm on one of chromosomes 12 in Flp-In-293 cells. Based on the currently available SNP data for human ABCG2, we have created a total of seven variants by site-directed mutagenesis and stably expressed them in Flp-In-293 cells. While mRNAs of those integrated ABCG2 variants and wild type were evenly expressed in Flp-In-293 cells, the protein expression levels of F208S and S441N variants were found to be markedly low. It is suggested that the protein instability due to enhanced degradation resulted in the low levels of their protein expression. Thus, the Flp recombinase system would provide a useful tool to validate the effect of nonsynonymous SNPs on the protein stability and post-translational modification of ABCG2.

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48 Standard method for functional validation of ABCG2 SNPs Journal of Experimental Therapeutics and Oncology Vol. 6 2006 3 Plasma Membrane inside outside S S S homodimer A B CH2N COOH V12M Q141K F208S S248P F431L S441N F489L R482G R482T Acquired mutation Figure 1. Login to comment
67 PCR primers and conditions for site-directed mutagenesis to create variants of ABCG2 Variant Forward/Reverse Primer sequence (5` →→ 3`) Primer length % GC Tm (ºC) (F/R) primers (bases) V12M F CGAAGTTTTTATCCCAATGTCACAAGGAAACAC 33 39 55 R GTGTTTCCTTGTGACATTGGGATAAAAACTTCG Q141K F CGGTGAGAGAAAACTTAAAGTTCTCAGCAGCTCTT 35 42 55 R AAGAGCTGCTGAGAACTTTAAGTTTTCTCTCACCG F208S F TGATCCTTCCATCTTGTCCTTGGATGAGCCTACAA 35 45 55 R TTGTAGGCTCATCCAAGGACAAGATGGAAGGATCA S248P F TTCATCAGCCTCGATATCCCATCTTCAAGTTGTTT 35 40 55 R AAACAACTTGAAGATGGGATATCGAGGCTGATGAA F431L F AGCTGGGGTTCTCCTCTTCCTGACGACC 28 60 62 R GGTCGTCAGGAAGAGGAGAACCCCAGCT S441N F AACCAGTGTTTCAGCAATGTTTCAGCCGTGGAAC 34 47 59 R GTTCCACGGCTGAAACATTGCTGAAACACTGGTT F489L F GAGGATGTTACCAAGTATTATACTTACCTGTATAGTGTACTTCATG 46 34 62 R CATGAAGTACACTATACAGGTAAGTATAATACTTGGTAACATCCTC Sites of mutagenesis are indicated by underbars. Login to comment
104 Standard method for functional validation of ABCG2 SNPs Journal of Experimental Therapeutics and Oncology Vol. 6 2006 0 1 2 RelativemRNAlevel Mock WT V12M Q141K mRNA A ABCG2 GAPDH Mock WT F208S S248P F431L S441N F489L ABCG2 GAPDH 0 1 2 RelativemRNAlevel mRNA B GAPDH ABCG2 Mock WT F208S S248P F431L S441N F489L Protein 0 1 2 Relativeproteinlevel * * * C DProtein GAPDH ABCG2 0 1 2 Relativeproteinlevel * * Mock WT V12M Q141K Figure 3. mRNA and protein expression levels of ABCG2 WT and variants expressed in Flp-In-293 cells. Login to comment
114 Characterization of V12M, Q141K, F208S, S248P, F431L, S441N, and F489L variants expressed in Flp-In-293 cells The mRNA levels of ABCG2 and GAPDH were measured by quantitative PCR, and the ratios of ABCG2 variants vs. GAPDH were plotted. Login to comment
119 Figure 3 demonstrates mRNA and protein levels of ABCG2 WT and V12M, Q141K, F208S, S248P, F431L, S441N, and F489L variants expressed in Flp-In-293 cells. Login to comment
121 The Q141K variant of ABCG2 stably expressed in Flp-In-293 cells had a lower expression level than did the wild-type ABCG2 or the V12M variant (Fig. 3C). Login to comment
124 The other variants, i.e., V12M, Q141K, S248P, F431L, and F489L, were expressed in plasma membrane as was ABCG2 WT. Login to comment
132 Figure 4 summarizes the characteristics of those Tamura et al. 8 Journal of Experimental Therapeutics and Oncology Vol. 6 2006 Class Class Class Class WT V12M Q141K F431L S248P F489L F208S S441N R482G R482T Protein expression + + + + + + - - + + SN-38 resistance + + + + + / - - - - + + MX resistance + + + + / - - - - - + + Doxorubicin resistance - - - - - - - - + + Daunorubicin resistance - - - - - - - - + + Figure 4. Login to comment
138 WT, V12M, and Q141K form one group where protein expression and resistance to SN-38 and mitoxantrone are positive, but contribution to doxorubicin- and daurorubicin-resistance are negative. Login to comment
142 Finally, the acquired mutants R482G and R482T form another group, which is characteristic Standard method for functional validation of ABCG2 SNPs Journal of Experimental Therapeutics and Oncology Vol. 6 2006 9 Table 3 Remarks mRNA Protein Author Ref Host cell Vector Expression SNP expression expression Imai et al. (15) PA317 pHaL-IRES-DHFR bicistronic Stable V12M Similar to WT Similar to WT - - retrovirus vector plasmid - Q141K Similar to WT Lower than WT Mizuarai et al. (18) LLC-PK1 pcDNA3.1(+) Stable V12M Similar to WT N.D. - - - - Q141K Similar to WT N.D. Morisaki et al. (25) HEK293 pcDNA3.1 Stable V12M Vary among clones Vary among clones - - - - Q141K Vary among clones Vary among clones - - - - D620N Vary among clones Vary among clones Kondo et al. (26) LLC-PK1/ pcDNA3.1/ Stable/ V12M N.D. Similar to WT - HEK293 Adenovirus Transient Q141K N.D. 30 - 40% of WT - - - - A149P N.D. Similar to WT - - - - R163K N.D. Similar to WT - - - - Q166E N.D. Similar to WT - - - - P269S N.D. Similar to WT - - - - S441N N.D. Lower than WT Vethanayagam (27) HEK293 pcDNA3.1/myc-His(-) Stable I206L N.D. Vary among clones et al. - - - - N590Y N.D. Vary among clones - - - - D620N N.D. Vary among clones N.D.: No data Table 2. Login to comment
143 Resistance profile (IC50 ) of ABCG2 Compounds IC50 (nM) Mock WT V12M Q141K F208S S248P F431L S441N F489L SN-38 1.0 ± 0.2 49.9 ± 6.0 51.1 ± 13.8 17.7 ± 0.9 0.7 ± 0.0 3.6 ± 0.4 12.1 ± 1.5 0.8 ± 0.0 3.9 ± 0.4 (49.9)* (51.1)* (17.7)* (0.7) (3.6) (12.1)* (0.8) (3.9) Mitoxantorone 7.0 ± 1.1 108.0 ± 4.9 94.0 ± 18.6 46.7 ± 12.7 5.1 ± 1.0 13.4 ± 1.3 15.2 ± 1.4 5.7 ± 0.8 12.1 ± 6.2 (15.4)* (13.4)* (6.7)* (0.7) (1.9) (2.2)* (0.8) (1.7) Doxorubicin 38.8 ± 3.8 105.2 ± 24.9 123.6 ± 35.3 156.8 ± 27.5 19.9 ± 8.7 23.7 ± 6.7 43.5 ± 6.1 39.4 ± 4.1 47.6 ± 3.1 (2.7) (3.2) (4.0) (0.5) (0.6) (1.1) (1.0) (1.2) Daounorubicin 13.0 ± 0.6 32.3 ± 6.5 58.2 ± 5.0 57.7 ± 4.1 14.1 ± 2.3 22.1 ± 4.2 15.9 ± 1.2 13.3 ± 1.1 23.6 ± 1.6 (2.5) (4.5) (4.4) (1.1) (1.7) (1.2) (1.0) (1.8) Etoposide 117.1 ± 16.0 210.2 ± 18.4 297.3 ± 58.5 233.9 ± 54.2 122.9 ± 17.6 137.7 ± 14.8 139.1 ± 12.3 154.3 ± 8.5 186.9 ± 10.1 (1.8) (2.5) (2.0) (1.0) (1.2) (1.2) (1.3) (1.6) Vincristine 1.8 ± 0.2 4.3 ± 0.3 7.1 ± 1.4 5.6 ± 1.6 0.6 ± 0.0 4.3 ± 0.9 1.8 ± 0.3 0.9 ± 0.1 3.0 ± 0.7 (2.4) (3.0) (3.1) (0.3) (2.4) (1.0) (0.5) (1.7) The drug resistance profiles of ABCG2 WT and variants were obtained by incubating Flp-In-293/ABCG2 WT, V12M, Q141K, F208S, S248P, F431L, S441N, or F489L cells in the presence of SN-38, mitoxantrone, doxorubicin, daunorubicin, etoposide, or vincristine at different concentrations as described in Materials and Methods. Login to comment

[hide] Identification and functional assessment of BCRP p... Drug Metab Dispos. 2007 Apr;35(4):623-32. Epub 2007 Jan 19. Lee SS, Jeong HE, Yi JM, Jung HJ, Jang JE, Kim EY, Lee SJ, Shin JG
Identification and functional assessment of BCRP polymorphisms in a Korean population.
Drug Metab Dispos. 2007 Apr;35(4):623-32. Epub 2007 Jan 19., [PMID:17237154]

Abstract [show]
The breast cancer resistance protein (BCRP) is a member of the ATP-binding cassette transporters. The aim of the present study was to identify genetic variants of BCRP in Koreans and to assess the functional consequences of BCRP polymorphisms. Twenty single nucleotide polymorphisms (SNP), including four nonsynonymous SNP, were identified by DNA sequencing of the BCRP gene in 92 Korean subjects. BCRP V12M, Q141K, P269S, and Q126Stop were detected at frequencies of 23, 28, 0.2, and 1.9%, respectively. These four coding variants were also screened in Chinese and Vietnamese subjects; the allelic frequencies among the three populations were compared; and predictions were made as to the potential frequency of each variant. In vitro functional analyses of the P269S protein and the promoter SNP -19031C>T (mutated in the hypoxia-inducible factor-1alpha binding site) were performed and compared with those of the wild type. P269S exhibited a 35 to 40% decrease in vesicular uptake of [(3)H]estrone-3-sulfate and [(3)H]methotrexate compared with the wild type. The promoter SNP -19031C>T did not affect BCRP promoter activity in either the presence or absence of chemical-induced hypoxic stress. Our results suggest that the P269S variant could be a functionally altered variant. Genotyping of this variant in clinical studies is needed to address its phenotypic role. Genetic polymorphisms of BCRP were found to be very common in Koreans, as well as in other ethnic groups. Comparative analyses among three Asian populations revealed different frequencies for the four functional BCRP variants.

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3 BCRP V12M, Q141K, P269S, and Q126Stop were detected at frequencies of 23, 28, 0.2, and 1.9%, respectively. These four coding variants were also screened in Chinese and Vietnamese subjects; the allelic frequencies among the three populations were compared; and predictions were made as to the potential frequency of each variant. Login to comment
23 According to the current literature, the most frequent BCRP polymorphisms detected among different ethnic groups are 34GϾA, which codes for V12M, and 421CϾA, which codes for Q141K (Zamber et al., 2003). Login to comment
25 The BCRP V12M SNP has been reported as having similar activity to the wild type in terms of dehydroepiandro- This study was supported by the Ministry of Science and Technology (National Research Laboratory Program) and Korea Health 21 R&D Project, Ministry of Health and Welfare, Korea (03-PJ10-PG13-GD01-0002). Login to comment
31 However, Mizuarai et al. (2004) have shown disrupted membrane localization of the V12M variant, which results in decreased transport activity. Login to comment
34 The functional capability of the P269S variant to take up [3 H]estrone-3-sulfate (ES) and [3 H]MTX has been reported as being comparable with that of the wild-type protein TABLE 1 Primer sequences used for the amplification of the BCRP gene fragment and the annealing temperatures used in the PCR Name Region Primer Sequence (5Ј33Ј) Size PCR Condition base pair Tm; °C BCRP1P Promoter F: AACCCAGCTAGGTCAGACGA 557 60.0 R: TTTGAGTGGGCACAGCAC BCRP2P Promoter F: TTCCTAGGGTAGATGCAGCAG 509 60.0 R: CAGGGACAAGCCAAACACTC BCRP3P Promoter F: GTAGAGGCAGGGTTTCACCA 559 60.0 R: AAGTGATTGCGCATGTTCAG BCRP4P Promoter F: CGTGCCTGGCCTCTATGTAT 572 60.0 R: CTGACGCAGGCAGATCACT BCRP5P Promoter F: GCCACCACACCCAGTGTAAT 518 64.7 R: TGCAAAGTAAAAACAAATCAAAACC BCRP1E Exon 1 F: AGCTCGTCCCCTGGATGT 516 54.0 R: CCACCAACCTTTCCAGACAC BCRP2E Exon 2 F: CTGCTCATTGCCACACATTT 400 54.0 R: GCCAAAACCTGTGAGGTTCA BCRP3E Exon 3 F: GTCTCAAACTCCTGGCCTCA 403 54.0 R: GCGTTGCAAATGCTCAATAA BCRP4E Exon 4 F: TGGATTCAAAGTAGCCATGAGA 402 54.0 R: ATTCTCCCTGCCTTTTCACA BCRP5E Exon 5 F: GGTTCATCATTAGCTAGAACTTTACC 403 54.0 R: TGGAAAGCAACCATTTTTGA BCRP6E Exon 6 F: TCTTACAGGACTGGCACACG 426 54.0 R: CCTTCCCTACATTCTTACCTGCT BCRP7E Exon 7 F: TCAGGCTGAACTAGAGCAAACA 387 60.0 R: AGCACCAAATGGAACAAACA BCRP8E Exon 8 F: CATGGGAAGAAGAGAGAAAGAAA 412 60.0 R: CAAAAACACCAACAGCACTCA BCRP9E Exon 9 F: GGTGTTAGGGAAGCATCCAA 413 54.0 R: TGAAGCAGATGATAACAGAACCA BCRP10E Exon 10 F: GCCAAGCCATTGAGTGTTTA 386 60.0 R: TGGGCAACAGAGCATGAC BCRP11E Exon 11 F: CCACAACAATCCAAGACTGTG 423 60.0 R: GTAATCCTCCGGATCCCATC BCRP12E Exon 12 F: GGTCTAGCCCTGAGGATGTG 403 64.7 R: GAGTGCAAAATGGACAGGTG BCRP13E Exon 13 F: AGGGTGGTTGGAGAGTGGAT 412 60.0 R: AGCAGAGCCCCATTTACAGA BCRP14E Exon 14 F: TGAGTGTCTTGAGTAAGTGGAGAGA 420 54.0 R: GACTCCCCAGCCTTGTGTTA BCRP15E Exon 15 F: TCTTGATTGCCAGGGAAAAT 404 60.0 R: CGCGCACAACTCACTTTATG BCRP16E Exon 16 F: TGACGGATGCTAGGAATGAA 430 64.7 R: CCCATGGTTACTGTCTGAGGA TABLE 2 Primer sequences used for the pyrosequencing-based genotyping of functional BCRP variants SNPa Variant Primer Sequence (5Ј33Ј) Size PCR Condition base pair Tm; °C 34GϾA V12M 5Ј-Biotin-CTCTCCAGATGTCTTCCAGTAATG-3Ј 278 54.0 5Ј-GCCAAAACCTGTGAGGTTCA-3Ј For sequencing: 5Ј-AGTGTTCCTTTGTGGTTAC-3Ј 8191CϾT Q126Stop 5Ј-Biotin-ACTATCAGCCAAAGCACTTACCC-3Ј 174 54.5 5Ј-GTCTTAGCTGCAAGGAAAGATCCA-3Ј For sequencing: 5Ј-AATGTAATTCAGGTTACGTG-3Ј 8825CϾA Q141K 5Ј-Biotin-GTTGCAAGCCGAAGAGCTG-3Ј 69 54.0 5Ј-TGATGTTGTGATGGGCACTC-3Ј For sequencing: 5Ј-GACGGTGAGAGAAAACTT-3Ј 21850CϾT P269S 5Ј-Biotin-TAGCACCAAATGGAACAAACAC-3Ј 236 54.0 5Ј- TGTTTGATAGCCTCACCTTATTGG-3Ј For sequencing: 5Ј-GAAGACTTATGTTCCACG-3Ј a Position is indicated with respect to the start codon (ATG) of the BCRP gene; the A in the ATG triplet is designated as ϩ1, and the next base toward the 5Ј-end is designated as -1. Login to comment
37 Functional information on P269S is sparse, as compared with the amount of information that has been collected for other coding variants, such as V12M, Q141K, and the null allele Q126Stop. Login to comment
39 Therefore, we performed a functional study of the P269S variant among the four variants identified in the study (V12M, Q141K, P269S, and Q126Stop). Login to comment
65 All the subjects were screened for BCRP V12M, Q126Stop, Q141K, and P269S. Login to comment
105 SNP and Positionb Position Relative to Transcription Start Site Location Effect N Allelic Frequency % 1 -20296AϾG -1379 Promoter 92 13 2 -19855CϾT -938 Promoter 92 0.5 3 -19605AϾG -688 Promoter 92 0.5 4 -19031CϾT -114 Promoter 92 1.6 5 -18631CϾT ϩ286 5ЈUTR 92 2.2 6 34GϾA Exon 2 V12M 275 23 7 238AϾG Intron 2 92 25 8 7430AϾG Intron 3 92 9.8 9 8191CϾT Exon 4 Q126Stop 375 1.9 10 8825CϾA Exon 5 Q141K 275 28 11 21850CϾT Exon 7 P269S 674 0.2 12 26297GϾA Exon 9 92 1.1 13 38485AϾG Intron 11 92 24 14 40086insA Intron 12 92 0.5 15 40110GϾT Intron 12 92 22 16 42288CϾT Intron 13 92 67.4 17 42313TϾG Intron 13 92 2.2 18 44072CϾT Intron 13 92 23.4 19 44997AϾG Intron 14 92 49.5 20 45235CϾT Intron 15 92 20.1 a The reference sequence used has GenBank accession no. Login to comment
149 The four coding SNP were 34GϾA coding for V12M, 8191CϾT coding for Q126Stop, 8825CϾA coding for Q141K, and 21850CϾT coding for P269S. Login to comment
150 For more extensive evaluation of the allelic frequencies of the four BCRP variants found in the Korean population, the remaining 183 subjects were screened by pyrosequencing for the presence of V12M, Q126Stop, Q141K, and P269S. Login to comment
152 V12M and Q141K were found in 23 and 28% of Koreans, respectively. Login to comment
176 The haplotype analysis suggests that none of the Q141K-containing haplotypes are linked to the V12M variant. Login to comment
177 To support this strong linkage, the V12M and Q141K variations were assigned to the same haplotype block among two discrete haplotype blocks of the BCRP gene (Fig. 1B). Login to comment
200 From the screening of four nonsynonymous variants in other ethnic groups, the allelic frequencies of V12M, Q126Stop, Q141K, and P269S were obtained (Table 4). Login to comment
201 The frequency of V12M was 10 to 13% higher in Chinese and Vietnamese subjects than in Koreans, whereas Q141K showed no significant differences among the three Asian ethnic groups. Login to comment
219 Among the BCRP coding variants, V12M and Q14lK were the most common in Koreans, with allelic frequencies of 23 and 28%, respectively. These variants are also found frequently in other ethnic groups, such as Caucasians, Japanese, and Chinese (Zamber et al., 2003; Kobayashi et al., 2005). Login to comment
221 The allelic frequency of V12M in Koreans (23%) is much lower than that reported for Southeast Asians (45%), Pacific Islander (64%), Mexican-Indian (90%), and Hispanic (40%) subjects (Zamber et al., 2003). Login to comment
230 Haplotypes 4, 8, and 11 indicate that a single promoter SNP (20296AϾG) and the 238AϾG change accompany the V12M nonsynonymous change in Koreans (Table 3). Login to comment
234 Our results on BCRP haplotypes in the Korean population TABLE 4 Haplotype distribution of BCRP gene in Koreans PNS 69202- G>A 43 A>G 832 G>A 0347 G>A 5288 A>C 58483 G>A 01104 T>G 88224 T>C 27044 T>C 79944 G>A 53254 T>C ycneuqerF )%( egnahcAA K141QM21V 4.621 2 9.91 3 8.7 4 6.7 5 4.7 6 9.5 7 7.4 8 9.2 9 5.2 01 8.1 11 7.1 21 4.1 31 1.1 Haplotype 41 1.1 TABLE 5 Expected allelic frequencies of BCRP V12M, Q126Stop, Q141K, and P269S variants in different Asian populations Population No. Login to comment
235 of Subjects Allelic Frequency (95% CI) V12M Q126Stop Q141K P269S % % % % Korean 275-674a 23 (19.6-26.6) 1.9 (0.9-2.9) 28 (23.8-31.2) 0.2 (0-0.4) Chinese 191 33b (28.5-37.9) 0.5 (0-1.2) 29 (24.3-33.3) 0 (0-0.1) Vietnamese 140 36b (30.8-42.0) 0.4 (0-1.1) 31 (25.7-36.5) 0.7 (0-1.7) a The numbers of subjects genotyped for the V12M, Q126Stop, Q141K, and P269S variants were 275, 375, 275, and 674, respectively. Login to comment
239 The V12M SNP has been reported to be associated with membrane localization (Mizuarai et al., 2004). Login to comment
259 Similarly, BCRP V12M has been reported to exhibit the same transport function as the wild type (Kondo et al., 2004), whereas another study has shown decreased activity caused by disrupted membrane localization (Mizuarai et al., 2004). Login to comment

[hide] Re-evaluation and functional classification of non... Cancer Sci. 2007 Feb;98(2):231-9. Tamura A, Wakabayashi K, Onishi Y, Takeda M, Ikegami Y, Sawada S, Tsuji M, Matsuda Y, Ishikawa T
Re-evaluation and functional classification of non-synonymous single nucleotide polymorphisms of the human ATP-binding cassette transporter ABCG2.
Cancer Sci. 2007 Feb;98(2):231-9., [PMID:17297656]

Abstract [show]
Impacts of genetic polymorphisms of the ATP-binding cassette (ABC) transporter BCRP/MXR1/ABCP (ABCG2) on drug response have been implicated; however, the hitherto reported data involve some inconsistencies. To re-evaluate the effect of single nucleotide polymorphisms (SNP) of ABCG2 in vitro, we created a total of seven variant cDNAs (V12M, Q141K, F208S, S248P, F431L, S441N and F489L) by site-directed mutagenesis and stably expressed each of them in Flp-In-293 cells using the Flp recombinase system. Multicolor fluorescence in situ hybridization mapping analysis revealed that one single copy of ABCG2 cDNA was incorporated into the telomeric region of chromosome 12p. It was proven that mRNAs of those integrated ABCG2 variants were expressed evenly in Flp-In-293 cells. However, the protein expression levels varied among those variants. In particular, expression of the F208S and S441N variants was markedly low, suggesting the instability of these variant proteins. Drug resistance profiles of Flp-In-293 cells expressing two major SNP variants (V12M and Q141K) toward the drug SN-38 demonstrated that the IC50 value (drug concentrations producing a 50% reduction of cell growth) for Q141K was approximately 50% of that for wild type. The contributions of the minor SNP variants (F208S, S248P, F431L, S441N and F489L) to drug resistance toward SN-38, mitoxantrone, doxorubicin, daunorubicin or etoposide were significantly lower than wild type. Based on our functional validation, the above-mentioned non-synonymous polymorphisms as well as acquired mutants (R482G and R482T) of ABCG2 were classified into four groups. Furthermore, new camptothecin analogs synthesized by our research group had potent effects in circumventing ABCG2-mediated drug resistance without any influence from major non-synonymous polymorphisms.

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3 To re-evaluate the effect of single nucleotide polymorphisms (SNP) of ABCG2 in vitro, we created a total of seven variant cDNAs (V12M, Q141K, F208S, S248P, F431L, S441N and F489L) by site-directed mutagenesis and stably expressed each of them in Flp-In-293 cells using the Flp recombinase system. Login to comment
7 Drug resistance profiles of Flp-In-293 cells expressing two major SNP variants (V12M and Q141K) toward the drug SN-38 demonstrated that the IC50 value (drug concentrations producing a 50% reduction of cell growth) for Q141K was approximately 50% of that for wild type. Login to comment
104 Characterization of WT ABCG2, V12M and Q141K expressed in Flp-In-293 cells. Login to comment
105 As shown in Fig. 2A, mRNA levels of WT ABCG2 as well as its major SNP variants (V12M and Q141K) were represented evenly in Flp-In cells. Login to comment
112 Figure 2B depicts the immunofluorescence images of Flp-In-293/Mock, Flp-In-293/ABCG2 (WT), Flp-In-293/ABCG2 (V12M) and Flp-In-293/ABCG2 (Q141K) cells. Login to comment
116 Drug resistance profiles of Flp-In-293 cells expressing WT ABCG2, V12M and Q141K variants toward camptothecin analogs. Login to comment
117 To examine the drug resistance profiles, we incubated Flp-In-293/ABCG2 (WT), Flp-In-293/ABCG2 (V12M) and Flp-In-293/ABCG2 (Q141K) cells with SN-38 and the new camptothecin analogs at different concentrations for 96 h, after which we observed the cell survival rates. Login to comment
118 Flp-In-293/ABCG2 (WT), Flp-In-293/ABCG2 (V12M) and Flp-In-293/ABCG2 (Q141K) cells exhibited strong resistance to SN-38, SN-355 and SN-398, as represented by large IC50 values (Fig. 3). Login to comment
119 Interestingly, the V12M variant provided the cells with higher drug resistance to SN-38, SN-355 and SN-398 than did WT ABCG2 (Fig. 3). Login to comment
135 (V12M) or Flp-In-293/ABCG2 (Q141K) cells exhibited resistance toward SN-22, SN-343, SN-348, SN-349, SN-351, SN-352, SN-353, SN-364, SN-397, SN-443 or SN-444. Login to comment
136 These results suggest that camptothecin analogs lacking the hydroxyl or amino group at position 10 or 11 are not substrates for WT ABCG2 or the V12M and Q141K variants. Login to comment
152 Considered overall, the minor SNP variants were less effective in drug resistance than the V12M and Q141K variants. Login to comment
155 For this purpose, we expressed WT ABCG2, V12M, Q141K, S248P, F431L, F489L, R482G and R482T in Sf9 insect cells and prepared plasma membranes as described previously,(16,35) as the plasma membrane of Sf9 cells has lower endogenous background ATPase activity than Flp-In-293 cells. Login to comment
159 Honjo et al. first identified non-synonymous SNP of V12M and Q141K. Login to comment
160 (23) The V12M polymorphism in exon 2 (34G >A) affects the N-terminal intracellular region of the protein. Login to comment
162 The V12M polymorphism was found in all ethnic groups tested, with the highest allele frequency in Mexican-Indians (90% of only five individuals tested), but only 1.7% in a Swedish population. Login to comment
164 Thus, there is a large difference in the allele frequency of the V12M polymorphism among different ethnic groups. Login to comment
169 The effect of camptothecin analogs on the growth of Flp-In-293/ABCG2 (wild type), Flp-In-293/ABCG2 (V12M) or Flp-In-293/ABCG2 (Q141K) cells. Login to comment
176 Resistance profile (IC50) of ABCG2 Compound IC50 (nM) Mock Wild type V12M Q141K F208S S248P F431L S441N F489L SN-38 0.9 40.0 (44.4) 40.0 (44.4) 17.0 (18.9) 0.6 (0.7) 3.0 (3.3) 10.0 (11.1) 0.7 (0.8) 3.1 (3.4) Mitoxantorone 5.2 >100 (>19) 92.0 (17.7) 45.0 (8.7) 4.5 (0.9) 11.0 (2.1) 21.0 (4.0) 4.6 (0.9) 11.0 (2.1) Doxorubicin 32.0 78.0 (2.4) 100.0 (3.1) 110.0 (3.4) 20.0 (0.6) 20.0 (0.6) 40.0 (1.3) 21.0 (0.7) 45.0 (1.4) Daunorubicin 12.0 30.0 (2.5) 50.0 (4.2) 50.0 (4.2) 12.0 (1.0) 21.0 (1.8) 14.0 (1.2) 12.0 (1.0) 19.0 (1.6) Etoposide 110.0 200.0 (1.8) 220.0 (2.0) 200.0 (1.8) 110.0 (1.0) 120.0 (1.1) 120.0 (1.1) 130.0 (1.2) 170.0 (1.5) Vincristine 1.4 4.0 (2.9) 5.0 (3.6) 4.5 (3.2) 0.6 (0.4) 4.0 (2.9) 1.4 (1.0) 0.8 (0.6) 2.8 (2.0) Relative resistances to mock cells are described in parentheses. Login to comment
202 As one of the specific aims of the present study, we functionally classified the non-synonymous polymorphisms (V12M, Q141K, F208S, S248P, F431L, S441N and F489L) in terms of their protein expression level, drug resistance profile and prazosin-stimulated ATPase activity. Login to comment
206 As shown in Fig. 5B, it is obvious that WT, V12M and Q141K form one group where protein expression, methotrexate and porphyrin transport, and resistance to SN-38 and mitoxantrone are positive, but contribution to doxorubicin- and daurorubicin- Fig. 4. Login to comment
221 (32,33) As demonstrated in Fig. 3, the new camptothecin analogs that were non-substrates for ABCG2 circumvented ABCG2-mediated drug resistance without any influence from major SNP (i.e. V12M and Q141K). Login to comment

[hide] The identification of two germ-line mutations in t... Pharm Res. 2007 Jun;24(6):1108-17. Epub 2007 Mar 21. Yoshioka S, Katayama K, Okawa C, Takahashi S, Tsukahara S, Mitsuhashi J, Sugimoto Y
The identification of two germ-line mutations in the human breast cancer resistance protein gene that result in the expression of a low/non-functional protein.
Pharm Res. 2007 Jun;24(6):1108-17. Epub 2007 Mar 21., [PMID:17373578]

Abstract [show]
PURPOSE: We examined the effects of the nine nonsynonymous germ-line mutations/SNPs in the breast cancer resistance protein (BCRP/ABCG2) gene on the expression and function of the protein. MATERIALS AND METHODS: We generated cDNAs for each of these mutants (G151T, C458T, C496G, A616C, T623C, T742C, T1291C, A1768T, and G1858A BCRP) and compared the effects of their exogenous expression in PA317 cells with a wild-type control. RESULTS: PA/F208S cells (T623C BCRP-transfectants) expressed marginal levels of a BCRP protein species (65kDa), which is slightly smaller than wild-type (70kDa), but this mutant did not appear on the cell surface or confer drug resistance. PA/F431L cells (T1291C BCRP-transfectants) were found to express both 70 kDa and 65 kDa BCRP protein products. In addition, although PA/F431L cells expressed 70 kDa BCRP at comparable levels to PA/WT cells, they showed only marginal resistance to SN-38. PA/T153M cells (C458T BCRP-transfectants) and PA/D620N cells (G1858A BCRP-transfectants) expressed lower amounts of BCRP and showed lower levels of resistance to SN-38 compared with PA/WT cells. CONCLUSIONS: We have shown that T623C BCRP encodes a non-functional BCRP and that T1291C BCRP encodes a low-functional BCRP. Hence, these mutations may affect the pharmacokinetics of BCRP substrates in patients harboring these alleles.

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21 In our previous study, we identified three nonsynonymous SNPs within the BCRP gene, G34A substituting Met for Val-12 (V12M), C376T substituting a stop codon for Gln-126 (Q126Stop), and C421A substituting Lys for Gln141 (Q141K). Login to comment
42 The cells were selected with 120 ng/mL of methotrexate, and the resulting mixed populations of resistant cells were designated as PA/WT, PA/V12M, PA/ G51C, PA/Q141K, PA/T153M, PA/I206L, PA/F208S, PA/ S248P, PA/F431L, PA/N590Y and PA/D620N, respectively. The PA/F208S clones and PA/F431L clones were obtained by limiting dilution. Login to comment
43 Cell Growth Inhibition Assay Anticancer agent resistance levels in both the parental PA317 cells and in the various BCRP transfectants were Table I. Frequencies of Germ-line Mutations/SNPs Within The BCRP Gene Variation Frequency (%) Number Population Reference Nucleotide Amino acid G34A V12M 19 29 Japanese 17 G151T G51C 0.1a 350 Japanese C376T Q126Stop 1.2 124 Japanese 17 C421A Q141K 26.6 124 Japanese 17 C458T T153M 3.3 30 Cell line 32 C496G Q166E 0.3a 200 Japanese A616C I206L 20 10 Hispanic 33 T623C F208S 0.3a 200 Japanese T742C S248P 0.5a 200 Japanese T1291C F431L 0.6b 260 Japanese 34 A1768T N590Y 1.1 88 Caucasians 33 G1858A D620N 1.1 90 unknown 35 a Determined in this study. Login to comment
45 V12M Q141K D620N N590Y F431L S248P F208S I206L T153M G51C Q166E OUT MEMBRANE IN Fig. 1. Login to comment
75 SN-38 Resistance Levels of PA317 Transfectantsa Cell type IC50 (nmol/L) Degree of resistance PA317 11 T 0.2 1 PA/WT 550 T 16 50 PA/V12M 490 T 13 45 PA/Q141K 110 T 5.9 10 PA/T153M 260 T 15 24 PA/Q166E 680 T 40 62 PA/F208S 10 T 0.7 1 PA/F431L 34 T 0.9 3 PA/D620N 190 T 5.7 17 a Cells were cultured for 5 days with various concentrations of SN-38. Login to comment
85 Similar to previous findings (14), PA/V12M cells were observed to express similar amounts of BCRP compared with PA/WT cells, whereas PA/Q141K cells expressed significantly lower amounts of BCRP than PA/WT (Fig. 2a). Login to comment
130 The resulting mixed populations of cells were designated a PA/WT, PA/V12M, PA/G51C, PA/Q141K, PA/ T153M, PA/I206L, PA/F208S, PA/S248P, PA/F431L, PA/ N590Y and PA/D620N. Login to comment

[hide] The emerging pharmacotherapeutic significance of t... Br J Pharmacol. 2007 May;151(2):163-74. Epub 2007 Mar 20. Hardwick LJ, Velamakanni S, van Veen HW
The emerging pharmacotherapeutic significance of the breast cancer resistance protein (ABCG2).
Br J Pharmacol. 2007 May;151(2):163-74. Epub 2007 Mar 20., [PMID:17375082]

Abstract [show]
The breast cancer resistance protein (also termed ABCG2) is an ATP-binding cassette transporter, which mediates the extrusion of toxic compounds from the cell, and which was originally identified in relation to the development of multidrug resistance of cancer cells. ABCG2 interacts with a range of substrates including clinical drugs but also substances such as sterols, porphyrins and a variety of dietary compounds. Physiological functions of ABCG2 at both cellular and systemic levels are reviewed. For example, ABCG2 expression in erythrocytes may function in porphyrin homeostasis. In addition, ABCG2 expression at apical membranes of cells such as hepatocytes, enterocytes, endothelial and syncytiotrophoblast cells may correlate to protective barrier or secretory functions against environmental or clinically administered substances. ABCG2 also appears influential in the inter-patient variation and generally poor oral bioavailability of certain chemotherapeutic drugs such as topotecan. As this often precludes an oral drug administration strategy, genotypic and environmental factors altering ABCG2 expression and activity are considered. Finally, clinical modulation of ABCG2 activity is discussed. Some of the more recent strategies include co-administered modulating agents, hammerhead ribozymes or antisense oligonucleotides, and with specificity in cell targeting, these may be used to reduce drug resistance and increase drug bioavailability to improve the profile of chemotherapeutic efficacy versus toxicity. While many such strategies remain in relative infancy at present, increased knowledge of modulators of ABCG2 could hold the key to novel approaches in medical treatment.

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145 Imai et al. (2002a) sequenced cDNA from 11 human tumours and identified SNPs G34A (V12M) and C421A (Q141K), a splice variant 944-949 deletion (A315- T316), and later, an additional C376T (G126Stop) polymorphism. Login to comment

[hide] BCRP gene polymorphisms are associated with suscep... Carcinogenesis. 2007 Aug;28(8):1740-4. Epub 2007 May 10. Hu LL, Wang XX, Chen X, Chang J, Li C, Zhang Y, Yang J, Jiang W, Zhuang SM
BCRP gene polymorphisms are associated with susceptibility and survival of diffuse large B-cell lymphoma.
Carcinogenesis. 2007 Aug;28(8):1740-4. Epub 2007 May 10., [PMID:17494054]

Abstract [show]
To date, the biological significance of breast cancer resistance protein (BCRP) G34A and C421A polymorphisms is largely unknown. Analysis of these two polymorphisms in 156 diffuse large B-cell lymphoma (DLBCL) patients and 376 control subjects revealed an increased risk of DLBCL associated with variant BCRP 421 genotypes (CA and AA), when compared with the wild-type CC genotype [odds ratio = 1.49, 95% confidence interval (CI) 1.02-2.17, P = 0.042]. Moreover, the increased risk was more evident in younger patients (<or=50 years, odds ratio = 2.14, 95% CI 1.25-3.68, P = 0.006). Further evaluation for the association of these polymorphisms with overall survival of DLBCL showed that patients with 34AA alleles displayed worse survival compared with those carrying GG/GA genotypes [hazard ratio (HR) = 3.69, 95% CI 1.56-8.71, P = 0.001]. Significant association between 421CC genotypes and poorer survival of DLBCL was observed in patients younger at diagnosis (<or=50 years, HR = 5.80, 95% CI 1.16-28.90, P = 0.015) or with bulky tumor (HR = 4.36, 95% CI 1.04-18.31, P = 0.027). Furthermore, we found the combined effects of BCRP G34A and C421A on the overall survival. Compared with patients carrying BCRP 34(GG + GA)421(AA + CA) genotype, the individual with 34AA421CC displayed the worst survival (HR = 7.55, 95% CI 2.36-24.17, P = 0.001), while those with 34(GG + GA)421CC and 34AA421(AA + CA) combinations showed the intermediate survival. These results suggest that the BCRP G34A and C421A polymorphisms are associated with the risk and survival of DLBCL. Our finding warrants further investigations on the association of BCRP polymorphisms with susceptibility and clinical outcome of cancer.

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18 BCRP G34A (Val12Met) and C421A (Gln141Lys) polymorphisms occurred at high frequency in most ethnic populations and have been shown to be associated with the expression and activity of BCRP protein. Login to comment
21 Based on these evidences, we hypothesize that BCRP G34A (Val12Met) and C421A (Gln141Lys) polymorphisms should have potential effect on the susceptibility and prognosis of diseases. Login to comment

[hide] Evaluation of drug-transporter interactions using ... Curr Drug Metab. 2007 May;8(4):341-63. Xia CQ, Milton MN, Gan LS
Evaluation of drug-transporter interactions using in vitro and in vivo models.
Curr Drug Metab. 2007 May;8(4):341-63., [PMID:17504223]

Abstract [show]
Drug transporters, including efflux transporters (the ATP binding cassette (ABC) proteins) and uptake transporters (the solute carrier proteins (SLC)), have an important impact on drug disposition, efficacy, drug-drug interactions and toxicity. Identification of the interactions of chemical scaffolds with transporters at the early stages of drug development can assist in the optimization and selection of new drug candidates. In this review, we discuss current in vitro and in vivo models used to investigate the interactions between drugs and transporters such as P-gp, MRP, BCRP, BSEP, OAT, OATP, OCT, NTCP, PEPT1/2 and NT. In vitro models including cell-based, cell-free, and yeast systems as well as in vivo models such as genetic knockout, gene deficient and chemical knockout animals are discussed and compared. The applications, throughput, advantages and limitations of each model are also addressed in this review.

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119 The function of seven single nucleotide polymorphisms (SNPs) in BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S, and S441N BCRP) was determined using membrane vesicles from HEK293 cells infected with the recombinant adenoviruses containing the corresponding BCRP cDNAs [45]. Login to comment
121 Furthermore, the transport rate of estrone sulfate, dehydroepiandrosterone sulfate (DHEAS), methotrexate, and p-aminohippurate was almost the same for the wild type, V12M, Q141K, A149P, R163K, Q166E, and P269S BCRP variants when it is normalized by the expression levels of BCRP protein. Login to comment

[hide] ATP-binding cassette transporter ABCG2 (BCRP) and ... Scand J Gastroenterol. 2007 Jun;42(6):726-33. Fischer S, Lakatos PL, Lakatos L, Kovacs A, Molnar T, Altorjay I, Papp M, Szilvasi A, Tulassay Z, Osztovits J, Papp J, Demeter P, Schwab R, Tordai A, Andrikovics H
ATP-binding cassette transporter ABCG2 (BCRP) and ABCB1 (MDR1) variants are not associated with disease susceptibility, disease phenotype response to medical therapy or need for surgeryin Hungarian patients with inflammatory bowel diseases.
Scand J Gastroenterol. 2007 Jun;42(6):726-33., [PMID:17505995]

Abstract [show]
OBJECTIVE: MDR1 (ABCB1), a member of the ATP-binding cassette (ABC) transporters, is an attractive candidate gene for the pathogenesis of inflammatory bowel diseases (IBD) and perhaps for response to therapy. Since limited data are available on MDR1 and ABCG2 polymorphisms in East European IBD patients, the aim of this study was to investigate ABCG2 and MDR1 variants and responses to medical therapy and/or disease phenotype in Hungarian patients. MATERIAL AND METHODS: A total of 414 unrelated IBD patients (Crohn's disease (CD): 265, age: 35.2+/-12.1 years, duration: 8.7+/-7.6 years and ulcerative colitis (UC): 149, age: 44.4+/-15.4 years, duration: 10.7+/-8.9 years) and 149 healthy subjects were investigated. ABCG2 G34A, C421A and MDR1 C3435T, G2677T/A single nucleotide polymorphisms (SNPs) were detected using real-time polymerase chain reaction (PCR). Detailed clinical phenotypes were determined by reviewing the medical charts. RESULTS: The frequency of the ABCG2 and MDR1 SNPs was not significantly different among IBD, CD, UC patients and controls. There was no difference in risk for steroid resistance in CD patients carrying variant ABCG2 (19.6% versus non-carriers 18.4%, p=NS) or MDR1 3435T (CC: 22.2% versus CT/TT: 17.6%) alleles. In addition, carriage of the variant allele was not associated with disease phenotype, presence of extra-intestinal manifestations, smoking, response to infliximab therapy or the need for surgery. In UC, the carriage of variant ABCG2 alleles seemed to be preventive for arthritis (15.5% versus 31.7%, OR: 0.39, 95% CI: 0.16-0.98). CONCLUSIONS: MDR1 and ABCG2 SNPs were not associated with disease susceptibility or disease phenotype in Hungarian patients, and variant alleles did not predict the response to medical therapy or the need for surgery. Further studies are needed to clarify the association between the presence of ABCG2 variants and arthritis in UC.

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60 Detection of MDR1 and ABCG2 polymorphisms The sequence variants (SNPs) of the two ABC transporters studied were: ABCB1 (MDR1): c.2677G/T/A or G2677T/A (Ala893Ser/Thr, exon 21, SNP database ID: rs2032582) and c.3435C/T or C3435T (silent base-substitution I1145I, exon 26, SNP database ID: rs1045642); ABCG2 (BCRP/MXR): c.34G/A or G34A (Val12Met, exon 2, SNP database ID: rs2231137; c.421C/A or C421A (Gln141Lys, exon 5, SNP database ID: rs2231142). Login to comment

[hide] Concordance of pharmacogenetic polymorphisms in tu... Cancer Epidemiol Biomarkers Prev. 2007 May;16(5):1038-41. Weiss JR, Baer MR, Ambrosone CB, Blanco JG, Hutson A, Ford LA, Moysich KB
Concordance of pharmacogenetic polymorphisms in tumor and germ line DNA in adult patients with acute myeloid leukemia.
Cancer Epidemiol Biomarkers Prev. 2007 May;16(5):1038-41., [PMID:17507636]

Abstract [show]
Archived tumor tissue is a useful resource for retrospective studies addressing relationships between genetic polymorphisms and treatment outcomes. However, genotypes determined in tumor and somatic tissues may differ due to cytogenetic and molecular changes associated with malignant transformation and progression. Discordance between germ line and tumor genotypes may be particularly relevant in leukemia because cytogenetic abnormalities are frequent. We compared genotypes determined in DNA extracted from paired pretreatment bone marrow and buccal samples from 80 adult patients with acute myeloid leukemia (AML). Paired AML and buccal DNA samples were genotyped for polymorphisms (21 single nucleotide polymorphisms and 2 gene deletions) on genes encoding proteins involved in drug metabolism (CYP3A4, CYP2C8, CDA, and GSTP1), oxidative stress mechanisms (CAT, MnSOD, GSTT1, GSTM1, GSTA1, and GPX1), drug transport (MDR1, MRP1, and BCRP), and DNA repair (MGMT, XPD, and XRCC1). Genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, except GSTM1 and GSTT1, for which deletion genotypes were determined using multiplex PCR. Concordance of genotypes was tested by kappa statistics. kappa statistics for paired AML and buccal DNA samples ranged between 0.94 and 1.00, indicating excellent agreement. The GSTT1 and GSTM1 genotypes were in perfect concordance for the paired samples. Agreement was also excellent for genes at AML chromosome deletion and translocation breakpoints, including MDR1 at 7q21.1 and MRP1 at 16p13.1. Based on these data, genotypes derived from archived AML bone marrow samples were not likely to differ from those from genomic DNA, and archived bone marrow samples may be useful for the conduct of retrospective pharmacogenetic studies.

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60 Gene information and K statistics for matched AML and buccal DNA samples (N = 80) Gene Single nucleotide polymorphism location Chromosome rs nos. j Asymptotic error Confidence interval No. of evaluable cases (%) No. of nonmatching genotype calls ABCB1-03 Ex27-55A>C>G>T; I1144M 7q21.1 rs1045642 1.00 77 (96.3) 0 ABCB1-05 Ex22-9A>C>G>T; A892S 7q21.1 rs2032582 0.96 0.031 0.89-1.02 76 (95.0) 2 ABCB1-24 Ex13+12 A>G; G412G 7q21.1 rs1128503 0.98 0.023 0.95-1.02 76 (95.0) 1 ABCC1 Ex8 T825C; V275V 16p13.1 rs246221 1.00 76 (95.0) 0 ABCC1 Ex28 G4002A; S1334S 16p13.1 rs2230671 1.00 78 (97.5) 0 ABCC1 Ex9 T1062C; L562L 16p13.1 rs35587 0.98 0.022 0.93-1.02 77 (96.3) 1 ABCG2 Ex5 C421A; Q141K 4q22 rs2231142 1.00 75 (93.8) 0 ABCG2 Ex2 G34A; V12M 4q22 rs2231137 1.00 75 (93.8) 0 CAT-01 À329T>C 11p13 rs1001179 1.00 78 (97.5) 0 GPX1-01 Ex1-226C>T; P200L 3p21.3 rs1050450 0.96 0.029 0.90-1.02 79 (98.8) 2 SOD2-01 Ex2+24C>T; V16A 6q25.3 rs1799725 0.98 0.020 0.94-1.02 77 (96.3) 1 GSTA1-01 À4621T>C 6p12.1 rs3957357 1.00 78 (97.5) 0 GSTP1-01 Ex5-24A>G; I105V 11q13 rs947894 0.96 0.030 0.90-1.02 78 (97.5) 2 GSTM1 Gene deletion 1p13.3 1.00 77 (96.3) 0 GSTT1 Gene deletion 22q11.23 1.00 77 (96.3) 0 CYP3A4-02 À391A>G 7q21.1 rs2740574 0.94 0.053 0.89-1.05 77 (96.3) 1 CYP2C8 A1196G; R399K 10q23.33 rs10509681 0.96 0.040 0.88-1.04 77 (96.3) 1 CYP2C8 C792G; M264I 10q23.33 rs1058930 0.96 0.041 0.88-1.04 77 (96.3) 1 MGMT-01 Ex4-13A>G; I143V 10q26 rs2308321 1.00 80 (100.0) 0 XPD312 Ex10-16G>A; D312N 19q13.3 rs1799793 1.00 73 (91.3) 0 XPD751 Ex23-61A>C; K751Q 19q13.3 rs13181 0.98 0.022 0.93-1.02 76 (95.0) 1 XRCC1 Ex10-4A>G; Q399R 19q13.2 rs25487 1.00 74 (92.5) 0 CDA A79C; K27Q 1p36.2-p35 rs2072671 1.00 77 (96.3) 0 NOTE: Values of n: j > 0.75 (excellent agreement beyond chance), j between 0.40 and 0.75 (fair to good agreement), j < 0.40 (poor agreement). Login to comment
62 j Asymptotic error Confidence interval No. of evaluable cases (%) No. of nonmatching genotype calls ABCB1-03 Ex27-55A>C>G>T; I1144M 7q21.1 rs1045642 1.00 77 (96.3) 0 ABCB1-05 Ex22-9A>C>G>T; A892S 7q21.1 rs2032582 0.96 0.031 0.89-1.02 76 (95.0) 2 ABCB1-24 Ex13+12 A>G; G412G 7q21.1 rs1128503 0.98 0.023 0.95-1.02 76 (95.0) 1 ABCC1 Ex8 T825C; V275V 16p13.1 rs246221 1.00 76 (95.0) 0 ABCC1 Ex28 G4002A; S1334S 16p13.1 rs2230671 1.00 78 (97.5) 0 ABCC1 Ex9 T1062C; L562L 16p13.1 rs35587 0.98 0.022 0.93-1.02 77 (96.3) 1 ABCG2 Ex5 C421A; Q141K 4q22 rs2231142 1.00 75 (93.8) 0 ABCG2 Ex2 G34A; V12M 4q22 rs2231137 1.00 75 (93.8) 0 CAT-01 À329T>C 11p13 rs1001179 1.00 78 (97.5) 0 GPX1-01 Ex1-226C>T; P200L 3p21.3 rs1050450 0.96 0.029 0.90-1.02 79 (98.8) 2 SOD2-01 Ex2+24C>T; V16A 6q25.3 rs1799725 0.98 0.020 0.94-1.02 77 (96.3) 1 GSTA1-01 À4621T>C 6p12.1 rs3957357 1.00 78 (97.5) 0 GSTP1-01 Ex5-24A>G; I105V 11q13 rs947894 0.96 0.030 0.90-1.02 78 (97.5) 2 GSTM1 Gene deletion 1p13.3 1.00 77 (96.3) 0 GSTT1 Gene deletion 22q11.23 1.00 77 (96.3) 0 CYP3A4-02 À391A>G 7q21.1 rs2740574 0.94 0.053 0.89-1.05 77 (96.3) 1 CYP2C8 A1196G; R399K 10q23.33 rs10509681 0.96 0.040 0.88-1.04 77 (96.3) 1 CYP2C8 C792G; M264I 10q23.33 rs1058930 0.96 0.041 0.88-1.04 77 (96.3) 1 MGMT-01 Ex4-13A>G; I143V 10q26 rs2308321 1.00 80 (100.0) 0 XPD312 Ex10-16G>A; D312N 19q13.3 rs1799793 1.00 73 (91.3) 0 XPD751 Ex23-61A>C; K751Q 19q13.3 rs13181 0.98 0.022 0.93-1.02 76 (95.0) 1 XRCC1 Ex10-4A>G; Q399R 19q13.2 rs25487 1.00 74 (92.5) 0 CDA A79C; K27Q 1p36.2-p35 rs2072671 1.00 77 (96.3) 0 NOTE: Values of n: j > 0.75 (excellent agreement beyond chance), j between 0.40 and 0.75 (fair to good agreement), j < 0.40 (poor agreement). Login to comment

[hide] The effect of ABCG2 V12M, Q141K and Q126X, known f... Br J Clin Pharmacol. 2007 Nov;64(5):645-54. Epub 2007 May 17. Kim HS, Sunwoo YE, Ryu JY, Kang HJ, Jung HE, Song IS, Kim EY, Shim JC, Shon JH, Shin JG
The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine.
Br J Clin Pharmacol. 2007 Nov;64(5):645-54. Epub 2007 May 17., [PMID:17509035]

Abstract [show]
AIMS: To evaluate the effects of three ABCG2 variants (Q141K, V12M and Q126X), which are known to have altered transport properties in vitro, on the disposition of lamivudine in healthy subjects. METHODS: To evaluate whether lamivudine is a substrate of ABCG2, intracellular accumulation and vectorial transport of 3H-lamivudine were determined in MDCK-ABCG2 cells. The pharmacokinetic parameters of lamivudine were compared among subjects with four different ABCG2 genotypes, including wild type (seven subjects), K141/K141 (six subjects), Q126/Stop126 (four subjects) and M12/M12 (five subjects) after a single oral dose of 100 mg lamivudine. RESULTS: The intracellular accumulation of lamivudine in MDCK-ABCG2 cells was significantly lower than that in MDCK-mock cells, but fumitremorgin C reversed the intracellular lamivudine concentration to that of MDCK-mock cells. The ABCG2-mediated transport of lamivudine was saturable and the values of Km and Vmax were 216.5 +/- 58 microm and 20.42 +/- 2.9 nmol h(-1) per 10(6) cells, respectively. After lamivudine administration to healthy subjects, the AUC of lamivudine showed no difference among subjects with different ABCG2 genotypes; 2480 +/- 502, 2207 +/- 1019, 2422 +/- 239, 2552 +/- 698 ng h(-1) ml(-1) for wild type, K141/K141, Q126/Stop126 and M12/M12 genotype, respectively (P = 0.85). The estimated 95% confidence intervals for the mean difference between K141/K141, Q126/Stop126, M12/M12 and wild as reference were (-1053, 507), (-555, 439) and (-552, 696), respectively. No other pharmacokinetic parameters were estimated to be significantly different among four different ABCG2 genotypes tested. CONCLUSIONS: Lamivudine appeared to be a substrate of ABCG2 in vitro, but the disposition of lamivudine was not significantly influenced by known in vitro functional variants of ABCG2, Q141K, V12M and Q126X in healthy subjects.

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0 The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine Ho-Sook Kim,1 Yu Eun Sunwoo,1 Ji Young Ryu,1 Ho-Jin Kang,1 Hye-Eun Jung,1 Im-Sook Song,1 Eun-Young Kim,1,2 Joo-Cheol Shim,1,3 Ji-Hong Shon1,2 & Jae-Gook Shin1,2 1 Department of Pharmacology and Pharmacogenomics Research Centre, Inje University College of Medicine, 2 Department of Clinical Pharmacology and 3 Department of Psychiatry, Inje University Busan Paik Hosptial, Busan, Korea Correspondence Jae-Gook Shin, MD, PhD, Department of Pharmacology and Clinical Pharmacology, Pharmacogenomics Research Centre, Inje University College of Medicine, 633-165 Gaegum-dong, Jin-gu, Busan 614-735, Korea. Login to comment
2 Received 19 September 2006 Accepted 15 March 2007 Published OnlineEarly 17 May 2007 Aims To evaluate the effects of three ABCG2 variants (Q141K, V12M and Q126X), which are known to have altered transport properties in vitro, on the disposition of lamivudine in healthy subjects. Login to comment
10 Conclusions Lamivudine appeared to be a substrate of ABCG2 in vitro, but the disposition of lamivudine was not significantly influenced by known in vitro functional variants of ABCG2, Q141K, V12M and Q126X in healthy subjects. Login to comment
23 It has also been reported that the ABCG2 G34A allele, resulting in a Val12Met substitution, causes the apical plasma membrane dislocalization of ABCG2 and produces a protein with significantly reduced ability to transport several drugs [15]. Login to comment
53 Weighted nonlinear regression analysis was performed in the fitting using Sigma plot (version 9.0; Systat Software Inc., Richmond, CA, USA) Subjects Unrelated Korean subjects (n = 183) had been genotyped for theABCG2 variants G34A(Val12Met), C376T (Gln126stop) and C421A (Gln141Lys). Login to comment
62 ABCG2 gene to determine the presence of the Val12Met, Gln126Stop and Gln141Lys alleles. Login to comment
85 After washing Table 2 Sequences of primers used for the amplification and sequencing analysis of ABCG2 genotype and the denaturation temperatures used in the PCR Name Primer sequence (5Ј,3Ј) Size PCR ( Tm; °C) ABCG2 V12M F: Biotin-CTCTCCAGATGTCTTCCAGTAATG 278 54 R: GCCAAAACCTGTGAGGTTCA S: CATTGGTGTTTCCTTGTGA ABCG2 Q126X F: GTCTTAGCTGCAAGGAAAGATCCA 174 54.5 R: Biotin-ACTATCAGCCAAAGCACTTACCC S: AATGTAATTCAGGTTACGTG ABCG2 Q141K F: TGATGTTGTGATGGGCACTC 69 54 R: Biotin-GTTGCAAGCCGAAGAGCTG S: GACGGTGAGAGAAAACTT F, forward primer; R, reverse primer; S, sequencing primer; Tm, melting temperature; PCR, polymerase chain reaction. Login to comment
116 Effect of ABCG2 variants on the pharmacokinetics of lamivudine To study the influence of ABCG2 variants on lamivudine pharmacokinetics, we included subjects with the Val12Met, Gln126Stop or Gln141Lys ABCG2 variants. Login to comment
135 The Val12Met polymorphism has also been associated with change in membrane localization and produces a protein with significantly decreased activity in transporting several Table3 Pharmacokineticparametersoflamivudineaftersingleoraladministrationof100mglamivudineinsubjectswithwild,Lys141/Lys141,Gln126/Stop126and Met12/Met12variantofABCG2 WildMet12/Met12Gln126/Stop126Lys141/Lys141 Meandifferencebetweenvariantsandwild P-valueMet12/Met12Gln126/Stop126Lys141/Lys141 Cmax(ngml-1 )742Ϯ297808Ϯ193840Ϯ151655Ϯ30966(-210,342)98(-198,394)-87(-389,215)0.68 Cmax,normal(ngml-1 )*736Ϯ303850Ϯ208926Ϯ230746Ϯ320114(-171,399)190(-133,513)10(-300,320)0.57 tmax(h)0.8Ϯ0.41.0Ϯ0.30.7Ϯ0.30.8Ϯ0.40.2(-0.2,0.6)-0.1(-0.5,0.3)0(-0.4,0.4)0.63 t1/2(h)5.5Ϯ2.47.1Ϯ2.05.5Ϯ2.17.7Ϯ4.91.6(-0.8,4)0(-2.6,2.6)2.2(-1.5,5.9)0.59 AUCinf(ngh-1 ml-1 )2480Ϯ5022552Ϯ6982422Ϯ2392207Ϯ101972(-552,696)-58(-555,439)-273(-1053,507)0.85 AUCinf,normal(ngh-1 ml-1 )*2440Ϯ3972604Ϯ5822654Ϯ3192573Ϯ1326164(-345,673)214(-214,642)133(-807,1073)0.69 CLtotal/F(lkg-1 h-1 )0.60Ϯ0.120.59Ϯ0.120.54Ϯ0.070.66Ϯ0.25-0.01(-0.14,0.12)-0.06(-0.18,0.06)0.06(-0.13,0.25)0.76 CLR(lkg-1 h-1 )0.29Ϯ0.050.26Ϯ0.050.26Ϯ0.050.28Ϯ0.09-0.03(-0.08,0.02)-0.03(-0.09,0.03)-0.01(-0.08,0.06)0.85 Vd/F(lkg-1 )4.8Ϯ2.65.9Ϯ1.44.2Ϯ1.24.7Ϯ2.41.1(-1.2,3.4)-0.6(-3.2,2.0)-0.1(-2.6,2.4)0.66 *Cmax,normalandAUCinf,normal:CmaxandAUCinfnormalizedto70kgbodyweight.EachvalueindicatesmeanϮSD(95%confidenceinterval). Login to comment
138 The ABCG2 Val12Met and Gln141Lys variants are common in Koreans, with allelic frequencies of 23 and 27.5%, respectively. Login to comment
157 Anderson et al. have recently shown that the intracellular concentration of lamivudine-triphosphate is not associated with ABCG2 Val12Met, Glu141Lys [33]. Login to comment
165 However, the Val12Met, Gln126stop and Gln141Lys polymorphisms of ABCG2 studied here, which have been previously shown to cause functional differences in the protein, did not alter the disposition of a single oral dose of 100 mg lamivudine in healthy volunteers. Login to comment

[hide] Associations of ABCB1, ABCC2, and ABCG2 polymorphi... Cancer. 2007 Jul 1;110(1):138-47. Han JY, Lim HS, Yoo YK, Shin ES, Park YH, Lee SY, Lee JE, Lee DH, Kim HT, Lee JS
Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer.
Cancer. 2007 Jul 1;110(1):138-47., 2007-07-01 [PMID:17534875]

Abstract [show]
BACKGROUND: The authors investigated whether ABCB1, ABCC2, and ABCG2 genetic polymorphisms affect pharmacokinetics (PK) of irinotecan and treatment outcome of patients with advanced nonsmall cell lung cancer (NSCLC). METHODS: Blood samples from 107 NSCLC patients treated with irinotecan and cisplatin chemotherapy were used for genotyping ABCB1 (1236C > T, 2677G > T/A, 3435C > T), ABCC2 (-24C > T, 1249G > A, 3972C > T), and ABCG2 (34G > A, 421C > A) polymorphisms. Genotypes were correlated with irinotecan-PK, toxicity, tumor response, and survival. RESULTS: Among 8 polymorphisms, 3435TT and 2677TT were associated with AUC(SN-38G) and CL(SN-38G). When haplotypes are assigned, 2677TT/3435TT carriers showed significantly lower AUC(SN-38G) (P = .006), whereas 2677GG/3435CC carriers showed significantly higher AUC(SN-38) (P = .039). These findings suggest that 2677TT and 3435TT variants are associated with higher efflux activity. In toxicity, the 2677G/T or A was associated with grade 4 neutropenia. The 2677GG carriers showed significantly lower absolute neutrophil count during the 1(st) cycle (P = .012) as well as entire course of chemotherapy (P = .042). The 3435TT was associated with higher frequency of grade 3 diarrhea (P = .047). In tumor response, ABCC2 -24TT and 3972TT genotypes were associated with higher response rates (P = .031 and P = .048, [corrected] respectively) and longer progression-free survival (P = .010 and P = .019, [corrected] respectively), which was sustained in haplotype analysis. CONCLUSIONS: Specific polymorphisms of ABCB1 and ABCC2 can influence disposition and tumor response to irinotecan by regulating transporter activity. These findings may help to individualize irinotecan-based chemotherapy in patients with advanced NSCLC.

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81 of patients Genotype frequencies{ Allele frequencies§ w/w w/m m/m w m ABCB1 1236C > T Synonymous 105 14 57 34 0.405 0.595 2677G > T Ala893Ser 105 22 37 (GT) 10 (TT) 0.457 0.338 (T) 2677G > A Ala893Thr 15 (GA) 14 (TA) 0.205 (A) 7 (AA) 3435C > T Synonymous 105 43 51 11 0.652 0.348 ABCC2 À24C > T - 107 57 47 3 0.752 0.248 1249G > A Val417Ile 107 86 19 2 0.893 0.107 3972C > T Synonymous 107 51 48 8 0.701 0.299 ABCG2 34G > A Val12Met 106 60 41 5 0.759 0.241 421C > A Gln141Lys 105 59 42 4 0.762 0.238 w indicates wild type allele; m, mutant type allele. Login to comment

[hide] A polymorphism in the protease-like domain of apol... Arterioscler Thromb Vasc Biol. 2007 Sep;27(9):2030-6. Epub 2007 Jun 14. Luke MM, Kane JP, Liu DM, Rowland CM, Shiffman D, Cassano J, Catanese JJ, Pullinger CR, Leong DU, Arellano AR, Tong CH, Movsesyan I, Naya-Vigne J, Noordhof C, Feric NT, Malloy MJ, Topol EJ, Koschinsky ML, Devlin JJ, Ellis SG
A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease.
Arterioscler Thromb Vasc Biol. 2007 Sep;27(9):2030-6. Epub 2007 Jun 14., [PMID:17569884]

Abstract [show]
OBJECTIVES: The purpose of this study was to identify genetic variants associated with severe coronary artery disease (CAD). METHODS AND RESULTS: We used 3 case-control studies of white subjects whose severity of CAD was assessed by angiography. The first 2 studies were used to generate hypotheses that were then tested in the third study. We tested 12,077 putative functional single nucleotide polymorphisms (SNPs) in Study 1 (781 cases, 603 controls) and identified 302 SNPs nominally associated with severe CAD. Testing these 302 SNPs in Study 2 (471 cases, 298 controls), we found 5 (in LPA, CALM1, HAP1, AP3B1, and ABCG2) were nominally associated with severe CAD and had the same risk alleles in both studies. We then tested these 5 SNPs in Study 3 (554 cases, 373 controls). We found 1 SNP that was associated with severe CAD: LPA I4399M (rs3798220). LPA encodes apolipoprotein(a), a component of lipoprotein(a). I4399M is located in the protease-like domain of apolipoprotein(a). Compared with noncarriers, carriers of the 4399M risk allele (2.7% of controls) had an adjusted odds ratio for severe CAD of 3.14 (confidence interval 1.51 to 6.56), and had 5-fold higher median plasma lipoprotein(a) levels (P=0.003). CONCLUSIONS: The LPA I4399M SNP is associated with severe CAD and plasma lipoprotein(a) levels.

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99 Unadjusted Association of 5 SNPs With Severe CAD in Study 1 and Study 2 SNP ID Gene Symbol Chromosome Study Major Allele* Minor Allele* Type of SNP* Case AF† Control AF† OR‡ CI P Value§ rs3798220 LPA 6 1 A G I4399M 0.04 0.01 3.79 1.97-7.29 Ͻ0.001 2 A G 0.04 0.02 2.25 1.27-3.97 0.010 rs3814843 CALM1 14 1 T G 3ЈUTR 0.05 0.03 1.66 1.11-2.49 0.012 2 T G 0.06 0.04 1.74 1.13-2.67 0.020 rs4796603 HAP1 17 1 A T T58S 0.83 0.79 1.34 1.10-1.63 0.004 2 A T 0.83 0.78 1.36 1.09-1.68 0.012 rs6453373 AP3B1 5 1 A T E585V 0.94 0.92 1.51 1.11-2.04 0.008 2 A T 0.93 0.90 1.50 1.09-2.05 0.022 rs2231137 ABCG2 4 1 G A V12M 0.97 0.95 1.60 1.08-2.37 0.020 2 G A 0.96 0.94 1.62 1.10-2.38 0.028 *The polymorphic nucleotides on the sense strands are shown. Login to comment

[hide] Membrane cholesterol selectively modulates the act... Biochim Biophys Acta. 2007 Nov;1768(11):2698-713. Epub 2007 Jul 10. Telbisz A, Muller M, Ozvegy-Laczka C, Homolya L, Szente L, Varadi A, Sarkadi B
Membrane cholesterol selectively modulates the activity of the human ABCG2 multidrug transporter.
Biochim Biophys Acta. 2007 Nov;1768(11):2698-713. Epub 2007 Jul 10., [PMID:17662239]

Abstract [show]
The human ABCG2 multidrug transporter provides protection against numerous toxic compounds and causes multidrug resistance in cancer. Here we examined the effects of changes in membrane cholesterol on the function of this protein. Human ABCG2 was expressed in mammalian and in Sf9 insect cells, and membrane cholesterol depletion or enrichment was achieved by preincubation with beta cyclodextrin or its cholesterol-loaded form. We found that mild cholesterol depletion of intact mammalian cells inhibited ABCG2-dependent dye and drug extrusion in a reversible fashion, while the membrane localization of the transporter protein was unchanged. Cholesterol enrichment of cholesterol-poor Sf9 cell membrane vesicles greatly increased ABCG2-driven substrate uptake, substrate-stimulated ATPase activity, as well as the formation of a catalytic cycle intermediate (nucleotide trapping). Interestingly, modulation of membrane cholesterol did not significantly affect the function of the R482G or R482T substrate mutant ABCG2 variants, or that of the MDR1 transporter. The selective, major effect of membrane cholesterol on the wild-type ABCG2 suggests a regulation of the activity of this multidrug transporter during processing or in membrane micro-domain interactions. The experimental recognition of physiological and pharmacological substrates of ABCG2, as well as the fight against cancer multidrug resistance may be facilitated by demonstrating the key role of membrane cholesterol in this transport activity.

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30 There are several polymorphic variants of ABCG2 present in large percentage in the human population (e.g. V12M, Q141K), and the possible alterations in the transport capacity and substrate handling of these variants have been examined in numerous experimental systems [18-24]. Login to comment

[hide] Synergistic interaction of ABCB1 and ABCG2 polymo... Pharmacogenomics J. 2008 Oct;8(5):321-7. Erdilyi DJ, Kamory E, Csokay B, Andrikovics H, Tordai A, Kiss C, Filni-Semsei A, Janszky I, Zalka A, Fekete G, Falus A, Kovacs GT, Szalai C
Synergistic interaction of ABCB1 and ABCG2 polymorphisms predicts the prevalence of toxic encephalopathy during anticancer chemotherapy.
Pharmacogenomics J. 2008 Oct;8(5):321-7., [PMID:17938643]

Abstract [show]
Polymorphisms of the ABCB1 (MDR1) and ABCG2 (BCRP) genes were reported to alter the expression and function of these drug transporters. Both proteins are present at the main pharmacokinetic barriers including the blood-brain barrier. Data from 291 children with acute lymphoblastic leukaemia were analysed in this retrospective study. ABCB1 3435T>C, 2677G>T/A, 1236C>T and ABCG2 421C>A, 34G>A genotypes were determined. Encephalopathy episodes were more frequent among those with ABCB1 3435TT genotype than in the 3435CC/CT group (odds ratio (OR) 3.5; P=0.03). Patients with the ABCG2 421A allele tended to have more complications than wild type homozygotes (OR=2.0; P=0.25). The rate of the adverse effect was similar in those harbouring no or only one of the predisposing genotypes, that is, either ABCB1 3435TT or ABCG2 421AA/AC. However, significantly more children suffered encephalopathy in the group with both predisposing genotypes (OR=12.3; P=0.005). In conclusion, these variations exert synergistic effect in predisposing patients to toxic neurological complications of chemotherapy.

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23 According to the first theory this SNP and other variations (2677G4T/A and 1236C4T) in linkage disequilibrium are linked to a putative functional polymorphism that causes the differences observed.10 On the other hand it was shown that the 3435T mRNA is characterized by decreased stability, while the linked alleles themselves have no effect on gene expression.11 The ABCG2 34G4A and 421C4A are rare non-synonymous polymorphisms resulting in V12M and Q141K variations. Login to comment

[hide] ABC multidrug transporters: structure, function an... Pharmacogenomics. 2008 Jan;9(1):105-27. Sharom FJ
ABC multidrug transporters: structure, function and role in chemoresistance.
Pharmacogenomics. 2008 Jan;9(1):105-27., [PMID:18154452]

Abstract [show]
Three ATP-binding cassette (ABC)-superfamily multidrug efflux pumps are known to be responsible for chemoresistance; P-glycoprotein (ABCB1), MRP1 (ABCC1) and ABCG2 (BCRP). These transporters play an important role in normal physiology by protecting tissues from toxic xenobiotics and endogenous metabolites. Hydrophobic amphipathic compounds, including many clinically used drugs, interact with the substrate-binding pocket of these proteins via flexible hydrophobic and H-bonding interactions. These efflux pumps are expressed in many human tumors, where they likely contribute to resistance to chemotherapy treatment. However, the use of efflux-pump modulators in clinical cancer treatment has proved disappointing. Single nucleotide polymorphisms in ABC drug-efflux pumps may play a role in responses to drug therapy and disease susceptibility. The effect of various genotypes and haplotypes on the expression and function of these proteins is not yet clear, and their true impact remains controversial.

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355 Over 80 SNPs, missense, nonsense and frameshift mutations in the ABCG2 gene have been identified in different ethnic groups [23,170], including V12M (N-terminal cytosolic region), Q141K (NBD) and Q126stop (in which no active protein is produced). Login to comment
359 Compared with wild-type ABCG2, the Q141K variant displayed lower ATPase activity and lower mitoxantrone efflux when expressed in HEK-293 cells, whereas the V12M and D620N proteins showed little change [172]. Login to comment
360 Somewhat different results were reported by another group for the V12M and Q141K variants [173]. Login to comment
361 A recent study examined seven ABCG2 variants in detail, and found that cells expressing both V12M and Q141K had reduced resistance towards the drug SN-38 [174]. Login to comment

[hide] In vitro evaluation of photosensitivity risk relat... Drug Metab Pharmacokinet. 2007 Dec;22(6):428-40. Tamura A, Onishi Y, An R, Koshiba S, Wakabayashi K, Hoshijima K, Priebe W, Yoshida T, Kometani S, Matsubara T, Mikuriya K, Ishikawa T
In vitro evaluation of photosensitivity risk related to genetic polymorphisms of human ABC transporter ABCG2 and inhibition by drugs.
Drug Metab Pharmacokinet. 2007 Dec;22(6):428-40., [PMID:18159130]

Abstract [show]
Since porphyrins are regarded as endogenous substrates for the ATP-binding cassette (ABC) transporter ABCG2, it is hypothesized that functional impairment owing to genetic polymorphisms or inhibition of ABCG2 by drugs may result in a disruption of cellular porphyrin homeostasis. In the present study, we expressed ABCG2 genetic variants, i.e., V12M, Q141K, S441N, and F489L, as well as the wild type (WT) in Flp-In-293 cells to examine the hypothesis. Cells expressing S441N and F489L variants exhibited high levels of both cellularly accumulated pheophorbide a and photosensitivity, when those cells were incubated with pheophorbide a and irradiated with visible light. To further elucidate the significance of ABCG2 in cellular porphyrin homeostasis, we observed cellular accumulation and compartmentation of porphyrin and pheophorbide a by means of a new fluorescence microscopy technology, and found that accumulation of porphyrin and pheophorbide a in the cytoplasm compartment was maintained at low levels in Flp-In-293 cells expressing ABCG2 WT, V12M, or Q141K. When ABCG2 was inhibited by imatinib or novobiocin, however, those cells became sensitive to light. Based on these results, it is strongly suggested that certain genetic polymorphisms and/or inhibition of ABCG2 by drugs can enhance the potential risk of photosensitivity.

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8 In the present study, we expressed ABCG2 genetic variants, i.e., V12M, Q141K, S441N, and F489L, as well as the wild type (WT) in Flp-In-293 cells to examine the hypothesis. Login to comment
10 To further elucidate the signiˆcance of ABCG2 in cellular porphyrin homeostasis, we observed cellular accumulation and compartmentation of porphyrin and pheophorbide a by means of a new ‰uorescence microscopy technology, and found that accumulation of porphyrin and pheophorbide a in the cytoplasm compartment was maintained at low levels in Flp-In-293 cells expressing ABCG2 WT, V12M, or Q141K. Login to comment
98 Genetic polymorphisms of human ABCG2 and pheophorbide a-photosensitivity In vitro experiments SNP data IC50 (mM) Photosensitivity ratio (fold) Ethnic group N Allele frequency (z) Reference WT 3.0 1.0 - - - - V12M 4.1 0.7 Caucasian 546 5.6 22, 13, 21, 20, 14 Japanese 259 17.6 18, 22, 20 African 181 6.3 22, 20 Q141K 2.9 1.0 Caucasian 717 11.0 22, 13, 21, 15, 20, 14 Japanese 354 30.6 18, 22, 20 African 1213 1.4 22, 15, 14 S441N 0.5 6.0 Japanese 100 0.5 20 F489L 1.7 1.8 Japanese 160 0.6 19, 20 Pheophorbide a-photosensitivity ratios and IC50 values were determined from the data shown in Fig. 2B. 432 Ai TAMURA, et al. a Fluoroskan Ascent FL (Thermo Labsystems, Helsinki, Finland) (excitation at 405 nm; emission at 612 nm). Login to comment
99 Results Expression of ABCG2 WT and SNP variants in Flp-In-293 cells: In the present study, we aimed to examine the impact of hitherto reported major SNPs (V12M, Q141K, S441N, or F489L) on the photo-sensitivity. Login to comment
110 Figure 1B depicts the immuno‰uorescence images of Flp-In-293 cells expressing ABCG2 WT and those SNP variants (i.e., V12M, Q141K, S441N, and F489L) as well as mock vector-transfected cells (Flp-In-293/ Mock). Login to comment
114 In contrast, strong green ‰uorescence was observed at the plasma membrane and within intracellular compartments in Flp-In-293 cells expressing ABCG2 WT as well as the SNP variants of V12M, Q141K, and F489L. Login to comment
121 In contrast, intracellular accumulations of pheophorbide a in both Flp-In-293/ABCG2 (V12M) and Flp-In-293/ABCG2 (Q141K) cells were signiˆcantly lower, being similar to the levels observed in Flp-In-293/ABCG2 (WT) cells. Login to comment
122 It is suggested that two variants, V12M and Q141K, actively extruded pheophorbide a out of cells as did ABCG2 WT, 1. Login to comment
123 Expression of human ABCG2 WT, V12M, Q141K, S441N, and F489L in Flp-In-293 cells. Login to comment
130 Photosensitivity of Flp-In-293 cells expressing ABCG2 WT and SNP variants: Figure 2B demonstrates the cellular photosensitivity proˆles of Flp-In-293 cells expressing ABCG2 WT, V12M, Q141K, S441N, and F489L, as well as that of Flp-In-293/Mock cells. Login to comment
136 Flp-In-293/Mock and Flp-In-293/ABCG2 (S441N) cells were very sensitive to light, whereas Flp-In-293/ABCG2 (V12M), Flp-In-293/ABCG2 (Q141K), and Flp-In-293/ABCG2 (WT) cells were signiˆcantly more resistant. Login to comment
141 A, Flp-In-293 cells expressing human ABCG2 WT and SNP variants (V12M, Q141K, S441N, and F489L) were incubated with pheophorbide a at diŠerent concentrations (0, 0.63, 1.25, and 2.5 mM) at 379C for 4 hours. Login to comment

[hide] Association of breast cancer resistance protein/AB... Drug Metab Dispos. 2008 Apr;36(4):780-95. Epub 2008 Jan 7. Poonkuzhali B, Lamba J, Strom S, Sparreboom A, Thummel K, Watkins P, Schuetz E
Association of breast cancer resistance protein/ABCG2 phenotypes and novel promoter and intron 1 single nucleotide polymorphisms.
Drug Metab Dispos. 2008 Apr;36(4):780-95. Epub 2008 Jan 7., [PMID:18180275]

Abstract [show]
The hypothesis was tested that sequence diversity in breast cancer resistance protein (BCRP)'s cis-regulatory region is a significant determinant of BCRP expression. The BCRP promoter and intron 1 were resequenced in lymphoblast DNA from the polymorphism discovery resource (PDR) 44 subset. BCRP single nucleotide polymorphisms (SNPs) were genotyped in donor human livers, intestines, and lymphoblasts quantitatively phenotyped for BCRP mRNA expression. Carriers of the -15622C>T SNP had lower BCRP expression in multiple tissues. The intron 1 SNP 16702C>T was associated with high expression in livers; 1143G>A was associated with low expression in intestine; 12283T>C was associated with higher expression in the PDR44 and White livers. The -15994C>T promoter SNP was significantly associated with higher BCRP expression in multiple tissues. Patients with the -15994C>T genotype had substantially higher clearance of p.o. imatinib. We next determined whether BCRP expression was related to polymorphic alternative splicing or alternative promoter use. Liver polymorphically expressed an alternatively spliced mRNA [splice variant (SV) 1] skipping exon 2. Although SV1+ livers did not uniformly carry the exon 2 G34A allele, 90% of G34A livers expressed SV1 (versus 4% of 34GG livers). BCRP mRNA was significantly lower among Hispanic livers with the G34A variant genotype and may be due, in part, to polymorphic exon 2 splicing. Analysis of allele expression imbalance (AEI) showed that PDR44 samples with AEI had lower BCRP mRNA expression; however, no linked cis-polymorphisms were identified. BCRP used multiple promoters, and livers differentially using alternative exon 1b had lower BCRP. In conclusion, BCRP expression in lymphoblasts, liver, and intestine is associated with novel promoter and intron 1 SNPs.

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32 Among the coding single nucleotide polymorphisms (SNPs), G34A (V12M) in exon 2 and C421A (Q141K) in exon 5 occur in most racial groups but with a higher allele frequency in Asians and Hispanics. Login to comment

[hide] BCRP/ABCG2 in the placenta: expression, function a... Pharm Res. 2008 Jun;25(6):1244-55. Mao Q
BCRP/ABCG2 in the placenta: expression, function and regulation.
Pharm Res. 2008 Jun;25(6):1244-55., [PMID:18202831]

Abstract [show]
Knowledge concerning transport of maternally administered drugs across the placental barrier is essential for determining potential toxicity of drugs to the fetus and the value of drug therapy during pregnancy. An important determinant for fetal drug exposure is the expression of efflux transporters in the placenta. Among human tissues, the ATP-binding cassette efflux transporter BCRP (gene symbol ABCG2) is most abundantly expressed in the apical membrane of placental syncytiotrophoblasts. Although the precise physiological role of BCRP in the placenta is still unclear, existing data strongly suggest that BCRP plays an important role in protecting the fetus against the potential toxicity of drugs, xenobiotics, and metabolites by expelling them across the placental barrier. In this review, we summarize the current knowledge with respect to the expression, function, and polymorphisms of BCRP, as well as transcriptional and posttranscriptional regulation of the transporter in the placenta. Finally, clinical significance of BCRP in the placenta for drug therapy in pregnant women is discussed.

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138 Notably, the single nucleotide polymorphisms (SNPs) G34A and C421A, resulting in alterations of BCRP protein at position 12 (V12M) and 141 (Q141K), respectively, occur at a relatively high frequency in most ethnic populations. Login to comment

[hide] Ubiquitin-mediated proteasomal degradation of non-... Biochem J. 2008 May 1;411(3):623-31. Nakagawa H, Tamura A, Wakabayashi K, Hoshijima K, Komada M, Yoshida T, Kometani S, Matsubara T, Mikuriya K, Ishikawa T
Ubiquitin-mediated proteasomal degradation of non-synonymous SNP variants of human ABC transporter ABCG2.
Biochem J. 2008 May 1;411(3):623-31., 2008-05-01 [PMID:18237272]

Abstract [show]
Clinical relevance is implicated between the genetic polymorphisms of the ABC (ATP-binding cassette) transporter ABCG2 (ABC subfamily G, member 2) and the individual differences in drug response. We expressed a total of seven non-synonymous SNP (single nucleotide polymorphism) variants in Flp-In-293 cells by using the Flp (flippase) recombinase system. Of these, ABCG2 F208S and S441N variants were found to be expressed at markedly low levels, whereas their mRNA levels were equal to those of the other SNP variants and ABCG2 WT (wild-type). Interestingly, protein expression levels of the ABCG2 F208S and S441N variants increased 6- to 12-fold when Flp-In-293 cells were treated with MG132, a proteasome inhibitor. Immunoprecipitation followed by immunoblot analysis showed that the ABCG2 F208S and S441N variant proteins were endogenously ubiquitinated in Flp-In-293 cells, and treatment with MG132 significantly enhanced the level of these ubiquitinated variants. Immunofluorescence microscopy demonstrated that MG132 greatly affected the ABCG2 F208S and S441N variants in terms of both protein levels and intracellular distribution. Immunoblot analysis revealed that those variants were N-glycosylated; however, their oligosaccharides were immature compared with those present on ABCG2 WT. The ABCG2 F208S and S441N variant proteins do not appear to be processed in the Golgi apparatus, but undergo ubiquitin-mediated protein degradation in proteasomes, whereas ABCG2 WT is sorted to the plasma membrane and then degraded via the lysosomal pathway. The present study provides the first evidence that certain genetic polymorphisms can affect the protein stability of ABCG2. Control of proteasomal degradation of ABCG2 would provide a novel approach in cancer chemotherapy to circumvent multidrug resistance of human cancers.

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208 In a previous study using the Flp recombinase system [33], we functionally characterized the non-synonymous polymorphisms (V12M, Q141K, F208S, S248P, F431L, S441N and F489L) in terms of their protein expression level, drug resistance profile and prazosin-stimulated ATPase activity. Login to comment

[hide] Homology modeling of breast cancer resistance prot... J Struct Biol. 2008 Apr;162(1):63-74. Epub 2007 Dec 15. Hazai E, Bikadi Z
Homology modeling of breast cancer resistance protein (ABCG2).
J Struct Biol. 2008 Apr;162(1):63-74. Epub 2007 Dec 15., [PMID:18249138]

Abstract [show]
BCRP (also known as ABCG2, MXR, and ABC-P) is a member of the ABC family that transports a wide variety of substrates. BCRP is known to play a key role as a xenobiotic transporter. Since discovering its role in multidrug resistance, considerable efforts have been made in order to gain deeper understanding of BCRP structure and function. The recent study was aimed at predicting BCRP structure by creating a homology model. Based on sequence similarity with known structures of full-length, NB and TM domain of ABC transporters, TM, NB, and linker regions of BCRP were defined. The NB domain of BCRP was modeled using MalK as a template. Based on secondary structure prediction of BCRP and comparison of the transmembrane connecting regions of known structures of ABC transporters, the TM domain arrangement of BCRP was established and was found to resemble to that of the recently published crystal structure of Sav1866. Thus, an initial alignment of TM domain of BCRP was established using Sav1866 as a template. This alignment was subsequently refined using constrains derived from secondary structure and TM predictions and the final model was built. Finally, the complete homodimer ABCG2 model was generated using Sav1866 as template. Furthermore, known ligands of BCRP were docked to our model in order to define possible binding sites. The results of molecular dockings of known BCRP substrates to the BCRP model were in agreement with recently published experimental data indicating multiple binding sites in BCRP.

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245 However, in our model, R482 cannot form interaction with rhodamine, but L484 is in interacting distance Table 3 Mutations on BCRP and their effect on its function Mutation Effect/results Reference V12M Did not effect Hemato and MTX transport Tamura et al. (2006) G51C Did not effect Hemato and MTX transport Tamura et al. (2006) K86M Inactivates transporter (dominant negative effect on ATPase activity); alters subcellular distribution Henriksen et al. (2005a) K86M Transporter inactive, but still able to bind ATP Ozvegy et al. (2002) Q126stop Defective porphyrin transport Tamura et al. (2006) Q141K Did not effect Hemato and MTX transport Tamura et al. (2006) T153M Did not effect Hemato and MTX transport Tamura et al. (2006) Q166E Did not effect Hemato and MTX transport Tamura et al. (2006) I206L Did not effect Hemato and MTX transport Tamura et al. (2006) F208S Defective porphyrin transport Tamura et al. (2006) S248P Defective porphyrin transport Tamura et al. (2006) E334stop Defective porphyrin transport Tamura et al. (2006) F431L Effects MTX transport Tamura et al. (2006) S441N Defective porphyrin transport Tamura et al. (2006) E446-mutants No drug resistance Miwa et al. (2003) R482G, R482T Effects MTX transport Tamura et al. (2006) R482T Substrate drug transport and inhibitor efficiency is not mediated by changes in drug-binding Pozza et al. (2006) R482G, R482T Substitution influence the substrate specificity of the transporter Ozvegy et al. (2002) R482G, R482T Altered substrate specificity Honjo et al. (2001) R482G Methotrexate not transported Chen et al. (2003b) Mitomo et al. (2003) R482G Resistance to hydrophilic antifolates in vitro, G482-ABCG2 mutation confers high-level resistance to various hydrophilic antifolates Shafran et al., (2005) R482G Three distinct drug, binding sites Clark et al. (2006) R482G Altered substrate specificity, granulocyte maturation uneffected Ujhelly et al. (2003) R482 mutants Higher resistance to mitoxantrone and doxorubicin than wt Miwa et al. (2003) R482X Affects substrate transport and ATP hydrolysis but not substrate binding Ejendal et al. (2006) F489L Impaired porphyrin transport Tamura et al. (2006) G553L; G553E Impaired trafficing, expression, and N-linked glycosylation Polgar et al. (2006) L554P Dominant negative effect on drug sensitivity Kage et al. (2002) N557D Resistance to MTX, but decreased transport of SN-38; N557E no change in transport compared to wt Miwa et al. (2003) F571I Did not effect Hemato and MTX transport Tamura et al. (2006) N590Y Did not effect Hemato and MTX transport Tamura et al. (2006) C592A Impaired function and expression Henriksen et al. (2005b) C592A/C608A Restored plasma mb expression; MTX transport normal, BODIPY-prazosin impaired Henriksen et al. (2005b) C603A Disulfide bridge; no functional or membrane targeting change Henriksen et al. (2005b) C608A Impaired function and expression Henriksen et al. (2005b) D620N Did not effect Hemato and MTX transport Tamura et al. (2006) H630X No change in transport Miwa et al. (2003) Cand N-terminal truncated Impaired trafficing Takada et al. (2005) with the ligand. Login to comment

[hide] Drug transporters: recent advances concerning BCRP... Br J Cancer. 2008 Mar 11;98(5):857-62. Epub 2008 Feb 5. Lemos C, Jansen G, Peters GJ
Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors.
Br J Cancer. 2008 Mar 11;98(5):857-62. Epub 2008 Feb 5., 2008-03-11 [PMID:18253130]

Abstract [show]
Multidrug resistance is often associated with the (over)expression of drug efflux transporters of the ATP-binding cassette (ABC) protein family. This minireview discusses the role of one selected ABC-transporter family member, the breast cancer resistance protein (BCRP/ABCG2), in the (pre)clinical efficacy of novel experimental anticancer drugs, in particular tyrosine kinase inhibitors.

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45 Breedveld et al (2005) showed that Table 1 BCRP substrates and polymorphisms Substrates Classical anticancer drugs Novel targeted drugs Mitoxantrone Canertinib (CI-1033)a Anthracyclinesb Imatiniba Camptothecins Nilotiniba Antifolatesb Gefitiniba Erlotinib Flavopiridol Polymorphismsc Variant Amino-acid change Effect G34A Val12Met (V12M) No change C376T Gln126stop (Q126T) No active BCRP protein C421A Gln141Lys (Q141K) Decreased protein levels and drug resistance Increased gefitinib-associated toxicity (diarrhoea) Increased imatinib accumulation in vitro, but no changes in the pharmacokinetic parameters of imatinib in vivo G1322A Ser441Asn (S441N) Decreased protein levels and different subcellular localisation BCRP ¼ breast cancer resistance protein. Login to comment
117 Finally, another BCRP SNP found in this Japanese population, G34A, which replaces valine by methionine at position 12 (V12M), showed similar protein expression and drug resistance levels as the wild-type (Imai et al, 2002). Login to comment

[hide] Pharmacogenomic and pharmacokinetic determinants o... J Clin Oncol. 2008 Mar 1;26(7):1119-27. Rudin CM, Liu W, Desai A, Karrison T, Jiang X, Janisch L, Das S, Ramirez J, Poonkuzhali B, Schuetz E, Fackenthal DL, Chen P, Armstrong DK, Brahmer JR, Fleming GF, Vokes EE, Carducci MA, Ratain MJ
Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity.
J Clin Oncol. 2008 Mar 1;26(7):1119-27., 2008-03-01 [PMID:18309947]

Abstract [show]
PURPOSE: To assess the pharmacogenomic and pharmacokinetic determinants of skin rash and diarrhea, the two primary dose-limiting toxicities of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib. PATIENTS AND METHODS: A prospective clinical study of 80 patients with non-small-cell lung cancer, head and neck cancer, and ovarian cancer was performed. Detailed pharmacokinetics and toxicity of erlotinib were assessed. Polymorphic loci in EGFR, ABCG2, CYP3A4, and CYP3A5 were genotyped, and their effects on pharmacokinetics and toxicities were evaluated. RESULTS: A novel diplotype of two polymorphic loci in the ABCG2 promoter involving -15622C/T and 1143C/T was identified, with alleles conferring lower ABCG2 levels associated with higher erlotinib pharmacokinetic parameters, including area under the curve (P = .019) and maximum concentration (P = .006). Variability in skin rash was best explained by a multivariate logistic regression model incorporating the trough erlotinib plasma concentration (P = .034) and the EGFR intron 1 polymorphism (P = .044). Variability in diarrhea was associated with the two linked polymorphisms in the EGFR promoter (P < .01), but not with erlotinib concentration. CONCLUSION: Although exploratory in nature, this combined pharmacogenomic and pharmacokinetic model helps to define and differentiate the primary determinants of skin and gastrointestinal toxicity of erlotinib. The findings may be of use both in designing trials targeting a particular severity of rash and in considering dose and schedule modifications in patients experiencing dose-limiting toxicities of erlotinib or similarly targeted agents. Further studies of the relationship between germline polymorphisms in EGFR and the toxicity and efficacy of EGFR inhibitors are warranted.

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28 Recent studies suggest that gefitinib and erlotinib are substrates of ABCG2.32-35 Two nonsynonymous ABCG2 SNPs, 421 CϾA (Q141K, rs2231142) and 34GϾA (V12M, rs2231137), are common.36-39 The 141K polymorphism has been associated with lower expression and activity of ABCG2 and with higher accumulation of both gefitinib and erlotinib.35,36,40 A recent clinical study showed an association between 141K and diarrhea in patients treated with gefitinib.41 We have recently identified four functional polymorphisms in the 5Ј-regulatory region of ABCG2 (Poonkuzhali et al, manuscript submitted for publication). Login to comment

[hide] Drug-induced phototoxicity evoked by inhibition of... Expert Opin Drug Metab Toxicol. 2008 Mar;4(3):255-72. Tamura A, An R, Hagiya Y, Hoshijima K, Yoshida T, Mikuriya K, Ishikawa T
Drug-induced phototoxicity evoked by inhibition of human ABC transporter ABCG2: development of in vitro high-speed screening systems.
Expert Opin Drug Metab Toxicol. 2008 Mar;4(3):255-72., [PMID:18363541]

Abstract [show]
BACKGROUND: Photosensitivity depends on both genetic and environmental factors. Pheophorbide a, present in various plant-derived foods and food supplements, can be absorbed by the small intestine. Accumulation of pheophorbide a and porphyrins in the systemic blood circulation can result in phototoxic lesions on light-exposed skin. OBJECTIVE: As the human ATP-binding cassette (ABC) transporter ABCG2 has been suggested to be critically involved in porphyrin-mediated photosensitivity, we aimed to develop in vitro screening systems for drug-induced phototoxicity. CONCLUSION: Functional impairment owing to inhibition of ABCG2 by drugs or its genetic polymorphisms can lead to the disruption of porphyrin homeostasis. This review article provides an overview on drug-induced photosensitivity, as well as our hypothesis on a potential role of ABCG2 in phototoxicity.

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230 Plasma membrane Outside Inside ATP-binding cassette H2 N COOH V12M G51C Q126stop Q141K T153M R160Q Q166E I206L F208S S248P E334stop F431L F489L S441N R482G R482T F571I R575stop N590Y D620N T542A A528T D296H P269S A. Login to comment
231 0.0 0.1 0.2 0.3 0.4 0.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T ATP-dependenthematoporphyrintransport (nmol/min/mgprotein) B. interactions should also take into consideration the presence of multiple flavonoids. Login to comment
245 Based on the presently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells. Login to comment
249 To further elucidate the significance of ABCG2 in cellular porphyrin homeostasis, we observed the cellular accumulation and compartmentation of porphyrin and pheophorbide a by means of a new fluorescence microscopy technology, and found that the accumulation of porphyrin and pheophorbide a in the cytoplasmic compartment was significantly higher in Flp-In-293 cells expressing S441N and F489L variants, as compared with those expressing WT, V12M, or Q141K [88]. Login to comment
252 Amino acid Porphyrin transport* Allele frequency (%)‡ cDNA position Location Wild-type allele Variant alllele V12M ++ 2.0 - 90.0 34 Exon 2 G A Q126stop - 0.0 - 1.7 376 Exon 4 C T Q141K ++ 0.0 - 35.5 421 Exon 5 C A T153M ++ 3.3 458 Exon 5 C T Q166E ++ N.D. 496 Exon 5 C G I206L ++ 10.0 616 Exon 6 A C F208S - N.D. 623 Exon 6 T C S248P - N.D. 742 Exon 7 T C E334stop - N.D. 1000 Exon 9 G T F431L ++ 0.8 1291 Exon 11 T C S441N - 0.5 1322 Exon 11 G A F489L + 0.5 - 0.8 1465 Exon 12 T C F571L ++ 0.5 1711 Exon 14 T A N590Y ++ 0.0 - 1.0 1768 Exon 15 A T D620N ++ 0.5 1858 Exon 16 G A *Transport of hematoporphyrin is indicated by either '+` (positive) or '-' (negative). Login to comment

[hide] Pharmacogenomics of drug-metabolizing enzymes and ... Methods Mol Biol. 2008;448:63-76. Bosch TM
Pharmacogenomics of drug-metabolizing enzymes and drug transporters in chemotherapy.
Methods Mol Biol. 2008;448:63-76., [PMID:18370231]

Abstract [show]
There is wide variability in the response of individuals to standard doses of drug therapy. This is an important problem in clinical practice, where it can lead to therapeutic failures or adverse drug events. Polymorphisms in genes coding for metabolizing enzymes and drug transporters can affect drug efficacy and toxicity. Pharmacogenomics aims to identify individuals predisposed to high risk of toxicity and low response from standard doses of anticancer drugs. This chapter focuses on the clinical significance of polymorphisms in drug-metabolizing enzymes and drug transporters in influencing efficacy and toxicity of anticancer therapy. The most important examples to demonstrate the influence of pharmacogenomics on anticancer therapy are thiopurine methyltransferase (TPMT), UGT (uridine diphosphate glucuronosyltransferase) 1A1*28, and DPD (dihydropyrimidine dehydrogenase) *2A, respectively, for 6-mercaptopurine, irinotecan, and 5-fluorouracil therapy. However, in most other anticancer therapies no clear association has been found for polymorphisms in drug-metabolizing enzymes and drug transporters and pharmacokinetics or pharmacodynamics of anticancer drugs. Evaluation of different regimens and tumor types showed that polymorphisms can have different, sometimes even contradictory, pharmacokinetic and pharmacodynamic effects in different tumors in response to different drugs. The clinical application of pharmacogenomics in cancer treatment therefore requires more detailed information regarding the different polymorphisms in drug-metabolizing enzymes and drug transporters. A greater understanding of complexities in pharmacogenomics is needed before individualized therapy can be applied on a routine basis.

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139 Mizuarai et al. (77) analyzed the effect of the polymorphisms G34A and C8825A, leading to an amino acid change of V12M and Q141K, respectively, on the transporter function of the protein. Login to comment
140 Drug resistance to indolocarbazole, a topoisomerase I inhibitor, of cells expressing V12M or Q141K was less than 1/10 compared to wild-type ABCG2-transfected cells and was accompanied by increased drug accumulation and decreased drug efflux in the variant ABCG2-expressing cells. Login to comment
141 A possible explanation for this altered function of the ABCG2 enzyme is the fact that the ABCG2 transporter is not localized to the apical membrane in the V12M clone. Login to comment

[hide] ABCG2: structure, function and role in drug respon... Expert Opin Drug Metab Toxicol. 2008 Jan;4(1):1-15. Polgar O, Robey RW, Bates SE
ABCG2: structure, function and role in drug response.
Expert Opin Drug Metab Toxicol. 2008 Jan;4(1):1-15., [PMID:18370855]

Abstract [show]
ABCG2 was discovered in multi-drug-resistant cancer cells, with the identification of chemotherapeutic agents, such as mitoxantrone, flavopiridol, methotrexate and irinotecan as substrates. Later, drugs from other therapeutic groups were also described as substrates, including antibiotics, antivirals, HMG-CoA reductase inhibitors and flavonoids. An expanding list of compounds inhibiting ABCG2 has also been generated. The wide variety of drugs transported by ABCG2 and its normal tissue distribution with highest levels in the placenta, intestine and liver, suggest a role in protection against xenobiotics. ABCG2 also has an important role in the pharmacokinetics of its substrates. Single nucleotide polymorphisms of the gene were shown to alter either plasma concentrations of substrate drugs or levels of resistance against chemotherapeutic agents in cell lines. ABCG2 was also described as the determinant of the side population of stem cells. All these aspects of the transporter warrant further research aimed at understanding ABCG2's structure, function and regulation of expression.

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82 Some of these are in the coding region of ABCG2 and alter the protein sequence, such as V12M, Q141K, I206L and N590Y. Login to comment
175 Membrane Out In 200 100 300 400 500 600 ATP site N-terminus C-terminus V12M Q141K I206L GXXXG, G406/G410 R482 G553 C603 N596 N590Y protein synthesis. Login to comment

[hide] Breast cancer resistance protein (ABCG2) and drug ... Pharmacogenet Genomics. 2008 May;18(5):439-48. Urquhart BL, Ware JA, Tirona RG, Ho RH, Leake BF, Schwarz UI, Zaher H, Palandra J, Gregor JC, Dresser GK, Kim RB
Breast cancer resistance protein (ABCG2) and drug disposition: intestinal expression, polymorphisms and sulfasalazine as an in vivo probe.
Pharmacogenet Genomics. 2008 May;18(5):439-48., [PMID:18408567]

Abstract [show]
Breast cancer resistance protein (BCRP) is an efflux transporter expressed in tissues that act as barriers to drug entry. Given that single nucleotide polymorphisms (SNPs) in the ABCG2 gene encoding BCRP are common, the possibility exists that these genetic variants may be a determinant of interindividual variability in drug response. The objective of this study is to confirm the human BCRP-mediated transport of sulfasalazine in vitro, evaluate interindividual variation in BCRP expression in human intestine and to determine the role of ABCG2 SNPs to drug disposition in healthy patients using sulfasalazine as a novel in vivo probe. To evaluate these objectives, pinch biopsies were obtained from 18 patients undergoing esophagogastro-duodenoscopy or colonoscopy for determination of BCRP expression in relation to genotype. Wild-type and variant BCRP were expressed in a heterologous expression system to evaluate the effect of SNPs on cell-surface trafficking. A total of 17 healthy individuals participated in a clinical investigation to determine the effect of BCRP SNPs on sulfasalazine pharmacokinetics. In vitro, the cell surface protein expression of the common BCRP 421 C>A variant was reduced in comparison with the wild-type control. Intestinal biopsy samples revealed that BCRP protein and mRNA expression did not significantly differ between patients with 34GG/421CC versus patients with 34GG/421CA genotypes. Remarkably, in subjects with 34GG/421CA genotype, sulfasalazine area under the concentration-time curve was 2.4-fold greater compared with 34GG/421CC subjects (P<0.05). This study links commonly occurring SNPs in BCRP with significantly increased oral sulfasalazine plasma exposure in humans. Accordingly, sulfasalazine may prove to have utility as in vivo probe for assessing the clinical impact of BCRP for the disposition and efficacy of drugs.

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21 In addition, several nonsynonymous single nucleotide polymorphisms (SNPs) of the ABCG2 gene have been described including ABCG2 34G > A (V12M) located in exon 2 and 421C > A (Q141K) in exon 5. Login to comment
62 Site-directed mutagenesis was utilized to create the nonsynonymous allelic variants, 34G > A (V12M) and 421C > A (Q141K). Login to comment

[hide] Sequential topoisomerase targeting and analysis of... Anticancer Drugs. 2008 Apr;19(4):411-20. Saraiya B, Gounder M, Dutta J, Saleem A, Collazo C, Zimmerman L, Nazar A, Gharibo M, Schaar D, Lin Y, Shih W, Aisner J, Strair RK, Rubin EH
Sequential topoisomerase targeting and analysis of mechanisms of resistance to topotecan in patients with acute myelogenous leukemia.
Anticancer Drugs. 2008 Apr;19(4):411-20., [PMID:18454051]

Abstract [show]
Resistance to topoisomerase I (TOP1)-targeting drugs such as topotecan often involves upregulation of topoisomerase II (TOP2), with accompanying increased sensitivity to TOP2-targeting drugs such as etoposide. This trial was designed to investigate sequential topoisomerase targeting in the treatment of patients with high-risk acute myelogenous leukemia. An initial cohort of patients received topotecan and cytosine arabinoside daily for 5 days. Serial samples of circulating mononuclear cells were examined to evaluate peak elevations of TOP2-alpha protein expression. In subsequent cohorts, etoposide was administered daily for 3 days, beginning 6 h after initiation of the topotecan infusion. The etoposide dose was escalated to determine a maximum-tolerated dose. Circulating mononuclear cells were analyzed for TOP1 mutations and ABCG2 protein expression. In addition, systemic and intracellular topotecan concentrations were measured. Thirty-one patients were enrolled. On the basis of TOP1-alpha protein levels in three patients with peripheral blast counts greater than 50%, etoposide administration began 6 h after initiation of the topotecan/cytosine arabinoside infusion. Using this schedule of administration, the maximum-tolerated dose of etoposide was 90 mg/m. No TOP1 mutations were identified, but increases in ABCG2 expression during the infusion were observed in mononuclear cells from two of four evaluable patients. Administration of etoposide 6 h after initiation of a topotecan/cytosine arabinoside infusion is feasible and is associated with clinical activity. Analysis of TOP2-alpha protein levels in this small number of patients indicated that peak increases occurred earlier than expected based on earlier publications. Upregulation of ABCG2 was detected in circulating cells and may represent an inducible form of drug resistance that should be investigated further.

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91 For ABCG2, primers were designed to amplify regions containing the following four SNPs: G34A (V12M, exon 1), C376T (stop, exon 3), A616C (I206L, exon 5), C421A (Q141K, exon 12), and A1768T (N590Y, exon 14). Login to comment
144 A SNP was identified in two patients (enrolled in cohorts 2 and 5, respectively), involving a coding region G-to-A substitution that yields a V12M substitution in the ABCG2 protein (refSNP ID: rs2231137). Login to comment

[hide] Pharmacogenomics of MRP transporters (ABCC1-5) and... Drug Metab Rev. 2008;40(2):317-54. Gradhand U, Kim RB
Pharmacogenomics of MRP transporters (ABCC1-5) and BCRP (ABCG2).
Drug Metab Rev. 2008;40(2):317-54., [PMID:18464048]

Abstract [show]
Elucidation of the key mechanisms that confer interindividual differences in drug response remains an important focus of drug disposition and clinical pharmacology research. We now know both environmental and host genetic factors contribute to the apparent variability in drug efficacy or in some cases, toxicity. In addition to the widely studied and recognized genes involved in the metabolism of drugs in clinical use today, we now recognize that membrane-bound proteins, broadly referred to as transporters, may be equally as important to the disposition of a substrate drug, and that genetic variation in drug transporter genes may be a major contributor of the apparent intersubject variation in drug response, both in terms of attained plasma and tissue drug level at target sites of action. Of particular relevance to drug disposition are members of the ATP Binding Cassette (ABC) superfamily of efflux transporters. In this review a comprehensive assessment and annotation of recent findings in relation to genetic variation in the Multidrug Resistance Proteins 1-5 (ABCC1-5) and Breast Cancer Resistance Protein (ABCG2) are described, with particular emphasis on the impact of such transporter genetic variation to drug disposition or efficacy.

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250 It should be noted that many xeno- and endobiotic BCRP Figure 5 Predicted membrance topology of BCRP (ABCG2) based on hydrophobicity analysis. Locations of the non-synonymous polymorphisms are indicated with arrows. See Table 5 for allele frequencies and description of funtional consequences. NH2 COOH NBD Val12Met Gly51Cys Gln126* Ala149Pro Gln141Lys Thr153Met Arg160Gln Arg163Lys Gln166Glu Phe506Ser Phe507Leu Val508Leu Met509* Phe489Leu Ser441Asn Phe431Leu Glu334* Ile206Leu Ala315del Thr316del Phe208Ser Asp296His Ser248Pro Pro269Ser Phe571Ile Arg575* Asn590Tyr Asp620Asn in out Membrane BCRP (ABCG2) NBD Val12Met NBDNBD Val12Met substrates are also transported by other efflux transporters, especially P-glycoprotein, thus extrapolating BCRP related in vitro data to the in vivo situation may be difficult. Login to comment
278 This SNP which is more frequently found in Asian populations than in Caucasians or Africans (Table 5), leads to the amino acid change, Val12Met. Login to comment
318 Available data in relation to BCRP pharmacogenetics suggest at least one of the known non-synonymous polymorphisms (421C>A/Gln141Lys) and possibly a few others (34G>A/Val12Met and 1322G>T/Ser441Asn) may be of functional and clinical importance. Login to comment

[hide] A dose-ranging study of the pharmacokinetics and p... Cancer Chemother Pharmacol. 2009 Feb;63(3):477-89. Epub 2008 May 29. O'Bryant CL, Lieu CH, Leong S, Boinpally R, Basche M, Gore L, Leonardi K, Schultz MK, Hariharan S, Chow L, Diab S, Gibbs A, Eckhardt SG
A dose-ranging study of the pharmacokinetics and pharmacodynamics of the selective apoptotic antineoplastic drug (SAAND), OSI-461, in patients with advanced cancer, in the fasted and fed state.
Cancer Chemother Pharmacol. 2009 Feb;63(3):477-89. Epub 2008 May 29., [PMID:18509645]

Abstract [show]
PURPOSE: To evaluate the safety, pharmacokinetics and determine the recommended dose of the selective apoptotic antineoplastic drug, OSI-461 administered on a twice-daily regimen to patients with advanced solid malignancies. METHODS: In this phase I trial, 33 patients were treated with OSI-461 doses ranging from 400 to 1,200 mg given twice daily in 4-week cycles. Pharmacokinetic studies were performed to characterize the plasma disposition of OSI-461 and the effect of food intake on OSI-461 absorption. Secondary biomarker studies were performed to assess the biologic activity of OSI-461 including the measurement of pGSK-3beta, a PKG substrate, and pharmacogenetic studies to identify polymorphisms of CYP3A that influence drug metabolism and of ABCG2, involved in drug resistance. RESULTS: Thirty-three patients were treated with 86 courses of OSI-461. The dose-limiting toxicities were grade 3 abdominal pain, found in one patient at the 1,000 mg BID fed dose level and all patients at the 1,200 mg BID fed dose level. There was also one episode each of grade 3 fatigue and grade 3 constipation at the 1,000 and 1,200 mg BID fed dose levels, respectively. Other common toxicities included mild to moderate fatigue, nausea, anorexia and mild elevation in bilirubin. Pharmacokinetic studies of OSI-461 revealed approximately a twofold increase in AUC(0-24) when OSI-461 was administered with food. An increase in pGSK-3beta post-dose was seen in the majority of patients and was greater at higher dose levels. No patients exhibited CYP3A4 polymorphisms, while 100% of patients were found to have the CYP3A5*3/CYP3A5*3 polymorphism. Two known polymorphisms of the ABCG2 gene, G34 --> A34 and C421 --> A421, occurred at frequencies of 11.76 and 29%, respectively. CONCLUSIONS: Toxicity and pharmacodynamic data show that the recommended oral dose of OSI-461 is 800 mg twice daily administered with food. The drug appears to be well-tolerated, and overall bioavailability appears to be markedly increased when the drug is administered with food. These results support further disease-directed evaluations of OSI-461 at a dose of 800 mg BID in combination with other chemotherapeutic agents.

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273 A mutation results in markedly decreased protein expression, and low level drug resistance, as compared to wild-type BRCP c For ABCG-2 #34 the of the A mutation frequency in Caucasians is 4.7%; and for ABCG-2 #421 the A mutation frequency in Caucasians is 25.9% Pt # ABCG-2 #34a ABCG-2 #421b Racec Val12 Met mutation Sequencing result Gln141 Lys mutation Sequencing result 01015 No Wild-type: G/G No Wild-type: C/C White 01016 No Wild-type: G/G Yes Heterozygote: C/A White 01017 Yes Homozygote: A/A No Wild-type: C/C Asian 01018 No Wild-type: G/G Yes Heterozygote: C/A White 01019 No Wild-type: G/G No Wild-type: C/C White 01020 Yes Heterozygote: A/G No Wild-type: C/C White 01021 No Wild-type: G/G Yes Heterozygote: C/A White 01022 No Wild-type: G/G No Wild-type: C/C Black 01023 No Wild-type: G/G Yes Heterozygote: C/A White 01024 No Wild-type: G/G No Wild-type: C/C White 01026 No Wild-type: G/G No Wild-type: C/C White 01027 No Wild-type: G/G No Wild-type: C/C White 01028 No Wild-type: G/G No Wild-type: C/C White 01029 No Wild-type: G/G No Wild-type: C/C White 01031 No Wild-type: G/G Yes Homozygote: A/A White 01032 No Wild-type: G/G No Wild-type: C/C White 01033 No Wild-type: G/G No Wild-type: C/C White A prior study of OSI-461 demonstrated that Cmax and AUC values increased in an approximate linear fashion as the dose was increased from 100 to 400 mg BID with a signiWcant amount of interpatient variability [35]. Login to comment

[hide] Human ABC transporters ABCG2 (BCRP) and ABCG4. Xenobiotica. 2008 Jul;38(7-8):863-88. Koshiba S, An R, Saito H, Wakabayashi K, Tamura A, Ishikawa T
Human ABC transporters ABCG2 (BCRP) and ABCG4.
Xenobiotica. 2008 Jul;38(7-8):863-88., [PMID:18668433]

Abstract [show]
1. The human ABC transporter ABCG2 is regarded as a member of the phase III system for xenobiotic metabolism, and it has been suggested that this efflux pump is responsible for protecting the body from toxic xenobiotics and for removing metabolites. 2. This review paper will address the new aspects of ABCG2 in terms of post-translational modifications (i.e., disulfide bond formation, ubiquitination, and endoplasmic reticulum-associated degradation) of ABCG2 protein, high-speed screening, and quantitative structure-activity relationship (QSAR) analysis to evaluate ABCG2-drug interactions, and genetic polymorphisms potentially associated with photosensitivity. 3. In addition, new aspects of human ABCG4 and mouse Abcg4 are presented with respect to their molecular properties and potential physiological roles. Considering a high sequence similarity between ABCG1 and ABCG4, both Abcg4 and ABCG4 may be involved in the transport of cholesterol from neurons and astrocytes. Furthermore, high expression of the mouse Abcg4 protein in the testis implicates its involvement in transport of certain sex hormones.

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225 Based on the currently available data on SNPs and acquired mutations, a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) were created by site-directed mutagenesis and expressed in Sf9 insect cells (Tamura et al. 2006, 2007). Login to comment

[hide] Pharmacogenetics of intestinal absorption. Curr Drug Deliv. 2008 Jul;5(3):153-69. Nakamura T, Yamamori M, Sakaeda T
Pharmacogenetics of intestinal absorption.
Curr Drug Deliv. 2008 Jul;5(3):153-69., [PMID:18673259]

Abstract [show]
The small intestine is the primary site of absorption for many drugs administered orally and so is the target tissue for pharmacotherapeutic strategies to control the oral absorption of drugs. Drug transporters, including the ATP-binding cassette (ABC) superfamily and the solute carrier (SLC) superfamily, have been considered to play a physiological role in regulating the absorption of xenobiotics, and variations in their expression level and function in the small intestine cause intra- and inter-individual variation in the oral absorption of drugs. Recent advances in molecular biology have suggested that genetic polymorphisms are associated with the expression level and function, and thereby inter-individual variation. In this review, the pharmacogenetics of these transporters is summarized, and their future significance in the clinical setting is discussed.

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76 Among the SNPs identified so far, two nonsynonymous SNPs, 34G>A and 421C>A, in the coding region, resulting in Val12Met and Gln141Lys, respectively, are relatively frequently identified and well-studied. Login to comment
77 Honjo et al. sequenced 90 genomic DNA samples and identified Val12Met and Gln141Lys at a frequency of 12.2% and 6.1%, respectively [86]. Login to comment
78 The Val12Met and Gln141Lys polymorphisms were also identified in a sequence analysis of ABCG2 cDNA clones isolated from 11 human tumor cell lines and were confirmed to have allelic frequencies of 19.0% and 26.6%, respectively, by a genomic DNA analysis in 124 Japanese [85]. Login to comment
83 In Vitro Studies Associated with Common SNPs of Drug Transporter Genes Exon Polymorphism Effect dbSNP Cell Expression Function Reference ABCC2 Exon 1 -24C>T 5`-UTR rs717620 116A>T Tyr2Phe rs927344Exon 2 159A>G synonymous rs17222596 Exon 7 736A>C Met246Leu rs17222744 Exon 8 998A>G Asp333Gly rs17222674 Exon 9 1058G>A Arg353His rs7080681 1219C>T synonymous rs17216198 1249G>A Val417Ile rs2273697 LLC-PK1 Protein (n.s.) Membrane localization (n.s.) Transport activity (n.s.) Hirouchi et al. [51] 1434G>T synonymous 1434G>A synonymous rs4267009 Exon 10 1457C>T Thr486Ile rs17222589 Exon 11 1483A>G Lys495Glu rs17222561 Exon 13 1686T>G Phe562Leu rs17216233 2009T>C Ile670Thr rs17222632Exon 16 2073C>A synonymous rs17222624 Exon 17 2153A>G Asn718Ser rs3740072 Exon 19 2546T>G Leu849Arg rs17222617 Exon 20 2677G>C Glu893Gln rs3740071 2901C>A Tyr967stop rs17222547 2934G>A synonymous rs3740070 Exon 22 2944A>G Ile982Val rs17222554 3107T>C Ile1036Thr rs17216149Exon 23 3188A>G Asn1063Ser rs17222540 Exon 24 3396T>C synonymous rs17216345 3542G>T Arg1181Leu rs8187692 3561G>A synonymous rs17216324 Exon 25 3563T>A Val1188Glu rs17222723 Exon 27 3817A>G Thr1273Ara rs8187699 3872C>T Pro1291Leu rs17216317 3895A>C Lys1299Gln rs4148400 3927C>T synonymous rs4148401 Exon 28 3972C>T synonymous rs3740066 4062C>T synonymous rs17216275Exon 29 4110C>T synonymous rs7899457 4242C>T synonymous rs17216296Exon 30 4290G>T synonymous rs1137968 4410G>A synonymous rs8187706Exon 31 4488C>T synonymous rs8187707 4527C>T synonymous rs8187709Exon 32 4544G>A Cys1515Tyr rs8187710 ABCG2 PA317 mRNA (n.s.) Protein (n.s.) Drug sensitivity (n.s.) Topotecan uptake (n.s.) Imai et al. [85] mRNA (n.s.) Protein (n.s.) Apical localization (impaired) Drug sensitivity ( ) Indolocarbazole uptake ( ) Indolocarbazole efflux ( ) Mizuarai et al. [88] Exon 2 34G>A Val12Met rs2231137 LLC-PK1 Apical localization (n.s.) . Login to comment
93 Exon Polymorphism Effect dbSNP Subject Expression Function Reference Exon 24 3396T>C synonymous rs17216345 3542G>T Arg1181Leu rs8187692 3561G>A synonymous rs17216324 3563T>A Val1188Glu rs17222723 Healthy (Finnish) Pravastatin PK (TT TA) Niemi et al. [48] HIV patient (Caucasian) Nelfinavir intracellular AUC (TT TA) Colombo et al. [58] Exon 25 Patient Acute anthracycline-induced cardiotoxicity (TT<TA) Chronic anthracycline-induced cardiotoxicity (TT TA) Wojnowski et al. [59] Exon 27 3817A>G Thr1273Ara rs8187699 3872C>T Pro1291Leu rs17216317 3895A>C Lys1299Gln rs4148400 3927C>T synonymous rs4148401 3972C>T synonymous rs3740066 Women undergoing cesarean section Placental mRNA (GG GA AA) Placental protein (GG GA AA) Meyer zu Schwabedissen et al. [52] DNT patient Tumoral protein (GG GA) Peritumoral protein (GG GA) Vogelgesang et al. [54] Patient 9-nitrocamptotecin PK and toxicity (CC CT TT) 9-aminocamptotecin PK and toxicity (CC CT TT) Zamboni et al. [55] Exon 28 Colorectal cancer patient (Japanese) Tumoral mRNA (CC CT TT) Drug sensitivity (CC CT TT) Tumor growth rate (CC CT TT) Nishioka et al. [57] 4062C>T synonymous rs17216275Exon 29 4110C>T synonymous rs7899457 4242C>T synonymous rs17216296Exon 30 4290G>T synonymous rs1137968 Exon 31 4410G>A synonymous rs8187706 4488C>T synonymous rs8187707 HIV patient (Caucasian) Nelfinavir intracellular AUC (CC CT) Colombo et al. [58] 4527C>T synonymous rs8187709 4544G>A Cys1515Tyr rs8187710 Healthy (Finnish) Pravastatin PK (GG GA) Niemi et al. [48] HIV patient (Caucasian) Nelfinavir intracellular AUC (GG GA) Colombo et al. [58] Exon 32 Patient Acute anthracycline-induced cardiotoxicity (GG<GA) Chronic anthracycline-induced cardiotoxicity (GG GA) Wojnowski et al. [59] ABCG2 34G>A Val12Met rs2231137 Nasopharyngeal cancer patient Irinotecan PK (GG GA+AA) SN-38 PK (GG GA+AA) SN-38G PK (GG GA+AA) Zhou et al. [56] HIV patient (Caucasian) Nelfinavir intracellular AUC (GG GA) Colombo et al. [58] Exon 2 Patient (Japanese) Placental mRNA (GG GA AA) Placental protein (GG GA AA) Kobayashi et al. [91] (Table 3) contd…. Login to comment
99 In the report of Mizuarai et al., Val12Met but not Gln141Lys affected apical membrane localization of ABCG2 in transfectant- LLC-PK1 cells, whereas Morisaki et al. reported impaired membrane trafficking or incorrect membrane insertion of Gln141Lys ABCG2 in HEK-293 cells. Login to comment
101 Reduced drug resistance to ABCG2 substrates was also observed in Val12Met ABCG2-transfected LLC-PK1 cells, but not significantly in Val12Met ABCG2-transfected HEK-293 cells. Login to comment

[hide] Pharmacogenomic importance of ABCG2. Pharmacogenomics. 2008 Aug;9(8):1005-9. Cusatis G, Sparreboom A
Pharmacogenomic importance of ABCG2.
Pharmacogenomics. 2008 Aug;9(8):1005-9., [PMID:18681776]

Abstract [show]
The ATP-binding cassette transporter ABCG2 (BCRP, MXR and ABCP) is highly expressed in the gastrointestinal tract and liver, and governs absorption, distribution and excretion of a wide variety of clinically important drugs. Common germline polymorphisms in the ABCG2 gene have been described that can affect expression, cellular localization and/or substrate recognition of the encoded protein. Alteration of transporter function by either of these mechanisms contributes significantly to interindividual variability in drug disposition and treatment outcome with certain, but not all, substrates for ABCG2.

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27 Several other SNPs have been identified in coding regions of the gene, and at least three additional nonsynonymous SNPs have been identified, occurring at positions 34 (V12M, exon 2), 616 (I206L, exon 6) and 1768 (N590Y, exon 15). Login to comment

[hide] Clinical pharmacogenetics and potential applicatio... Curr Drug Metab. 2008 Oct;9(8):738-84. Zhou SF, Di YM, Chan E, Du YM, Chow VD, Xue CC, Lai X, Wang JC, Li CG, Tian M, Duan W
Clinical pharmacogenetics and potential application in personalized medicine.
Curr Drug Metab. 2008 Oct;9(8):738-84., [PMID:18855611]

Abstract [show]
The current 'fixed-dosage strategy' approach to medicine, means there is much inter-individual variation in drug response. Pharmacogenetics is the study of how inter-individual variations in the DNA sequence of specific genes affect drug responses. This article will highlight current pharmacogenetic knowledge on important drug metabolizing enzymes, drug transporters and drug targets to understand interindividual variability in drug clearance and responses in clinical practice and potential use in personalized medicine. Polymorphisms in the cytochrome P450 (CYP) family may have had the most impact on the fate of pharmaceutical drugs. CYP2D6, CYP2C19 and CYP2C9 gene polymorphisms and gene duplications account for the most frequent variations in phase I metabolism of drugs since nearly 80% of drugs in use today are metabolised by these enzymes. Approximately 5% of Europeans and 1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant drug metabolising enzyme that demonstrates genetic variants. Studies into CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and CYP2C9*3 alleles. Extensive polymorphism also occurs in a majority of Phase II drug metabolizing enzymes. One of the most important polymorphisms is thiopurine S-methyl transferases (TPMT) that catalyzes the S-methylation of thiopurine drugs. With respect to drug transport polymorphism, the most extensively studied drug transporter is P-glycoprotein (P-gp/MDR1), but the current data on the clinical impact is limited. Polymorphisms in drug transporters may change drug's distribution, excretion and response. Recent advances in molecular research have revealed many of the genes that encode drug targets demonstrate genetic polymorphism. These variations, in many cases, have altered the targets sensitivity to the specific drug molecule and thus have a profound effect on drug efficacy and toxicity. For example, the beta (2)-adrenoreceptor, which is encoded by the ADRB2 gene, illustrates a clinically significant genetic variation in drug targets. The variable number tandem repeat polymorphisms in serotonin transporter (SERT/SLC6A4) gene are associated with response to antidepressants. The distribution of the common variant alleles of genes that encode drug metabolizing enzymes, drug transporters and drug targets has been found to vary among different populations. The promise of pharmacogenetics lies in its potential to identify the right drug at the right dose for the right individual. Drugs with a narrow therapeutic index are thought to benefit more from pharmacogenetic studies. For example, warfarin serves as a good practical example of how pharmacogenetics can be utilized prior to commencement of therapy in order to achieve maximum efficacy and minimum toxicity. As such, pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and licensed drugs.

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618 Only a small portion of them are non-synonymous (V12M, Q141K, Q166E, I206L, F208S, S248P, D296H, L525R, A528T, F571I, and Y590N) and there is one frameshift (1515delC) mutation observed in the coding region of ABCG2. Login to comment
619 Among the above variations, 34G>A (V12M) AND 421C>A (Q141K) have been testified to be polymorphic in numerous populations [267, 271]. Login to comment
620 The V12M polymorphism located in exon 2 influenced the N-terminal intracellular region of the protein. Login to comment
622 The V12M polymorphism was discovered in all ethnic groups tested, found with the highest allele frequency in Mexican-Indians (90%, but only 10 individuals were tested), while only 2% in a Swedish population [272]. Login to comment
623 Upon the combination of several population studies, a consistent and significant difference can be seen between the overall allele frequencies of V12M in Caucasian, African American and Japanese populations [271]. Login to comment
630 Studies have discovered that the expression levels of Q141K ABCG2 protein is lower than the wild-type, or the V12M variant when expressed in PA317 or HEK-293 cells [273]. Login to comment
631 It was also found that a portion of Q141K remained intracellular despite having a low level of expression, as both V12M and Q141K BCRP could reach the plasma membrane in the HEK-293 cells [273]. Login to comment
635 ABCG2 is expressed in polarized LLC-PKI cells, and a study has demonstrated that the V12M variant has an intracellular localization whereas the wild-type ABCG2 and Q141K show mainly apical staining [275]. Login to comment
636 The localization of other variants including V12M, A149P, R163K, Q166E, P269S and S441N was also examined. Login to comment
637 All polymorphisms, including V12M and Q141K, had an apical localization, and only the S441N variant displayed an intracellular staining [275]. Login to comment
639 Further studies are required to clarify the mechanism of a reduced protein expression for Q141K, and the change of cellular localization for the V12M and Q141K variants found under specific conditions. Login to comment
641 There was a 10-fold decrease in drug resistance compared with the wild-type ABCG2 when the V12M or Q141K-transfected LLC-PKI cells were challenged by mitoxantrone or topotecan [275]. Login to comment
645 Experiments were undertaken to observe between the vanadate-sensitive ATPase activity of ABCG2 V12M and Q141K variants, using Sf9 (Spodoptera frugiperda) cell membranes [276]. Login to comment
646 There was a 1.3 and 1.8-fold lower basal ATPase activity, respectively, for V12M and Q141K compared to wild-type [276]. Login to comment
647 On the other hand, the V12M (and D620N) ABCG2 displayed a comparable ATPase activity as the wild-type protein. Login to comment

[hide] The 315-316 deletion determines the BXP-21 antibod... Mol Cell Biochem. 2009 Feb;322(1-2):63-71. Epub 2008 Nov 11. Polgar O, Deeken JF, Ediriwickrema LS, Tamaki A, Steinberg SM, Robey RW, Bates SE
The 315-316 deletion determines the BXP-21 antibody epitope but has no effect on the function of wild type ABCG2 or the Q141K variant.
Mol Cell Biochem. 2009 Feb;322(1-2):63-71. Epub 2008 Nov 11., [PMID:19002564]

Abstract [show]
ABCG2 is a half-transporter initially described in multidrug-resistant cancer cells and lately identified as an important factor in the pharmacokinetics of its substrates. Q141K is by far the most intensively studied single nucleotide polymorphism of ABCG2 with potential clinical relevance. Here we used stably transfected HEK cells to study the Q141K polymorphism together with the deletion of amino acids 315-316, which were recently reported to coexist in two cancer cell lines (A549 and SK-OV-3). Functional studies confirmed our previous report that when normalized to surface expression, Q141K has impaired transport of mitoxantrone. This result was extended to include the ABCG2-specific substrate pheophorbide a. While we found no functional consequence of deleting amino acids 315 and 316, we did find that the deletion mutant is no longer recognized by the BXP-21 antibody. We conclude that amino acids 315 and 316 form part of the epitope for the BXP-21 antibody.

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62 We have previously used the same expression system to study non-synonymous SNPs, such as Q141K, V12M, and D620N, and found that Q141K results in impaired function [13]. Login to comment
64 We have previously used the same expression system to study non-synonymous SNPs, such as Q141K, V12M, and D620N, and found that Q141K results in impaired function [13]. Login to comment

[hide] Gene variants associated with ischemic stroke: the... Stroke. 2009 Feb;40(2):363-8. Epub 2008 Nov 20. Luke MM, O'Meara ES, Rowland CM, Shiffman D, Bare LA, Arellano AR, Longstreth WT Jr, Lumley T, Rice K, Tracy RP, Devlin JJ, Psaty BM
Gene variants associated with ischemic stroke: the cardiovascular health study.
Stroke. 2009 Feb;40(2):363-8. Epub 2008 Nov 20., [PMID:19023099]

Abstract [show]
BACKGROUND AND PURPOSE: The purpose of this study was to determine whether 74 single nucleotide polymorphisms (SNPs), which had been associated with coronary heart disease, are associated with incident ischemic stroke. METHODS: Based on antecedent studies of coronary heart disease, we prespecified the risk allele for each of the 74 SNPs. We used Cox proportional hazards models that adjusted for traditional risk factors to estimate the associations of these SNPs with incident ischemic stroke during 14 years of follow-up in a population-based study of older adults: the Cardiovascular Health Study (CHS). RESULTS: In white CHS participants, the prespecified risk alleles of 7 of the 74 SNPs (in HPS1, ITGAE, ABCG2, MYH15, FSTL4, CALM1, and BAT2) were nominally associated with increased risk of stroke (one-sided P<0.05, false discovery rate=0.42). In black participants, the prespecified risk alleles of 5 SNPs (in KRT4, LY6G5B, EDG1, DMXL2, and ABCG2) were nominally associated with stroke (one-sided P<0.05, false discovery rate=0.55). The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90% CI, 1.11 to 11.6) participants of CHS. Kaplan-Meier estimates of the 10-year cumulative incidence of stroke were greater among Val allele homozygotes than among Met allele carriers in both white (10% versus 6%) and black (12% versus 3%) participants of CHS. CONCLUSIONS: The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS.

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12 The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90% CI, 1.11 to 11.6) participants of CHS. Login to comment
14 Conclusions-The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS. Login to comment
76 ABCG2 Val12Met (rs2231137) was the only SNP associated with incident ischemic stroke in both white and black participants of CHS. Login to comment
82 The most notable finding, consistent in both whites and blacks, was the association between the Val allele of ABCG2 Val12Met and increased risk of incident ischemic stroke. Login to comment
84 The first of these 3 gene variants was the Val allele of ABCG2 Val12Met (rs2231137). Login to comment
97 The Val Allele Homozygotes of ABCG2 Val12Met, Compared With the Met Allele Carriers Are Associated With Increased Risk of Incident Ischemic Stroke in Both White and Black Participants of CHS Model 1* Model 2* ABCG2 Genotype Events, n Total, n HR (90% CI) P HR (90% CI) P White ValVal 370 3398 1.58 (1.12-2.23) 0.02 1.50 (1.06-2.12) 0.03 ValMetϩMetMet 24 335 1 (Reference) 1 (Reference) ValMet 23 321 MetMet 1 14 Black ValVal 66 592 3.80 (1.16-12.4) 0.03 3.62 (1.11-11.9) 0.04 ValMetϩMetMet 2 70 1 (Reference) 1 (Reference) ValMet 2 69 MetMet 0 1 *Model 1 was adjusted for baseline age and sex. Login to comment
100 Comparison of Kaplan-Meier estimates of the cumulative incidence of ischemic stroke among Val allele homozygotes of the ABCG2 Val12Met and among Met allele carriers in white (A) and in black (B) participants of CHS. Login to comment
113 Notably, the Val allele of the Val12Met SNP in ABCG2 (which encodes a transporter of sterols and anticancer drugs) was associated with increased risk of incident ischemic stroke in both white and black participants of CHS. Login to comment

[hide] ABCG2 Q141K polymorphism is associated with chemot... Cancer Sci. 2008 Dec;99(12):2496-501. Epub 2008 Nov 20. Kim IS, Kim HG, Kim DC, Eom HS, Kong SY, Shin HJ, Hwang SH, Lee EY, Lee GW
ABCG2 Q141K polymorphism is associated with chemotherapy-induced diarrhea in patients with diffuse large B-cell lymphoma who received frontline rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone chemotherapy.
Cancer Sci. 2008 Dec;99(12):2496-501. Epub 2008 Nov 20., [PMID:19032367]

Abstract [show]
ATP-binding cassette transporter G2 (ABCG2) is the most recently described transporter of the multidrug-resistance pump and it promotes resistance to anticancer drugs such as doxorubicin, mitoxantrone, topotecan, and SN-38. Of the ABCG2 polymorphisms, V12M and Q141K alter the functional activity of the ABCG2 transporter and influence the drug response and various toxicities to chemotherapeutic agents. We therefore evaluated the impact of the ABCG2 V12M and Q141K polymorphisms on the therapeutic outcomes and toxicities of primary rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) therapy in 145 Korean patients with diffuse large B-cell lymphoma (DLBCL). ABCG2 V12M and Q141K genotyping was carried out by pyrosequencing of polymerase chain reaction products. The clinical characteristics, treatment outcomes, toxicities of the patients, and the predictive value of the polymorphisms on response, survival, and adverse events to R-CHOP for 145 patients were analyzed according to the ABCG2 V12M and Q141K polymorphisms. No differences were observed according to ABCG2 Q141K and V12M genotype in patient characteristics, disease characteristics, response, survival, or hematology toxicity profiles in patients with DLBCL who received frontline R-CHOP chemotherapy. On multivariate analysis, grade I-IV diarrhea was statistically significant according to ABCG2 Q141K polymorphism (the QQ genotype vs the QK or KK genotypes; hazard ratio 2.835; 95% confidence interval 1.432-5.613; P = 0.003). This study demonstrates that the ABCG2 Q141K polymorphism may correlate with chemotherapy-induced diarrhea in patients with DLBCL who have received frontline R-CHOP chemotherapy, and this has implications for optimizing treatment with such agents.

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2 Of the ABCG2 polymorphisms, V12M and Q141K alter the functional activity of the ABCG2 transporter and influence the drug response and various toxicities to chemotherapeutic agents. Login to comment
3 We therefore evaluated the impact of the ABCG2 V12M and Q141K polymorphisms on the therapeutic outcomes and toxicities of primary rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) therapy in 145 Korean patients with diffuse large B-cell lymphoma (DLBCL). Login to comment
4 ABCG2 V12M and Q141K genotyping was carried out by pyrosequencing of polymerase chain reaction products. Login to comment
5 The clinical characteristics, treatment outcomes, toxicities of the patients, and the predictive value of the polymorphisms on response, survival, and adverse events to R-CHOP for 145 patients were analyzed according to the ABCG2 V12M and Q141K polymorphisms. No differences were observed according to ABCG2 Q141K and V12M genotype in patient characteristics, disease characteristics, response, survival, or hematology toxicity profiles in patients with DLBCL who received frontline R-CHOP chemotherapy. Login to comment
15 (7-11) In particular, two non-synonymous polymorphisms, c.34G>A (p.Val12Met, V12M) and c.421C>A (p.Gln141Lys, Q141K), have been detected at relatively high frequencies in most ethnic groups, including Asians, Caucasians, and Africans. Login to comment
17 (15) A recently published study found that the ABCG2 V12M and Q141K polymorphisms are associated with susceptibility to and survival from DLBCL. Login to comment
18 (16) In the present study, we evaluated the impact of the ABCG2 Q141K and V12M polymorphisms on the therapeutic outcomes and adverse reactions of primary R-CHOP therapy in 145 patients with DLBCL, including treatment response, overall survival (OS) and event-free survival (EFS), hematological toxicities, and non-hematological toxicities. Login to comment
35 ABCG2 Q141K and V12M genotyping was carried out by pyrosequencing of the polymerase chain reaction (PCR) products from the ABCG2 gene to determine the presence of the Q141K and V12M polymorphisms. Login to comment
39 Patient characteristics and treatment outcomes according to the ABCG2 Q141K and V12M polymorphisms ABCG2 Q141K P-value ABCG2 V12M P-value QQ QK KK VV VM MM No. patients (%) 67 (46.2%) 69 (47.6%) 9 (6.2%) 71 (49.0%) 63 (43.4%) 11 (7.6%) Sex (no. Login to comment
43 Sequences and information of primers used for pyrosequencing Name Primer sequence (5' to 3') Size (bp) Polymerase chain reaction (Tm; °C) ABCG2 V12M F: CTCTCCAGATGTCTTCCAGTAATG 110 59 R: Biotin-TCCTTCAGTAAATGCCTTCAGGT S: TCGAAGTTTTTATCCCA ABCG2 Q141K F: Biotin-ACTGCAGGTTCATCATTAGCTAGA 238 60 R: CCGTTCGTTTTTTTCATGATTC S: CGAAGAGCTGCTGAGAA F, forward; R, reverse; S, sequencing; Tm, melting temperature. Login to comment
55 The primary objective of the current study was to correlate the ABCG2 Q141K and V12M polymorphisms with the response and survival outcomes, including OS and EFS to R-CHOP therapy. Login to comment
56 The secondary objectives were to correlate the ABCG2 Q141K and V12M polymorphisms with the hematological and non- hemtological toxicities of R-CHOP therapy. Login to comment
57 The clinical characteristics, treatment outcomes, and toxicities of the patients were compared using χ2 -tests, Fisher`s exact tests, or Mann-Whitney U-tests according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
58 Logistic regression analysis was conducted to determine the predictive value of the polymorphisms on response and adverse reaction to R-CHOP for the 145 patients who had available both the ABCG2 Q141K and V12M polymorphism data. Login to comment
59 The variables included stage (stages 1 and 2 vs 3 and 4), IPI score (0-2 vs 3-5), age (<60 vs ≥60 years), performance status (Eastern Cooperative Oncology Group [ECOG] 0 and 1 vs ≥2), lactate dehydrogenase level (normal vs beyond normal range), extranodal involvement (≤1 vs ≥2 sites), B symptoms (absence vs presence), hematological toxicity (grade 0-II vs III-IV or grade 0 vs grade I-IV), non-hematological toxicity (grade 0-II vs III-IV or grade 0 vs grade I-IV), and ABCG2 Q141K (QQ, QK, and KK) and ABCG2 V12M (VV, VM, and MM) genotypes. Login to comment
66 Results Frequency of ABCG2 Q141K and V12M polymorphisms. Login to comment
68 The distribution of the VV, VM, and MM genotypes of the ABCG2 V12M polymorphism was 49.0, 43.4, and 7.6%, respectively (Table 1). Login to comment
70 Patient characteristics according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
72 In brief, no differences in the patient and disease characteristics were observed according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
73 Response to frontline R-CHOP therapy according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
75 As shown in Table 1, no significant difference in the response rate or the ORR was observed according to the ABCG2 Q141K and V12M polymorphisms. No statistically significant difference in the response rate or ORR was observed according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
76 Survival analysis according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
79 When comparing OS and EFS according to the ABCG2 Q141K and V12M polymorphisms, neither the Q141K nor V12M polymorphisms had any impact on OS or EFS (Fig. 1). Login to comment
80 Side effects according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
82 No significant differences of such hematological toxicities as anemia, leukocytopenia, neutropenia, and thrombocytopenia were observed according to the ABCG2 Q141K and V12M alleles. Login to comment
87 Discussion Among several naturally occurring ABCG2 polymorphisms, V12M in exon 2 and Q141K in exon 5 occur in most racial groups, but they occur with a higher allellic frequency in Asians. Login to comment
88 In the present study, the frequencies of two polymorphisms, V12M and Q141K, were 0.293 and 0.300, respectively, and these values were comparable to those reported in the literature for Asians (0.230-0.241 and 0.150-0.360, respectively). Login to comment
91 However, the allele frequency of ABCG2 V12M in the present study was higher than that of the Korean healthy controls, and the association between ABCG2 V12M and disease susceptibility should be further investigated (Table 5). Login to comment
92 The present study demonstrated that the ABCG2 Q141K and V12M polymorphisms were not predictive of the response, OS, or EFS to R-CHOP chemotherapy in patients with DLBCL. Login to comment
93 No association of the ABCG2 Q141K and V12M polymorphisms with response and survival was noted in the present study for the following reasons: (1) the relatively small number of patients; (2) the relatively short period of follow up may not have been enough to see a significant difference in survival; and (3) other unknown chemoresistance mechanisms are probably important in the mechanism of R-CHOP action, and this would be expected to affect the response and survival of DLBCL patients. Login to comment
103 Hematological and non-hematological toxicity outcomes according to the ABCG2 Q141K and V12M polymorphisms (grade 0-II vs grade III-IV) ABCG2 Q141K P-value ABCG2 V12M P-value QQ QK or KK VV VM or MM No. patients (%) 67 (46.2%) 78 (53.8%) 71 (49.0%) 74 (51.0%) Grade III-IV, n (%) Anemia 9 (13.4%) 9 (11.5%) 0.730 10 (14.1%) 8 (10.8%) 0.550 Leukocytopenia 29 (43.3%) 32 (41.0%) 0.784 33 (46.5%) 28 (37.8%) 0.292 Neutropenia 38 (56.7%) 39 (50.0%) 0.419 38 (53.5%) 39 (52.7%) 0.921 Thrombocytopenia 4 (6.0%) 11 (14.1%) 0.109 9 (12.7%) 6 (8.1%) 0.367 Grade III-IV, n (%) Fever 8 (11.9%) 20 (25.6%) 0.037 16 (22.5%) 12 (16.2%) 0.335 Mucostis 11 (16.4%) 22 (28.2%) 0.091 19 (26.8%) 14 (18.9%) 0.260 Infection 9 (13.4%) 21 (27.5%) 0.046 13 (18.3%) 17 (23.0%) 0.488 Nausea and vomiting 2 (3.0%) 5 (6.4%) 0.337 3 (4.2%) 4 (5.4%) 0.740 Diarrhea 2 (3.0%) 9 (11.5%) 0.052 4 (5.6%) 7 (9.5%) 0.384 Alopecia 27 (40.3%) 38 (48.7%) 0.309 32 (45.1%) 33 (44.6%) 0.954 Neurotoxicity 2 (3.0%) 4 (5.1%) 0.518 3 (4.2%) 3 (4.1%) 0.959 Bold and italic values significant at P < 0.05. Login to comment

[hide] Functions of the breast cancer resistance protein ... Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33. Epub 2008 Dec 3. Noguchi K, Katayama K, Mitsuhashi J, Sugimoto Y
Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy.
Adv Drug Deliv Rev. 2009 Jan 31;61(1):26-33. Epub 2008 Dec 3., 2009-01-31 [PMID:19111841]

Abstract [show]
The breast cancer resistance protein, BCRP/ABCG2, is a half-molecule ATP-binding cassette transporter that facilitates the efflux of various anticancer agents from the cell, including 7-ethyl-10-hydroxycamptothecin, topotecan and mitoxantrone. The expression of BCRP can thus confer a multidrug resistance phenotype in cancer cells, and its transporter activity is involved in the in vivo efficacy of chemotherapeutic agents. Thus, the elucidation of the substrate preferences and structural relationships of BCRP is essential to understanding its in vivo functions during chemotherapeutic treatments. Single nucleotide polymorphisms (SNPs) have also been found to be key factors in determining the efficacy of chemotherapeutics, and those therapeutics that inhibit BCRP activity, such as the SNP that results in a C421A mutant, may result in unexpected side effects of the BCRP- anticancer drugs interaction even at normal dosages. In order to modulate the BCRP activity during chemotherapy, various compounds have been tested as inhibitors of this protein. Estrogenic compounds including estrone, several tamoxifen derivatives in addition to phytoestrogens and flavonoids have been shown to reverse BCRP-mediated drug resistance. Intriguingly, recently developed molecular targeted cancer drugs, such as the tyrosine kinase inhibitors imatinib mesylate, gefitinib and others, can also interact with BCRP. Since both functional SNPs and inhibitory agents of BCRP modulate the in vivo pharmacokinetics and pharmacodynamics of its substrate drugs, BCRP activity is an important consideration in the development of molecular targeted chemotherapeutics.

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847 C421A (Q141K) BCRP SNP In a previous study, we screened for BCRP SNPs among a population of Japanese individuals and in human cancer cell lines where we identified three variant BCRP cDNAs harboring the following substitutions: G34A (V12M), C421A (Q141K) and an amino acid deletion of residues 944-949 that lacks Ala-315 and Thr-316 (Δ315-6) [54]. Login to comment
853 In contrast to the above results, the G34A BCRP-transfected PA317 (PA/V12M) cells showed comparable protein expression levels and drug resistance levels to the wild-type BCRP-transfected cells. Login to comment
874 Among these SNPs, with the exception of C376T and C421A, only a few have been studied Table 1 Identified SNPs within the BCRP gene Variation Effect Domain A-1379G - Δ-654/-651 - G-286C - T-476C - Δ-235A - A-113G - A-29G - G34A V12M N-terminal T114C No change N-terminal G151T G51C N-terminal C369T No change NBD C376T Q126stop NBD C421A Q141K NBD C458T T153M NBD C474T No change NBD C496G Q166E NBD A564G No change NBD A616C I206L NBD T623C F208S NBD T742C S248P Linker G1000T E334stop Linker G1098A No change Linker T1291C F431L TMD A1425G No change TMD T1465C F489L TMD A1768T N590Y TMD G1858A D620N TMD G2237T - G2393T - NBD, nucleotide-binding domain; TMD, transmembrane domain. Login to comment
876 The G34A SNP generating an amino acid substitution at position 12 (V12M) has been observed in the Japanese population [54]. Login to comment
878 Transfection studies of the V12M BCRP have shown, however, that the expression levels and drug-resistance associated with this variant are comparable to the wild type BCRP and therefore that this SNP has no significant impact on the BCRP protein activity [54]. Login to comment

[hide] Intracellular trafficking of MDR transporters and ... Curr Top Med Chem. 2009;9(2):197-208. Porcelli L, Lemos C, Peters GJ, Paradiso A, Azzariti A
Intracellular trafficking of MDR transporters and relevance of SNPs.
Curr Top Med Chem. 2009;9(2):197-208., [PMID:19200005]

Abstract [show]
Multi-drug resistance (MDR) frequently contributes to the failure of chemotherapeutic treatments in cancer patients. Mechanisms underlying the development of MDR have been extensively studied and are considered multifactorial. Among them, the ATP-Binding Cassette (ABC) family of proteins plays a pivotal role. Processes of cellular distribution and subcellular localization of MDR-ABC proteins are not yet well explored and to enlighten these topics could be crucial to understand cellular drug uptake and retention. In this review, we analysed literature data concerning i) intracellular trafficking of MDR-ABC proteins (BCRP, P-gp and MRP1) and ii) mechanisms altering their cellular localization and trafficking. Moreover, we describe single nucleotide polymorphisms (SNP) that have been reported for some multidrug resistance (MDR) transporters, such as BCRP and P-gp, emphasizing their ability to affect the expression, function and localization of the transporters, with implications on drug resistance phenotypes.

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149 Polymorphisms and Mutations Affecting the Cellular Localization of MDR Transporters Transporter Variant Amino-acid Change Localization References Intracellular + plasma membrane [99] C421A Q141K Plasma membrane [97, 98, 101] Intracellular + plasma membrane [98, 101] G34A V12M Plasma membrane [97, 99] ABCG2 G1322A S441N Intracellular [97, 98] ABCC1 G128C C43S Intracellular + plasma membrane [116] 4175-4180del RM1392-1393del Intracellular (ER) [118] C2302T R768W Intracellular (ER) [119] A3517T I1173F Intracellular (ER) [120, 121] C2366T S789F Intracellular + plasma membrane [122] ABCC2 G4348A A1459T Intracellular + plasma membrane [122] 293 transfected cells. Login to comment
176 Another nonsynonymous ABCG2 SNP, G34A, which replaces valine by methionine at position 12 (V12M), was identified by Imai et al. Login to comment
178 PA317 cells transfected with this variant (PA/V12M) showed similar levels of ABCG2 protein expression compared with PA/WT, along with similar levels of resistance to the anticancer drugs SN-38, mitoxantrone and topotecan [96]. Login to comment
187 [97] observed a similar cellular localization of V12M and wild-type ABCG2, at the apical membrane of transiently transfected LLC-PK1 cells. Login to comment
188 Although the authors don`t have a good answer to explain the discrepancy, they suggest that the cellular localization of V12M ABCG2 might be affected by the culture conditions of LLC-PK1 cells [97]. Login to comment
190 [98] reported a similar cellular localization of the V12M variant and the wild-type ABCG2 at the plasma membrane and within intracellular compartments in Flp-In-293 cells. Login to comment
191 Of note, these authors showed that the V12M variant provided the cells with higher drug resistance to SN-38 than did the wild-type ABCG2 [98]. Login to comment
192 A plasma membrane localization of the V12M and wild-type ABCG2 in HEK-293 cells was also described by Morisaki et al. Login to comment
217 From these studies it is clear that only the S441N and, possibly, the V12M and Q141K variants might affect ABCG2 localization within the cell. Login to comment

[hide] Clinical relevance of a pharmacogenetic approach u... Clin Cancer Res. 2009 Jul 15;15(14):4750-8. Epub 2009 Jul 7. Kim DH, Sriharsha L, Xu W, Kamel-Reid S, Liu X, Siminovitch K, Messner HA, Lipton JH
Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia.
Clin Cancer Res. 2009 Jul 15;15(14):4750-8. Epub 2009 Jul 7., 2009-07-15 [PMID:19584153]

Abstract [show]
PURPOSE: Imatinib resistance is major cause of imatinib mesylate (IM) treatment failure in chronic myeloid leukemia (CML) patients. Several cellular and genetic mechanisms of imatinib resistance have been proposed, including amplification and overexpression of the BCR/ABL gene, the tyrosine kinase domain point mutations, and MDR1 gene overexpression. EXPERIMENTAL DESIGN: We investigated the impact of 16 single nucleotide polymorphisms (SNP) in five genes potentially associated with pharmacogenetics of IM, namely ABCB1, multidrug resistance 1; ABCG2, breast-cancer resistance protein; CYP3A5, cytochrome P450-3A5; SLC22A1, human organic cation transporter 1; and AGP, alpha1-acid glycoprotein. The DNAs from peripheral blood samples in 229 patients were genotyped. RESULTS: The GG genotype in ABCG2 (rs2231137), AA genotype in CYP3A5 (rs776746), and advanced stage were significantly associated with poor response to IM especially for major or complete cytogenetic response, whereas the GG genotype at SLC22A1 (rs683369) and advanced stage correlated with high rate of loss of response or treatment failure to IM therapy. CONCLUSIONS: We showed that the treatment outcomes of imatinib therapy could be predicted using a novel, multiple candidate gene approach based on the pharmacogenetics of IM.

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203 In the present study, the ABCG2 genotype V12M (rs2231137) was found to be significantly associated with cytogenetic response to imatinib therapy. Login to comment

[hide] ABC-transporter gene-polymorphisms are potential p... Brain. 2009 Sep;132(Pt 9):2517-30. Epub 2009 Jul 15. Cotte S, von Ahsen N, Kruse N, Huber B, Winkelmann A, Zettl UK, Starck M, Konig N, Tellez N, Dorr J, Paul F, Zipp F, Luhder F, Koepsell H, Pannek H, Montalban X, Gold R, Chan A
ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis.
Brain. 2009 Sep;132(Pt 9):2517-30. Epub 2009 Jul 15., [PMID:19605531]

Abstract [show]
Escalation therapy with mitoxantrone (MX) in highly active multiple sclerosis is limited by partially dose-dependent side-effects. Predictors of therapeutic response may result in individualized risk stratification and MX dosing. ATP-binding cassette-transporters ABCB1 and ABCG2 represent multi-drug resistance mechanisms involved in active cellular MX efflux. Here, we investigated the role of ABC-gene single nucleotide polymorphisms (SNPs) for clinical MX response, corroborated by experimental in vitro and in vivo data. Frequencies of ABCB1 2677G>T, 3435C>T and five ABCG2-SNPs were analysed in 832 multiple sclerosis patients (Germany, Spain) and 264 healthy donors. Using a flow-cytometry-based in vitro assay, MX efflux in leukocytes from individuals with variant alleles in both ABC-genes (designated genotype ABCB1/ABCG2-L(ow), 22.2% of patients) was 37.7% lower than from individuals homozygous for common alleles (ABCB1/ABCG2-H(igh), P < 0.05, 14.8% of patients), resulting in genotype-dependent MX accumulation and cell death. Addition of glucocorticosteroids (GCs) inhibited MX efflux in vitro. ABC-transporters were highly expressed in leukocyte subsets, glial and neuronal cells as well as myocardium, i.e. cells/tissues potentially affected by MX therapy. In vivo significance was further corroborated in experimental autoimmune encephalomyelitis in Abcg2(-/-) animals. Using a MX dose titrated to be ineffective in wild-type animals, disease course and histopathology in Abcg2(-/-) mice were strongly ameliorated. Retrospective clinical analysis in MX monotherapy patients (n = 155) used expanded disability status scale, relapse rate and multiple sclerosis functional composite as major outcome parameters. The clinical response rate [overall 121 of 155 patients (78.1%)] increased significantly with genotypes associated with decreasing ABCB1/ABCG2-function [ABCB1/ABCG2-H 15/24 (62.5%) responders, ABCB1/ABCG2-I(ntermediate) 78/98 (79.6%), ABCB1/ABCG2-L 28/33 (84.8%), exact Cochran-Armitage test P = 0.039]. The odds ratio for response was 1.9 (95% CI 1.0-3.5) with each increase in ABCB1/ABCG2 score (from ABCB1/ABCG2-H to -I-, and -I to -L). In 36 patients with severe cardiac or haematological side effects no statistically relevant difference in genotype frequency was observed. However, one patient with biopsy proven cardiomyopathy only after 24 mg/m2 MX exhibited a rare genotype with variant, partly homozygous alleles in 3 ABC-transporter genes. In conclusion, SNPs in ABC-transporter genes may serve as pharmacogenetic markers associated with clinical response to MX therapy in multiple sclerosis. Combined MX/GC-treatment warrants further investigation.

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42 TaqManTM PCR was performed for ABCG2 V12M (reference SNP rs2231137) and Q141K (rs2231142) using Platinum qPCR SuperMix-UDG (Invitrogen, Karlsruhe, Germany) on a 7500 Real Time PCR system (Applied Biosystems, Darmstadt, Germany). Login to comment
70 Retrospective clinical correlation of genotype and MX response Patient samples were genotyped for ABCB1 2677 G4T, 3435C4T, ABCG2 V12M and Q141K and retrospectively correlated with clinical MX response. Login to comment
102 Of five different ABCG2 SNPs with potential functional significance investigated, only reference SNP (rs) 2231137 (G4A) leading to a V12M substitution and rs2231142 (C4A) resulting in a Q141K substitution were observed. Login to comment
110 A high degree of linkage disequilibrium was found between ABCG2 V12M and Q141K [linkage D` = 0.854, (Gaunt et al., 2007)]. Login to comment
207 For ABCG2, only V12M and Q141K polymorphisms could be detected, in vitro leading to disruption of apical membrane localization (V12M) or decreased ATPase function (Q141K) Table 3 Association of ABC-transporter genotype with therapeutic response to MX monotherapy, exact Cochran-Armitage test (P = 0.039) (panel A), or MX/GC combination therapy (P = 0.348) (panel B) Total, n (%) Responder, n (%) Non-Responder, n (%) A: MX monotherapy ABCB1/ABCG2-H 24 (15.5) 15 (62.5) 9 (37.5) ABCB1/ABCG2-I 98 (63.2) 78 (79.6) 20 (20.4) ABCB1/ABCG2-L 33 (21.3) 28 (84.8) 5 (15.2) Total 155 121 (78.1) 34 (21.9) B: MX/GC combination therapy ABCB1/ABCG2-H 21 (13.6) 12 (57.1) 9 (42.9) ABCB1/ABCG2-I 100 (64.9) 58 (58.0) 42 (42.0) ABCB1/ABCG2-L 33 (21.4) 21 (63.6) 12 (36.4) Total 154 91 (59.1) 63 (40.9) Retrospective analysis using EDSS, relapse rate and MSFC as main outcome parameters to define responders and non-responders, respectively. Login to comment

[hide] Single nucleotide polymorphism in ABCG2 is associa... J Hum Genet. 2009 Oct;54(10):572-80. Epub 2009 Aug 21. Cha PC, Mushiroda T, Zembutsu H, Harada H, Shinoda N, Kawamoto S, Shimoyama R, Nishidate T, Furuhata T, Sasaki K, Hirata K, Nakamura Y
Single nucleotide polymorphism in ABCG2 is associated with irinotecan-induced severe myelosuppression.
J Hum Genet. 2009 Oct;54(10):572-80. Epub 2009 Aug 21., [PMID:19696792]

Abstract [show]
Irinotecan is an anti-neoplastic agent that is widely used for treating colorectal and lung cancers, but often causes toxicities such as severe myelosuppression and diarrhea. In this study, we performed a two-stage case-control association study for irinotecan-induced severe myelosuppression (grades 3 and 4). In the first stage, 23 patients who developed severe myelosuppression and 58 patients who did not develop any toxicity were examined for 170 single nucleotide polymorphisms (SNPs) in 14 genes involved in the metabolism and transport of irinotecan. A total of five SNPs were identified to show the possible association with severe myelosuppression (P(Fisher)<0.01) and were further examined in 7 cases and 20 controls in the second stage of the study. An intronic SNP, rs2622604, in ABCG2 showed P(Fisher)=0.0419 in the second stage and indicated a significant association with severe myelosuppression in the combined study (P(Fisher)=0.000237; P(Corrected)=0.036). Although only limited subjects were investigated, our results suggested that a genetic polymorphism in ABCG2 might alter the transport activity for the drug and elevate the systemic circulation level of irinotecan, leading to severe myelosuppression.

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48 In addition to this SNP, rs7977213 in SLCO1B3 as well as the UGT1A7*3 variant Table 1 Demographical characteristic of patients First study Second study Combined study Case (N¼23) Control (N¼58) Case (N¼7) Control (N¼20) Case (N¼30) Control (N¼78) Age 62.04 (37-77) 60.29 (34-77) 60.29 (40-81) 67.60 (50-84) 61.63 (37-81) 62.21 (34-84) % of men 61 71 57 42 60 65 Types of cancers Lung 12 52% 10 17% 2 29% 4 17% 14 47% 14 18% Cervical 6 26% 2 3% 0 0% 0 0% 6 20% 2 3% Colorectal 3 13% 35 60% 3 43% 13 57% 6 20% 48 62% Gastric 1 4% 4 7% 1 14% 2 9% 2 7% 6 8% Ovarian 0 0% 2 3% 1 14% 1 4% 1 3% 3 4% Breast+cervical 1 4% 0 0% 0 0% 0 0% 1 3% 0 0% Pancreatic 0 0% 1 2% 0 0% 0 0% 0 0% 1 1% Esophageal 0 0% 1 2% 0 0% 0 0% 0 0% 1 1% Breast 0 0% 1 2% 0 0% 0 0% 0 0% 1 1% No information 0 0% 2 0% 0 0% 0 0% 0 0% 2 3% Types of regimens CPT-11 1 4% 11 19% 1 14% 2 9% 2 6% 13 17% Other drug combinations 22 96% 47 81% 6 86% 18 91% 28 94% 65 83% Associations of 170 SNPs with severe myelosuppression in subjects who received irinotecan therapy Allele Frequency of allele 1 Fisher test`s P-values Gene name SNP ID Position of SNP/functional SNP 1 2 dCase eControl f1vs2 g11vs h22vs Odds ratio UGT1A9 rs3832043 UGT1A9*1b or *22 9T 10T 0.63 0.63 1.00E+00 8.05EÀ01 7.33EÀ01 0.76 UGT1A7 rs17868323 Exon 1 (Lys 129 Asn) T G 0.54 0.63 3.72EÀ01 1.00E+00 1.16EÀ01 2.68 UGT1A7 1A7_R131Kaa Exon 1 (R131K) (UGT1A7*2) C A 0.54 0.63 3.72EÀ01 1.00E+00 1.16EÀ01 2.68 UGT1A7 1A7_R131Kba Exon 1 (R131K) (UGT1A7*2) G A 0.54 0.63 3.72EÀ01 1.00E+00 1.16EÀ01 2.68 UGT1A7 rs11692021 Exon 1 (Arg 208 Trp) (UGT1A7*3) T C 0.65 0.76 1.71EÀ01 1.00E+00 6.72EÀ03 15.56 UGT1A1 rs887829 Intron (tagged UGT1A1*28, promoter indel) G A 0.96 0.90 3.53EÀ01 1.64EÀ01 1.00E+00 5.15 UGT1A1 rs4148323 Exon 1 (Arg 71 Gly) (UGT1A1*6) G A 0.76 0.78 8.34EÀ01 4.51EÀ01 2.14EÀ02 12.00 UGT1A1 rs35350960 Exon 1 (Gln 229 Pro) (UGT1A1*27) C A 1.00 0.99 1.00E+00 1.00E+00 1.00E+00 NA BCHE rs697356 3' near gene G C 0.30 0.40 2.74EÀ01 4.95EÀ01 4.46EÀ01 1.64 BCHE rs1007845 3' near gene G A 0.83 0.78 6.67EÀ01 6.13EÀ01 1.00E+00 1.40 BCHE rs2048493 Intron 2 C G 0.78 0.62 6.41EÀ02 5.08EÀ02 4.29EÀ01 2.74 BCHE rs4639017 Intron 1 C G 0.72 0.60 2.07EÀ01 2.07EÀ01 7.17EÀ01 2.07 ABCC5 rs6810123 3' near gene A G 0.33 0.41 3.72EÀ01 1.00E+00 2.07EÀ01 2.07 ABCC5 rs12638772 3' near gene A G 0.36 0.32 7.07EÀ01 2.50EÀ01 1.00E+00 2.36 ABCC5 rs7613247 3' near gene A G 0.93 0.94 1.00E+00 1.00E+00 1.00E+00 1.15 ABCC5 rs2176825 3' near gene A G 0.25 0.37 1.81EÀ01 5.07EÀ01 2.07EÀ01 1.98 ABCC5 rs13066518 3' near gene T A 0.33 0.39 4.78EÀ01 1.00E+00 4.50EÀ01 1.62 ABCC5 rs3749443 3' near gene A G 0.20 0.18 1.00E+00 1.00E+00 7.90EÀ01 1.29 ABCC5 rs1402001 3' near gene A G 0.52 0.57 6.03EÀ01 7.95EÀ01 2.30EÀ01 2.10 ABCC5 rs6790814 3' near gene C G 0.66 0.76 2.33EÀ01 4.63EÀ01 1.25EÀ01 4.42 ABCC5 rs9838667 3' near gene T G 0.34 0.46 2.12EÀ01 5.64EÀ01 3.05EÀ01 1.85 ABCC5 rs2280392 3' near gene G A 0.25 0.23 8.35EÀ01 3.40EÀ01 8.02EÀ01 2.84 ABCC5 rs1879257 3' near gene A G 0.43 0.32 2.02EÀ01 3.07EÀ01 3.27EÀ01 2.02 ABCC5 rs3817403 3' near gene A G 0.87 0.90 7.82EÀ01 1.00E+00 1.00E+00 1.19 ABCC5 rs3805111 3' near gene T C 0.09 0.10 7.85EÀ01 1.00E+00 7.72EÀ01 1.24 ABCC5 rs3805108b 3' near gene A G 0.11 0.19 2.50EÀ01 6.69EÀ01 4.00EÀ01 1.97 ABCC5 rs2872247 3' near gene T G 0.76 0.70 4.49EÀ01 6.30EÀ01 6.67EÀ01 1.30 ABCC5 rs2293001 3' near gene T C 0.48 0.54 6.00EÀ01 7.79EÀ01 5.56EÀ01 1.44 ABCC5 rs4148572 Intron 2 C G 0.33 0.22 1.60EÀ01 1.36EÀ01 3.30EÀ01 4.20 ABCC5 rs4148568 Intron 2 A G 0.13 0.18 6.37EÀ01 5.85EÀ01 7.89EÀ01 NA ABCC5 rs4148564 Intron 2 A G 0.89 0.82 3.44EÀ01 3.00EÀ01 1.00E+00 1.89 ABCC5 rs4148560 Intron 2 A T 0.78 0.80 8.30EÀ01 7.96EÀ01 1.36EÀ01 4.20 ABCC5 rs7624838 Intron 2 T C 0.50 0.52 8.63EÀ01 7.82EÀ01 1.00E+00 1.26 ABCG2 rs2231164 Intron 14 C T 0.36 0.39 8.56EÀ01 5.57EÀ02 4.46EÀ01 NA ABCG2 rs2622611 Intron 10 T G 0.16 0.18 8.20EÀ01 3.29EÀ01 1.00E+00 NA ABCG2 rs1871744 Intron 6 T C 0.55 0.69 9.76EÀ02 3.22EÀ01 1.71EÀ01 2.73 ABCG2 rs2231142 Exon 5 (Gln 141 Lys) C A 0.78 0.78 1.00E+00 1.00E+00 1.00E+00 0.79 ABCG2 rs2231137 Exon 2 (Val 12 Met) G A 0.67 0.79 1.53EÀ01 3.19EÀ01 1.36EÀ01 4.20 ABCG2 rs1564481 Intron 1 C T 0.72 0.62 2.77EÀ01 3.15EÀ01 6.67EÀ01 1.74 ABCG2 rs2622624 Intron 1 A G 0.41 0.29 1.93EÀ01 2.78EÀ01 3.35EÀ01 2.41 ABCG2 rs2622604 Intron 1 T C 0.28 0.09 2.35EÀ03 7.81EÀ02 6.66EÀ03 4.40 ABCB1 rs1882478 Intron 27 C T 0.59 0.55 7.27EÀ01 4.31EÀ01 7.57EÀ01 1.57 ABCB1 rs6979885 Intron 27 G A 0.89 0.91 1.00E+00 1.00E+00 1.00E+00 1.19 ABCB1 rs2235047 Intron 27 T G 0.50 0.52 8.63EÀ01 7.82EÀ01 1.00E+00 1.26 ABCB1 rs1045642 Exon 27 (Ile 3 Ile) T C 0.37 0.44 4.80EÀ01 1.00E+00 4.34EÀ01 1.67 ABCB1 rs1002205 Intron 26 C G 0.52 0.60 3.75EÀ01 4.21EÀ01 7.14EÀ01 1.70 ABCB1 rs6949448 Intron 26 T C 0.35 0.40 5.91EÀ01 1.00E+00 6.09EÀ01 1.42 ABCB1 rs2235067 Intron 23 A G 0.07 0.11 5.60EÀ01 1.00E+00 5.36EÀ01 1.83 ABCB1 rs2373588 Intron 22 T C 0.43 0.39 5.98EÀ01 7.20EÀ01 7.99EÀ01 1.53 ABCB1 rs7787082 Intron 22 A G 0.50 0.50 1.00E+00 7.72EÀ01 7.72EÀ01 NA ABCB1 rs3789246 Intron 20 A G 0.09 0.19 1.50EÀ01 5.51EÀ01 2.69EÀ01 2.31 ABCB1 rs1922242b Intron 17 A T 0.78 0.68 2.45EÀ01 3.24EÀ01 4.90EÀ01 1.74 ABCB1 rs2235046 Intron 17 A G 0.72 0.59 1.51EÀ01 4.38EÀ02 1.00E+00 2.89 ABCB1 rs868755 Intron 9 C A 0.59 0.61 1.00E+00 1.00E+00 7.29EÀ01 1.36 ABCB1 rs4148734 Intron 8 C T 0.87 0.90 7.79EÀ01 5.42EÀ01 1.00E+00 1.55 ABCB1 rs2235018 Intron 6 A G 0.67 0.81 9.65EÀ02 2.09EÀ01 1.40EÀ01 4.13 ABCB1 rs10256836a Intron 5 C G 0.13 0.09 5.68EÀ01 1.00E+00 5.31EÀ01 1.73 ABCB1 rs10259849a Intron 5 C T 0.14 0.10 5.75EÀ01 1.00E+00 5.36EÀ01 1.65 ABCB1 rs1202172 Intron 5 T G 0.96 0.86 1.01EÀ01 8.01EÀ02 1.00E+00 4.00 Table 2 Continued Allele Frequency of allele 1 Fisher test`s P-values Gene name SNP ID Position of SNP/functional SNP 1 2 dCase eControl f1vs2 g11vs h22vs Odds ratio ABCB1 rs17327442 Intron 5 T A 0.89 0.94 5.12EÀ01 4.93EÀ01 1.00E+00 1.87 ABCB1 rs1202184 Intron 5 G A 0.24 0.33 3.44EÀ01 1.00E+00 2.25EÀ01 1.91 ABCB1 rs3789243 Intron 4 T C 0.50 0.31 2.81EÀ02 5.05EÀ02 1.38EÀ01 3.50 ABCB1 rs3213619 Exon 2 (5' UTR) C T 0.02 0.10 1.81EÀ01 1.00E+00 1.63EÀ01 5.02 ABCB1 rs4148732 Intron 1 A G 0.87 0.96 7.89EÀ02 6.87EÀ02 1.00E+00 3.67 ABCB1 rs13233308 Intron 1 T C 0.43 0.44 1.00E+00 7.60EÀ01 7.95EÀ01 0.82 ABCB1 rs1978095 Intron 1 T C 0.67 0.73 5.59EÀ01 6.21EÀ01 6.89EÀ01 1.36 ABCB1 rs2157929 Intron 1 T C 0.93 0.79 3.32EÀ02 5.60EÀ02 5.51EÀ01 3.81 ABCB1 rs10278483 Intron 1 T C 0.96 0.86 1.01EÀ01 1.36EÀ01 5.88EÀ01 3.34 CYP3A5 rs776746 Intron 3 (CYP3A5*3) A G 0.22 0.32 2.50EÀ01 6.67EÀ01 3.26EÀ01 1.79 CYP3A4 rs28371759c Exon 10 (Pro 293 Leu) (CYP3A4*18) 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA CYP3A4 rs12721627b Exon 7 (Ser 185 Thr) (CYP3A4*16) C G 1.00 0.96 3.23EÀ01 3.22EÀ01 1.00E+00 NA ABCC2 rs12268782 5' near gene A G 0.22 0.13 2.26EÀ01 1.00E+00 1.81EÀ01 2.21 ABCC2 rs2804398 Intron 7 T A 0.83 0.84 8.14EÀ01 7.90EÀ01 1.00E+00 1.29 ABCC2 rs2756109 Intron 7 G T 0.63 0.65 8.55EÀ01 1.00E+00 1.00E+00 1.12 ABCC2 rs2273697 Exon 10 (Ile 417 Val) G A 0.83 0.92 8.91EÀ02 5.96EÀ02 1.00E+00 3.33 ABCC2 rs11190291a Intron 11 T C 0.17 0.08 8.91EÀ02 1.00E+00 5.96EÀ02 3.33 ABCC2 rs2002042 Intron 19 T C 0.33 0.39 4.78EÀ01 2.78EÀ01 1.00E+00 3.52 ABCC2 rs17222723c Exon 25 (Glu 1188 Val) T A 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA ABCC2 rs3740065b Intron 29 T C 0.65 0.60 5.96EÀ01 6.18EÀ01 9.90EÀ02 6.36 ABCC2 rs12762549 3' near gene C G 0.48 0.36 2.13EÀ01 1.00E+00 6.81EÀ02 3.35 ABCC2 rs2862691 3' near gene T C 0.19 0.25 5.26EÀ01 6.05EÀ01 6.11EÀ01 NA ABCC2 rs11598781 3' near gene T C 0.17 0.27 2.30EÀ01 1.00E+00 1.40EÀ01 2.29 ABCC2 rs11190303 3' near gene T C 0.24 0.33 2.62EÀ01 5.33EÀ02 1.00E+00 NA SLCO1B3 rs12228798 Intron 1 C T 0.82 0.83 1.00E+00 7.77EÀ01 2.27EÀ01 NA SLCO1B3 rs7977213 Intron 2 G C 0.43 0.18 1.29EÀ03 1.31EÀ03 2.55EÀ02 NA SLCO1B3 rs10841661 Intron 2 T C 0.48 0.23 2.73EÀ03 5.65EÀ03 4.79EÀ02 9.88 SLCO1B3 rs4149118 Intron 4 A G 0.59 0.48 3.31EÀ01 3.49EÀ01 5.40EÀ01 1.85 SLCO1B3 rs3764009a Intron 4 A G 0.68 0.69 1.00E+00 1.00E+00 1.00E+00 1.16 SLCO1B3 rs7311358 Exon 7 (Ile 233 Met) A G 0.68 0.69 1.00E+00 1.00E+00 1.00E+00 1.16 SLCO1B3 rs11045585b Intron 12 G A 0.13 0.21 2.76EÀ01 3.14EÀ01 6.06EÀ01 NA SLCO1B3 rs980084 Intron 12 G C 0.28 0.45 7.48EÀ02 3.80EÀ01 7.66EÀ02 2.67 SLCO1B3 rs3764006 Exon 14 (Gly 611 Gly) T C 0.87 0.70 2.74EÀ02 1.32EÀ01 9.75EÀ02 NA SLCO1B3 rs919840 3' near gene C G 0.97 0.90 2.99EÀ01 2.77EÀ01 1.00E+00 3.74 SLCO1B3 rs2117032 3' near gene T C 0.52 0.47 6.05EÀ01 7.68EÀ01 7.82EÀ01 1.35 SLCO1B3 rs7312051 3' near gene C T 1.00 0.91 1.26EÀ01 1.04EÀ01 1.00E+00 NA SLCO1B3 rs10841714 3' near gene C T 0.15 0.17 8.01EÀ01 1.00E+00 1.00E+00 NA SLCO1B3 rs2174012 3' near gene T C 0.62 0.63 1.00E+00 5.72EÀ01 4.55EÀ01 0.39 SLCO1B3 rs11045639a 3' near gene G A 0.65 0.72 4.46EÀ01 2.17EÀ01 7.25EÀ01 2.05 SLCO1B3 rs2900459 3' near gene G A 0.46 0.56 2.95EÀ01 1.43EÀ02 5.70EÀ01 5.96 SLCO1B3 rs4762693 3' near gene G A 0.65 0.72 4.46EÀ01 2.17EÀ01 7.25EÀ01 2.05 SLCO1B3 rs10734711 3' near gene A G 0.28 0.35 4.61EÀ01 2.78EÀ01 8.05EÀ01 3.52 SLCO1B1 rs12228427 5' near gene (LST-3TM12 Intron 9) A G 0.96 0.88 1.59EÀ01 1.36EÀ01 1.00E+00 3.34 SLCO1B1 rs1910163 5' near gene (LST-3TM12 Intron 12) A T 0.28 0.34 4.66EÀ01 7.25EÀ01 6.21EÀ01 1.44 SLCO1B1 rs6487207 5' near gene (LST-3TM12 Intron 11) T G 0.78 0.73 5.54EÀ01 8.11EÀ01 3.22EÀ01 NA SLCO1B1 rs1604539 5' near gene (LST-3TM12 Intron 12) T G 0.80 0.75 5.41EÀ01 6.18EÀ01 1.00E+00 1.42 SLCO1B1 rs7973691 5' near gene T C 0.80 0.83 8.21EÀ01 7.98EÀ01 1.00E+00 1.22 SLCO1B1 rs10743408 Intron 2 C G 0.24 0.18 4.97EÀ01 1.00E+00 3.06EÀ01 1.73 SLCO1B1 rs976754 Intron 2 T C 0.83 0.69 1.15EÀ01 8.67EÀ02 6.67EÀ01 2.54 SLCO1B1 rs2291073 Intron 3 T G 0.78 0.72 4.35EÀ01 8.11EÀ01 1.76EÀ01 NA SLCO1B1 rs4149037 Intron 4 A G 0.70 0.80 2.12EÀ01 2.07EÀ01 6.19EÀ01 2.07 SLCO1B1 rs4149056 Exon 5 (Ala 174 Val) T C 0.72 0.84 8.02EÀ02 2.04EÀ01 8.01EÀ02 NA SLCO1B1 rs2417967 Intron 11 A G 0.33 0.21 1.54EÀ01 1.00E+00 8.68EÀ02 2.41 SLCO1B1 rs7969341b Intron 14 T C 0.50 0.46 7.24EÀ01 1.58EÀ01 5.60EÀ02 3.80 SLCO1B1 rs4149085 3' UTR T C 0.74 0.66 4.53EÀ01 8.05EÀ01 1.76EÀ01 NA SLCO1B1 rs12372067 3' near gene C A 0.21 0.33 2.06EÀ01 1.00E+00 1.68EÀ01 2.42 SLCO1B1 rs12310063 3' near gene A C 0.67 0.76 3.21EÀ01 2.13EÀ01 1.00E+00 2.07 ABCC1 rs8050881 5' near gene A G 0.33 0.23 2.37EÀ01 1.00E+00 1.44EÀ01 2.13 ABCC1 rs4148330 5' near gene G A 0.48 0.34 1.46EÀ01 2.95EÀ01 2.13EÀ01 2.02 Continued Allele Frequency of allele 1 Fisher test`s P-values Gene name SNP ID Position of SNP/functional SNP 1 2 dCase eControl f1vs2 g11vs h22vs Odds ratio ABCC1 rs7190484 Intron 1 T C 0.43 0.34 3.67EÀ01 5.03EÀ01 4.62EÀ01 1.52 ABCC1 rs215098 Intron 1 C A 0.41 0.34 4.63EÀ01 1.96EÀ01 1.00E+00 2.30 ABCC1 rs215096 Intron 1 T C 0.89 0.87 1.00E+00 5.63EÀ01 2.89EÀ01 0.00 ABCC1 rs152023 Intron 1 G A 0.48 0.41 4.75EÀ01 3.79EÀ01 8.05EÀ01 1.79 ABCC1 rs6498595 Intron 1 G C 0.41 0.31 2.70EÀ01 2.73EÀ02 1.00E+00 4.76 ABCC1 rs7196970 Intron 1 C G 0.70 0.63 4.71EÀ01 3.25EÀ01 1.00E+00 1.73 ABCC1 rs12935283 Intron 1 A G 0.67 0.61 4.78EÀ01 3.19EÀ01 1.00E+00 1.79 ABCC1 rs246240 Intron 5 A G 0.60 0.58 1.00E+00 1.00E+00 1.00E+00 1.06 ABCC1 rs924138b Intron 5 T C 0.68 0.63 5.84EÀ01 6.17EÀ01 1.00E+00 1.38 ABCC1 rs2062541 Intron 6 C T 0.71 0.64 4.46EÀ01 4.45EÀ01 7.51EÀ01 1.60 ABCC1 rs11647513 Intron 6 C T 0.78 0.70 3.34EÀ01 2.14EÀ01 1.00E+00 2.13 ABCC1 rs35593 Intron 11 T C 0.71 0.75 8.37EÀ01 1.00E+00 1.00E+00 2.70 ABCC1 rs3765129 Intron 11 C T 0.98 0.84 2.69EÀ02 1.75EÀ02 1.00E+00 9.90 ABCC1 rs17287570 Intron 12 A C 0.73 0.91 6.32EÀ03 1.03EÀ02 2.75EÀ01 4.27 ABCC1 rs35597 Intron 12 A G 0.59 0.55 7.19EÀ01 5.85EÀ01 1.00E+00 1.45 ABCC1 rs35598a Intron 12 A G 0.82 0.86 6.21EÀ01 7.86EÀ01 2.78EÀ01 NA ABCC1 rs9932506 Intron 12 G A 0.72 0.75 6.94EÀ01 6.21EÀ01 1.00E+00 1.44 ABCC1 rs35604 Intron 12 G A 0.24 0.25 1.00E+00 1.00E+00 1.00E+00 1.63 ABCC1 rs35606 Intron 13 C T 0.82 0.86 6.17EÀ01 7.82EÀ01 2.86EÀ01 NA ABCC1 rs35620 Intron 14 G C 0.26 0.23 8.39EÀ01 1.00E+00 6.19EÀ01 1.39 ABCC1 rs35625 Intron 14 C T 0.41 0.34 4.70EÀ01 7.52EÀ01 4.72EÀ01 1.45 ABCC1 rs35626 Intron 15 T G 0.43 0.40 7.21EÀ01 5.08EÀ01 2.96EÀ01 1.93 ABCC1 rs4148353 Intron 15 T G 0.20 0.07 2.42EÀ02 1.00E+00 1.69EÀ02 4.02 ABCC1 rs35629 Intron 15 C T 0.80 0.76 5.46EÀ01 6.24EÀ01 1.00E+00 1.32 ABCC1 rs2269800 Intron 20 A G 0.74 0.66 4.53EÀ01 8.06EÀ01 2.78EÀ01 3.52 ABCC1 rs11864374 Intron 21 G A 0.78 0.77 8.41EÀ01 1.00E+00 1.00E+00 1.63 ABCC1 rs3887893 Intron 22 A G 0.48 0.46 8.62EÀ01 2.30EÀ01 5.85EÀ01 2.10 ABCC1 rs4148376 Intron 23 A G 0.93 0.95 1.00E+00 1.00E+00 1.00E+00 1.30 ABCC1 rs2238475 Intron 23 C A 0.11 0.18 3.45EÀ01 1.00E+00 4.21EÀ01 1.80 ABCC1 rs212079 Intron 26 G A 0.76 0.83 3.77EÀ01 1.00E+00 6.71EÀ02 8.55 ABCC1 rs2283512 Intron 26 G T 0.48 0.46 1.00E+00 7.68EÀ01 1.00E+00 1.32 ABCC1 rs212081 Intron 27 T C 0.20 0.22 8.34EÀ01 5.73EÀ01 4.61EÀ01 1.50 ABCC1 rs212084 Intron 28 G A 0.68 0.77 2.90EÀ01 3.02EÀ01 6.00EÀ01 1.81 ABCC1 rs212087 Intron 28 C T 0.57 0.70 1.41EÀ01 1.38EÀ01 3.45EÀ01 2.30 ABCC1 rs4148380 3' UTR G A 0.87 0.89 7.88EÀ01 7.75EÀ01 1.00E+00 1.22 ABCC1 rs212091 3' UTR G A 0.22 0.34 1.84EÀ01 2.68EÀ01 3.35EÀ01 4.04 ABCC1 rs12448760 3' near gene G A 0.82 0.89 2.95EÀ01 3.79EÀ01 1.00E+00 1.79 ABCC1 rs9932935 3' near gene (ABCC6 Intron 29) A T 0.96 0.91 5.12EÀ01 5.00EÀ01 1.00E+00 1.93 ABCC1 rs2066738 3' near gene (ABCC6 Intron 28) C T 0.74 0.90 1.50EÀ02 5.28EÀ02 7.81EÀ02 2.95 ABCC1 rs169845 3' near gene (ABCC6 Intron 27) G C 0.26 0.40 1.04EÀ01 3.28EÀ01 2.13EÀ01 2.07 ABCC1 rs2238471 3' near gene (ABCC6 Intron 26) A C 0.93 0.81 5.49EÀ02 5.79EÀ02 1.00E+00 3.78 ABCC1 rs3213471 3' near gene (ABCC6 Intron 24) A G 0.91 0.92 1.00E+00 7.33EÀ01 1.00E+00 1.32 ABCC1 rs3213473 3' near gene (ABCC6 Intron 24) T G 0.16 0.13 7.98EÀ01 1.00E+00 7.71EÀ01 1.27 CES2 rs3843712 5' near gene G A 0.18 0.12 4.41EÀ01 1.00E+00 4.00EÀ01 1.80 CES2 rs8062110 5' near gene G C 0.61 0.65 7.16EÀ01 1.00E+00 7.28EÀ01 1.39 CES2 rs4783744 5' near gene G A 0.66 0.62 8.37EÀ01 7.76EÀ01 1.00E+00 1.24 CES2 rs7194513 5' near gene G A 0.26 0.27 1.00E+00 3.14EÀ01 6.29EÀ01 NA CES2 rs28382812c Exon 1 (Ile 37 Ile) C T 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA CES2 rs2241410 Intron 2 T G 0.10 0.11 7.85EÀ01 1.00E+00 7.71EÀ01 1.26 CES2 rs2303218 Intron 2 G A 0.09 0.21 1.03EÀ01 5.55EÀ01 1.15EÀ01 2.70 CES2 rs8192924c Exon 5 (His 270 Arg) G A 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA CES2 rs28382827c Exon 12 (Leu 613 Leu) C T 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA Abbreviations: Chrom, chromosome; HWE, Hardy-Weinberg equilibrium; NA, not available; SNP, single nucleotide polymorphism. 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[hide] Additive effects of drug transporter genetic polym... Cancer Chemother Pharmacol. 2010 May;66(1):95-105. Epub 2009 Sep 22. Sai K, Saito Y, Maekawa K, Kim SR, Kaniwa N, Nishimaki-Mogami T, Sawada J, Shirao K, Hamaguchi T, Yamamoto N, Kunitoh H, Ohe Y, Yamada Y, Tamura T, Yoshida T, Matsumura Y, Ohtsu A, Saijo N, Minami H
Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients.
Cancer Chemother Pharmacol. 2010 May;66(1):95-105. Epub 2009 Sep 22., [PMID:19771428]

Abstract [show]
PURPOSE: Effects of genetic polymorphisms/variations of ABCB1, ABCC2, ABCG2 and SLCO1B1 in addition to "UGT1A1*28 or *6" on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients were investigated. METHODS: Associations between transporter haplotypes/variations along with UGT1A1*28 or *6 and SN-38 area under the time-concentration curve (AUC) or neutropenia were examined in irinotecan monotherapy (55 patients) and irinotecan-cisplatin-combination therapy (62 patients). RESULTS: Higher SN-38 AUC values were observed in ABCB1 2677G>T (A893S) (*2 group) for both regimens. Associations of grade 3/4 neutropenia were observed with ABCC2 -1774delG (*1A), ABCG2 421C>A (Q141K) and IVS12 + 49G>T ((#) IIB) and SLCO1B1 521T>C (V174A) (*15 x 17) in the irinotecan monotherapy, while they were evident only in homozygotes of ABCB1*2, ABCG2 (#) IIB, SLCO1B1*15 x 17 in the cisplatin-combination therapy. With combinations of haplotypes/variations of two or more genes, neutropenia incidence increased, but their prediction power for grade 3/4 neutropenia is still unsatisfactory. CONCLUSIONS: Certain transporter genotypes additively increased irinotecan-induced neutropenia, but their clinical importance should be further elucidated.

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41 49G[T G 0.200 0.274 # IIIC [*1b-*3-*1c]e 34G[A(V12M), IVS9-30A[T 0.164 0.097 SLCO1B1 *1b 388A[G(N130D) 0.373 0.573 *15 Á 17 521T[C(V174A) S 0.191 0.153 a Number of chromosome b BJL consists of *1B (having -1789G[A), *1J (having -1789G[A and -371A[G) and *1L (having -1789G[A and -145C[G) previously defined [26] c *2 Group includes *2, *9, *12 and *14 haplotypes previously defined [26] d *10 Group includes *10 and *13 haplotypes previously defined [26] e Combination of ABCG2 haplotypes of three blocks [block (-1)-block 1-block 2] previously defined [28] haplotypes with 2677G[T (A893S), *2, *9, *12 and *14 [26], as the *2 group (*2 in this paper). Login to comment
49 49G[T] (0.251) and # IIIC [containing 34G[A (V12M) and IVS9-30A[T] (0.107). Login to comment
50 Note that # IIB and # IIIC are subgroups of block 1 *2 [421C[A (Q141K)] and block 1*3 [34G[A (V12M)], respectively [28]. Login to comment
157 ABCG2# IIIC contains a non-synonymous SNP 34G[A (V12M) which has no influence on BCRP expression or activity in vitro [36, 39-41]. Login to comment
159 In contrast, a report on Korean patients suggested the association of ABCG2 34G[A (V12M) with a higher incidence of grade 3 diarrhea in a combination therapy of irinotecan and cisplatin [24]. Login to comment

[hide] Drug transporters in the human blood-placental bar... Br J Pharmacol. 2009 Oct;158(3):665-78. Epub 2009 Sep 25. Vahakangas K, Myllynen P
Drug transporters in the human blood-placental barrier.
Br J Pharmacol. 2009 Oct;158(3):665-78. Epub 2009 Sep 25., [PMID:19788499]

Abstract [show]
Studies on the increasing number of transporters found in the placental barrier are gaining momentum, because of their tissue-specific expression, significance in physiology and disease, and the possible utilization of the emerging knowledge in pharmacology. In the placenta, both syncytiotrophoblast and fetal capillary endothelium express transporters. Fetal exposure is determined by the net effect of combination of transporters, their nature and localization in relation to placental cells and their substrate specificity. Although the significance of placental transporters on human fetal drug exposure is almost an unstudied field so far, their potential use to design drugs that do not cross the placenta is already being pursued. It is thus of interest to review the existing knowledge of human placental transporters. Transporters in all groups which take part in drug transport are found in human placenta. Especially, ATP-binding cassette transporters ABCG2/breast cancer resistance protein, ABCB1/P-glycoprotein and ABCC2/MRP2 are all expressed at the apical surface of syncytiotrophoblast facing maternal blood and are putatively important protective proteins both for placental tissue and the fetus, because they are efflux transporters and their substrates include many drugs and also environmental chemicals. Such protective effect has been shown in animals, but these results cannot be directly extrapolated to humans due to interspecies differences in placental structure and function. Experimental models utilizing human placental tissue, especially human placental perfusion, offer valuable possibilities, which have been insufficiently studied so far.

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99 Table 4 Significance of drug transporter polymorphisms in human placenta Protein Gene polymorphisms Type of study Significance in placenta Reference P-gp/MDR1 G2677A/T (Ala toThr/Ser) T-129C 100 human placentas Less P-gp protein Less P-gp protein 1 P-gp/MDR1 G2677T/A C3435T 73 human placentas from Caucasians No effect on MDR1 mRNA Homozygosity of 3435T and 2677T lead to lower protein levels 2 P-gp/MDR1 C3435T 44 human placentas T allele associated with a higher expression 3 P-gp/MDR1 C3435T and G2677A/T Human placental perfusion No effect on saquinavir transfer 3, 4 P-gp/MDR1 C3435T Human placental perfusion 3435T associated with increased transfer of quetiapine 5 MRP2 G1249A 58 human placentas Reduced expression of MRP2 mRNA in preterm placentas only 6 BCRP G34A (Val12Met) C421A (Gln141Lys) 99 human placentas No effect on protein level Protein decreased 7 References: (1) Tanabe et al. (2001), (2) Hitzl et al. (2004), (3) Rahi et al. (2008), (4) Mölsä et al. (2005), (5) Rahi et al. (2007), (6) Meyer zu Schwabedissen et al. (2005b), (7) Kobayashi et al. (2005). Login to comment

[hide] Human ABC transporter ABCG2 in cancer chemotherapy... J Exp Ther Oncol. 2009;8(1):5-24. Ishikawa T, Nakagawa H
Human ABC transporter ABCG2 in cancer chemotherapy and pharmacogenomics.
J Exp Ther Oncol. 2009;8(1):5-24., [PMID:19827267]

Abstract [show]
The ability of cancer cells to acquire resistance to multiple anticancer agents, termed multidrug resistance, is often mediated by overexpression of ATP-binding cassette (ABC) transporters that remove drugs out of the cell against a concentration gradient. ABCG2, or breast cancer resistance protein (BCRP), is an ABC transporter that has been the subject of intense study since its discovery a decade ago. While ABCG2 overexpression has been demonstrated in cancer cells after in vitro drug treatment, endogenous ABCG2 expression in certain cancers is considered as a reflection of the differentiated phenotype of the cell of origin and likely contributes to intrinsic drug resistance. Notably, ABCG2 is often expressed in stem cell populations, where it plays a critical role in cellular protection. ABCG2 exhibits a broad range of substrate specificity. New technologies of high-speed screening and quantitative structure-activity-relationship (QSAR) analysis have been developed to analyze the interactions of drugs with ABCG2. As ABCG2 reportedly transports porphyrins, its contribution to photodynamic therapy of human cancer is also implicated. Protein expression levels of ABCG2 in cancer cells are regulated by both transcriptional activation and protein degradation. The ABCG2 protein undergoes endosomal and/or ubiquitin-mediated proteasomal degradations. Furthermore, genetic polymorphisms in the ABCG2 gene are important factors in cancer chemotherapy to circumvent adverse effects and/or to enhance the efficacy of anticancer drugs. The present review article addresses recent advances in molecular pharmacology and pharmacogenomics of ABCG2 and provides novelideas to improve cancer chemotherapy.

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222 COOH H2N N590Y V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L F489L D620N R482G R482T S441N F571I OUT IN R160Q R575stop ATP-binding site Figure 7. Continued A 005-024 pp JETO-0900616-TI (Review).indd 8/7/2009 3:59:50 19 Q141K has been associated with lower levels of protein expression and impaired transport in vitro (Imai et al., 2002; Kobayashi et al., 2005; Misuarai et al., 2004; Zamber et al., 2003; Morisaki et al., 2008; Kondo et al., 2004). Login to comment
228 Furthermore, the F208S, S248P, F431L, S441N, and F489L variants exhibited greatly altered protein expression levels and drug resistance profiles Figure 7. Continued WT V12M Q141K F208S S248P F431L S441N F489L R482G R482T Protein expression + + + - + + - + + + MTX transport + + + - - - - +/ - - Porphyrin transport + + + - - + - +/ + + SN-38 resistance + + + - +/ + - - + + MX resistance + + + - - - - - -- - - - - - - - +/ - - - - - - - - + + Doxorubicin resistance + + Daunorubicin resistance + + ATPase activity (Prazosin) + + WTV12M Q141K F431L F489L S248P F208S S441L R482G R482T ∆1.5 ∆3 ∆3.5 ∆5 ∆4 - - - - - - -- - - B 005-024 pp JETO-0900616-TI (Review).indd 8/7/2009 3:59:51 20 Journal of Experimental Therapeutics and Oncology Vol. 8 2009 (Tamura et al., 2007b). Login to comment
232 It is known that, in the ER, the N-linked glycans play pivotal roles in protein fold- 0.0 0.5 1.0 1.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T Methotrexatetransport (nmol/min/mgprotein) Methotrexate 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T Methotrexatetransport (nmol/min/mgprotein) MethotrexateMethotrexate Porphyrintransport (nmol/min/mgprotein) 0.0 0.1 0.2 0.3 0.4 0.5 0.0 0.1 0.2 0.3 0.4 0.5 Porphyrin Figure 7. Login to comment
251 The new camptothecin analogues that were non-substrates for ABCG2 circumvented ABCG2-mediated drug resistance without any influence from major SNPs, i.e., V12M and Q141K (Tamura et al. 2007b). Login to comment

[hide] Pharmacogenetics of drug transporters. Curr Pharm Des. 2010;16(2):220-30. Franke RM, Gardner ER, Sparreboom A
Pharmacogenetics of drug transporters.
Curr Pharm Des. 2010;16(2):220-30., [PMID:19835554]

Abstract [show]
During the last decade, a greater focus has been given to impact of genetic variation in membrane transporters on the pharmacokinetics and toxicity of numerous therapeutic drugs. While the majority of transporter-related pharmacogenetic research has been in regards to classic genes encoding the outward-directed ATP-binding cassette (ABC) transporters, such as ABCB1 (P-glycoprotein), ABCC2 (MRP2), and ABCG2 (BCRP), more studies have been conducted in recent years evaluating genes encoding solute carriers (SLC) that mediate the cellular uptake of drugs, such as SLCO1B1 (OATP1B1) and SLC22A1 (OCT1). The distribution of ABC and SLC transporters in tissues key to pharmacokinetics, such as intestine (absorption), blood-brain-barrier (distribution), liver (metabolism), and kidneys (excretion), strongly suggests that genetic variation associated with changes in protein expression or function of these transporters may have a substantial impact on systemic drug exposure and toxicity. In this current article, we will review recent advances in understanding the contribution of critical ABC and SLC transporters to interindividual pharmacokinetic and dynamic variability of substrate drugs.

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104 Several other SNPs have been identified in coding regions of the gene, and at least three additional non-synonymous SNPs have been identified occurring at positions 34 (V12M; exon 2), 616 (I206L, exon 6), and 1768 (N590Y, exon 15). Login to comment

[hide] Pharmacogenetics of ATP-binding cassette transport... Methods Mol Biol. 2010;596:95-121. Cascorbi I, Haenisch S
Pharmacogenetics of ATP-binding cassette transporters and clinical implications.
Methods Mol Biol. 2010;596:95-121., [PMID:19949922]

Abstract [show]
Drug resistance is a severe limitation of chemotherapy of various malignancies. In particular efflux transporters of the ATP-binding cassette family such as ABCB1 (P-glycoprotein), the ABCC (multidrug resistance-associated protein) family, and ABCG2 (breast cancer resistance protein) have been identified as major determinants of chemoresistance in tumor cells. Bioavailability depends not only on the activity of drug metabolizing enzymes but also to a major extent on the activity of drug transport across biomembranes. They are expressed in the apical membranes of many barrier tissues such as the intestine, liver, blood-brain barrier, kidney, placenta, testis, and in lymphocytes, thus contributing to plasma, liquor, but also intracellular drug disposition. Since expression and function exhibit a broad variability, it was hypothesized that hereditary variances in the genes of membrane transporters could explain at least in part interindividual differences of pharmacokinetics of a variety of anticancer drugs and many others contributing to the clinical outcome of certain leukemias and further malignancies.

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224 Both identified 34G>A (V12M) and 421C>A (Q141K). Login to comment
232 Moreover, decreased transport rates were found in Sf9 insect cells, transfected with the V12M variant (119). Login to comment
239 0.235 c. 34 G>A V12M 0.17 0.04a 0.06b IVS 2 +16 A>G ? Login to comment
258 Interestingly, V12M was associated with elevated activity compared to the wild-type, whereas ABCG2 with premature stop-codon lacked any activity as expected (37). Login to comment

[hide] Flow cytometric evaluation of multidrug resistance... Methods Mol Biol. 2010;596:123-39. Aszalos A, Taylor BJ
Flow cytometric evaluation of multidrug resistance proteins.
Methods Mol Biol. 2010;596:123-39., [PMID:19949923]

Abstract [show]
There are several ways to detect proteins on cells. One quite frequently used method is flow cytometry. This method needs fluorescently labeled antibodies that can attach selectively to the protein to be investigated for flow cytometric detection. Flow cytometry scans individual cells, virtually without their surrounding liquid, and can scan many cells in a very short time. Because of this advantage of flow cytometry, it was adapted to investigate transport proteins on normal and cancerous human cells and cell lines. These transport proteins play important roles in human metabolism. Absorption in the intestine, excretion at the kidney, protection of the CNS compartment and the fetus from xenobiotics, and other vital functions depend on these transporters. However, several transporters are overexpressed in cancer cells. These overexpressed transporters pump out anticancer drugs from the cells and prevent their curative effects. The detection and quantitation of these types of transporters in cancer cells is important for this reason. Here, we review literature on flow cytometric detection of the three most studied transporters: P-glycoprotein, multidrug resistance-associated proteins, and breast cancer resistance protein.

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258 The V12M and Q141K variants were described by Zamber et al. Login to comment

[hide] Impact of breast cancer resistance protein on canc... Methods Mol Biol. 2010;596:251-90. Ross DD, Nakanishi T
Impact of breast cancer resistance protein on cancer treatment outcomes.
Methods Mol Biol. 2010;596:251-90., [PMID:19949928]

Abstract [show]
Breast cancer resistance protein (BCRP/ABCG2) was discovered in multidrug resistant breast cancer cells having an ATP-dependent transport-based resistance phenotype. This ABC transporter functions (at least in part) as a xenobiotic protective mechanism for the organism: in the gut and biliary tract, it prevents absorption and enhances elimination of potentially toxic substances. As a placental barrier, it protects the fetus; similarly, it serves as a component of blood-brain and blood-testis barrier; BCRP is expressed in stem cells and may protect them from potentially harmful agents. Therefore, BCRP could influence cancer outcomes by (a) endogenous BCRP affecting the absorption, distribution, metabolism, and elimination of anticancer drugs; (b) BCRP expression in cancer cells may directly cause resistance by active efflux of anticancer drugs; (c) BCRP expression in cancer cells could be a manifestation of the activity of metabolic and signaling pathways that impart multiple mechanisms of drug resistance, self-renewal (stemness), and invasiveness (aggressiveness)--i.e. impart a poor prognosis--to cancers. This chapter presents a synopsis of translational clinical studies relating BCRP expression in leukemias, lymphomas, and a variety of solid tumors with clinical outcome. Data are emerging that expression of BCRP, like P-glycoprotein/ABCB1, is associated with adverse outcomes in a variety of human cancers. Whether this adverse prognostic effect results from resistance imparted to the cancer cells as the direct result of BCRP efflux of anticancer drugs, or whether BCRP expression (and also Pgp expression - coexpression of these transporters is common among poor risk cancers) serves as indicators of the activity of signaling pathways that enhance cancer cellular proliferation, metastases, genomic instability, enhance drug resistance, and oppose programmed cell death mechanisms is yet unknown.

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70 A number of single nucleotide polymorphisms (SNPs) have been observed in the BCRP gene (77), and of those nonsynonymous SNPs observed in the coding region, the most common and most extensively studied are the G34A (exon 2) and C421A (exon 5) alleles, which cause alterations of amino acids 12 (V12M) and 141 (Q141K), respectively (78-81). Login to comment
90 found four nonsynonymous coding region SNPs among 92 Korean subjects (V12M, Q141K, P269S, Q126Stop), and four SNPs in the BCRP promoter region, one of which was in the HIF-1 response element (C-19031T) (86). Login to comment
93 Tamura et al. used multicolor fluorescence in situ hybridization to assure uniform mRNA expression of cDNAs of seven BCRP SNPs (V12M, Q141K, F208S, S248P, F431L, S441N and F489L) transduced into Flp-In-293 cells (87, 88). Login to comment
94 Protein expression from the F208S and S441N variants was found to be low; the V12M and Q141K alleles had IC50 s for SN-38 that were approximately half that of the wild-type; all the other alleles examined had significantly lower IC50 values for SN-38, mitoxantrone, doxorubicin, daunorubicin and etoposide when compared with wild type alleles (88). Login to comment

[hide] Pharmacogenetics of membrane transporters: an upda... Mol Biotechnol. 2010 Feb;44(2):152-67. Sissung TM, Baum CE, Kirkland CT, Gao R, Gardner ER, Figg WD
Pharmacogenetics of membrane transporters: an update on current approaches.
Mol Biotechnol. 2010 Feb;44(2):152-67., [PMID:19950006]

Abstract [show]
This review provides an overview of the pharmacogenetics of membrane transporters including selected ABC transporters (ABCB1, ABCC1, ABCC2, and ABCG2) and OATPs (OATP1B1 and OATP1B3). Membrane transporters are heavily involved in drug clearance and alters drug disposition by actively transporting substrate drugs between organs and tissues. As such, polymorphisms in the genes encoding these proteins may have significant effects on the absorption, distribution, metabolism and excretion of compounds, and may alter pharmacodynamics of many agents. This review discusses the techniques used to identify substrates and inhibitors of these proteins and subsequently to assess the effect of genetic mutation on transport, both in vitro and in vivo. A comprehensive list of substrates for the major drug transporters is included. Finally, studies linking transporter genotype with clinical outcomes are discussed.

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61 Another SNP exists at nucleotide 34, resulting in a V12M amino acid change. Login to comment

[hide] Placental P-glycoprotein and breast cancer resista... Placenta. 2010 May;31(5):351-7. Epub 2010 Mar 27. Hutson JR, Koren G, Matthews SG
Placental P-glycoprotein and breast cancer resistance protein: influence of polymorphisms on fetal drug exposure and physiology.
Placenta. 2010 May;31(5):351-7. Epub 2010 Mar 27., [PMID:20347140]

Abstract [show]
Recent studies have illustrated the importance of placental drug transport proteins, such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in limiting fetal exposure to drugs and toxins. Moreover, increasing evidence supports a role for Pgp and BCRP in the normal development and physiological function of the placenta. Several single nucleotide polymorphisms (SNPs) in the genes encoding Pgp and BCRP have been described and are associated with altered protein expression, transporter activity, and clinical outcome in studies focusing on tissues other than the placenta. This review aims to summarize current research regarding the association between these polymorphisms and expression and function in the placenta. The influence of these genotypes on fetal drug exposure and altered placental physiology or development is also presented. To date, evidence suggests that SNPs in both ABCB1 and ABCG1 can alter expression of their respective protein; however, the functional significance of these polymorphisms is less clear. An understanding of this genotype-phenotype relationship will allow for prediction of susceptible or favorable genotypes in order to personalize medication choices to minimize fetal exposure to teratogens, or to maximize pharmacological therapy to the fetus.

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142 The G34A and C421 SNPs result in amino acid changes (V12M and Q141K respectively). Login to comment

[hide] Effect of ABCG2 genotypes on the pharmacokinetics ... Eur J Clin Pharmacol. 2011 Feb;67(2):129-34. Epub 2010 Oct 23. Kim KA, Joo HJ, Park JY
Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level.
Eur J Clin Pharmacol. 2011 Feb;67(2):129-34. Epub 2010 Oct 23., [PMID:20972558]

Abstract [show]
OBJECTIVE: It has been reported that leflunomide and its active metabolite, A771726, are substrates of the ABCG2 (BCRP) transporter in vitro. Recent genome-wide association studies have shown that ABCG2 transporter modulates serum uric acid (UA) levels. We explored the role of ABCG2 genotypes in the pharmacokinetics of A771726 and the relationship between serum UA levels and pharmacokinetics of A771726 in healthy participants. METHODS: Twenty-four healthy individuals were recruited and genotyped for ABCG2. After administration of a single dose of 20 mg leflunomide, plasma concentrations of A771726 were measured. Serum UA levels were measured just before medication, and ABCG2 c.421C>A and c.34G> A polymorphism were genotyped. RESULTS: ABCG2 c.421C>A but not c.34G>A substantially influenced the pharmacokinetics of A771726. A771726 C(max) was 30% higher, area under the concentration-time curve (AUC) 83% larger, and oral clearance (CL/F) 41% lower in c.421C>A carriers than in noncarriers. Serum UA levels were also higher in carriers than in noncarriers and exhibited a strong and positive correlation with A771726 AUC (Spearman r = 0.6746, P = 0.0003), but a negative correlation was observed with A771726 CL/F (Spearman r = -0.6616, P = 0.0004). CONCLUSION: ABCG2 c.421C>A but not c.34G>A polymorphism appears to be a major determinant of interindividual variability in A771726 disposition. Additionally, serum UA levels exhibited a strong correlation with exposure to A771726.

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17 Several ABCG2 genetic variants have been reported; the most frequent ABCG2 polymorphisms detected among different ethnic groups are c.34G>A (rs2231137), which codes for V12M, and c.421C>A (rs2231142), which codes for Q141K [4]. Login to comment

[hide] ABCG2 polymorphisms, 34G>A and 421C>A in a Korean ... J Clin Pharm Ther. 2010 Dec;35(6):705-12. doi: 10.1111/j.1365-2710.2009.01127.x. Kim KA, Joo HJ, Park JY
ABCG2 polymorphisms, 34G>A and 421C>A in a Korean population: analysis and a comprehensive comparison with other populations.
J Clin Pharm Ther. 2010 Dec;35(6):705-12. doi: 10.1111/j.1365-2710.2009.01127.x., [PMID:21054463]

Abstract [show]
BACKGROUND AND OBJECTIVE: ABCG2, also known as Breast Cancer Resistance Peptide (BCRP) or mitoxantrone-resistant protein, is the second member of the G-family of ABC transporters. The frequencies of ABCG2 34G>A and 421C>A polymorphisms in a Korean population were assessed using a newly developed multiplex pyrosequencing method, and compared with the corresponding frequencies seen in other ethnic groups. METHOD: We designed a multiplex pyrosequencing method to simultaneously detect ABCG2 421C>A and 34G>A polymorphisms and analysed the allele frequencies of these polymorphisms in 250 Korean subjects. RESULTS: The results showed 100% concordance between single and multiplex pyrosequencing methods. We also validated the polymorphisms identified by pyrosequencing with a direct sequencing method using randomly selected samples. The allele frequencies of ABCG2 421C>A and 34G>A in the population tested were 0.298 and 0.190 respectively. The allele frequency of the 421C>A polymorphism is comparable to other Asian populations, including Japanese and Chinese. However, both frequencies are different from those of Caucasians and Africans. CONCLUSIONS: The multiplex pyrosequencing method used to detect two ABCG2 polymorphisms concurrently is a rapid and reliable genotyping method for the detection of important ABCG2 genetic polymorphisms. The ABCG2 34G>A and 421C>A polymorphisms are frequently found in the Korean population. The frequencies are similar to those seen in other Asian populations including Japanese and Chinese, but very different to those of Caucasian and African-American populations.

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21 The most frequent ABCG2 polymorphisms detected among different ethnic groups are 34G>A, which codes for V12M, and 421C>A, which codes for Q141K (14). Login to comment
39 Oligonucleotide primers used for PCR and pyrosequencing to detect ABCG2 polymorphisms SNP Amino acid change PCR primer Sequencing primer Size (bp) 34G>A Val12Met Forward 5'-GCTCATTGCCACACATTT-3' 5'-ATGTCGAAGTTTTTATCC-3' 188 Reverse B 5'-GAAGCCATTGGTGTTTCC-3' 421C>A Cln141Lys Forward B 5'- ATGTTGTGATGGGCACTCTGAC-3' 5'-GAAGAGCTGCTGAGAACT-3' 210 Reverse 5'-TATCCACACAGGGAAAGTCCTACT-3' B, biotinylated on 5'-end of primer. Login to comment
81 Comparisons of ABCG2 allele frequencies with other ethnic groups SNP Amino acid change Population (n) Frequency (%) Reference G34A V12M Korea (250) 19Æ8 Present study Southeast Asians (20) 45Æ0 14 Chinese (20) 20Æ0 14 Japanese (124) 19Æ0 15 Japanese (120) 17Æ5 27 Japanese (20) 15Æ0 14 Caucasian (150) 10Æ3 19 Ashkenazi Jewish (20) 10Æ0 14 Mexicans (20) 10Æ0 14 Dutch (100) 6Æ5 37 African-American (150) 6Æ3 27 Middle Eastern (40) 5Æ0 14 Caucasian (150) 3Æ7 27 Swedish (60) 1Æ7 36 C421A Q141K Korea (250) 27Æ8 Present study Japanese (20) 35Æ0 14 Chinese (20) 35Æ0 14 Chinese (95) 34Æ2 22 Japanese (120) 32Æ7 27 Japanese (124) 26Æ6 15 Southeast Asians (20) 15Æ0 14 Middle Eastern (40) 13Æ0 14 Dutch (100) 12Æ0 37 Caucasian (172) 11Æ3 22 Mexicans (20) 10Æ0 14 Swedish (60) 10Æ0 36 Caucasian (150) 8Æ7 19 Ashkenazi Jewish (20) 5Æ0 14 African-American (150) 2Æ3 27 was demonstrated that 421C>A carriers have a 1Æ3-fold decrease in ATPase activity compared to wild-type (19), and the bioavailability of sulfasalazine, diflomotecan and topotecan was significantly elevated by this polymorphism (29-31). Login to comment

[hide] Key Role of Human ABC Transporter ABCG2 in Photody... Adv Pharmacol Sci. 2010;2010:587306. Epub 2010 Jul 8. Ishikawa T, Nakagawa H, Hagiya Y, Nonoguchi N, Miyatake S, Kuroiwa T
Key Role of Human ABC Transporter ABCG2 in Photodynamic Therapy and Photodynamic Diagnosis.
Adv Pharmacol Sci. 2010;2010:587306. Epub 2010 Jul 8., [PMID:21188243]

Abstract [show]
Accumulating evidence indicates that ATP-binding cassette (ABC) transporter ABCG2 plays a key role in regulating the cellular accumulation of porphyrin derivatives in cancer cells and thereby affects the efficacy of photodynamic therapy and photodynamic diagnosis. The activity of porphyrin efflux can be affected by genetic polymorphisms in the ABCG2 gene. On the other hand, Nrf2, an NF-E2-related transcription factor, has been shown to be involved in oxidative stress-mediated induction of the ABCG2 gene. Since patients have demonstrated individual differences in their response to photodynamic therapy, transcriptional activation and/or genetic polymorphisms of the ABCG2 gene in cancer cells may affect patients' responses to photodynamic therapy. Protein kinase inhibitors, including imatinib mesylate and gefitinib, are suggested to potentially enhance the efficacy of photodynamic therapy by blocking ABCG2-mediated porphyrin efflux from cancer cells. This review article provides an overview on the role of human ABC transporter ABCG2 in photodynamic therapy and photodynamic diagnosis.

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167 Based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells [41, 90]. Login to comment
177 Gefitinib and imatinib are new anticancer drugs Outside Plasma membrane Inside H2N COOH V12M G51C Q126stop Q141K T153M R160Q Q166E I206L F208S S248P E334stop F431L F489L S441N R482G R482T F571I R575stop N590Y D620N T542A A528T D296H P269S ATP-binding cassette (a) 0 0.1 0.3 0.4 0.2 0.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T ATP-dependenthematoporphyrin transport(nmol/min/mgprotein) (b) Figure 4: (a) Schematic illustration of human ABCG2 and its nonsynonymous polymorphisms. Login to comment

[hide] Genetic polymorphisms of ATP-binding cassette (ABC... Int J Mol Epidemiol Genet. 2010;1(3):201-7. Epub 2010 May 20. Hampras SS, Sucheston L, Weiss J, Baer MR, Zirpoli G, Singh PK, Wetzler M, Chennamaneni R, Blanco JG, Ford L, Moysich KB
Genetic polymorphisms of ATP-binding cassette (ABC) proteins, overall survival and drug toxicity in patients with Acute Myeloid Leukemia.
Int J Mol Epidemiol Genet. 2010;1(3):201-7. Epub 2010 May 20., [PMID:21311724]

Abstract [show]
The overall survival of patients with acute myeloid leukemia (AML) remains poor due to both intrinsic and acquired chemotherapy resistance. Over expression of ATP binding cassette (ABC) proteins in AML cells has been suggested as a putative mechanism of drug resistance. Genetic variation among individuals affecting the expression or function of these proteins may contribute to inter-individual variation in treatment outcomes. DNA from pre-treatment bone marrow or blood samples from 261 patients age 20-85 years, who received cytarabine and anthracycline-based therapy at Roswell Park Cancer Institute between 1994 and 2006, was genotyped for eight non-synonymous single nucleotide polymorphisms in the ABCB1, ABCC1 and ABCG2 drug transporter genes. Heterozygous (AG) or homozygous (AA) variant genotypes for rs2231137 (G34A) in the ABCG2 (BRCP) gene, compared to the wild type (GG) genotype were associated with both significantly improved survival (HR=0.44, 95%CI=0.25-0.79), and increased odds for toxicity (OR=8.41, 95%CI= 1.10-64.28). Thus genetic polymorphisms in the ABCG2 (BRCP) gene may contribute to differential survival outcomes and toxicities in AML patients via a mechanism of decreased drug efflux in both, AML cells and normal progenitors.

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61 The rs2231137 (G34A) polymorphism results in valine to methionine substitution (V12M) in the amino acid sequence of the protein and findings across studies have been contradictory regarding its functional significance. Login to comment

[hide] Gene-wide tagging study of the association between... Pharmacogenomics. 2011 Mar;12(3):319-25. Kwan P, Wong V, Ng PW, Lui CH, Sin NC, Wong KS, Baum L
Gene-wide tagging study of the association between ABCC2, ABCC5 and ABCG2 genetic polymorphisms and multidrug resistance in epilepsy.
Pharmacogenomics. 2011 Mar;12(3):319-25., [PMID:21449672]

Abstract [show]
AIM: To determine the association between polymorphisms of the multidrug transporter genes ABCC2, ABCC5 and ABCG2, and drug resistance in epilepsy by genotyping comprehensive sets of tagging SNPs. MATERIALS & METHODS: A total of 25 tagging SNPs from ABCC2, ABCC5 and ABCG2 genes were genotyped in a total of 590 Han Chinese epilepsy patients (262 drug resistant and 328 drug responsive). Genotype and allele distributions in drug-responsive and drug-resistant patients were compared. RESULTS: Genotype distributions of all the selected SNPs were consistent with Hardy-Weinberg equilibrium. None of the polymorphisms, either genotype or allele distributions, were significantly associated with drug resistance. For each gene, no haplotypes of over 1% frequency, and that included all SNPs of the gene, were associated with drug resistance. CONCLUSION: This gene-wide tagging study revealed no association between ABCC2, ABCC5 and ABCG2 genetic polymorphisms and multidrug resistance in epilepsy.

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34 For ABCG2, 77 kbp from positions 89,365,500 to 89,442,500 on chromosome 4 were tagged by 11 poly-morphisms (with forced inclusion of two coding SNPs: rs2231137 or V12M and rs2231142 or Q141K), capturing 29 of 39 alleles at r2 ≥ 0.8. Login to comment

[hide] The MRP-related and BCRP/ABCG2 multidrug resistanc... Curr Drug Metab. 2004 Feb;5(1):21-53. Haimeur A, Conseil G, Deeley RG, Cole SP
The MRP-related and BCRP/ABCG2 multidrug resistance proteins: biology, substrate specificity and regulation.
Curr Drug Metab. 2004 Feb;5(1):21-53., [PMID:14965249]

Abstract [show]
Several members of different families of the ATP-binding cassette (ABC) superfamily of transport proteins are capable of transporting an extraordinarily structurally diverse array of endo- and xenobiotics and their metabolites across cell membranes. Together, these transporters play an important role in the absorption, disposition and elimination of these chemicals in the body. In tumor cells, increased expression of these drug transporters is associated with resistance to multiple chemotherapeutic agents. In this review, current knowledge of the biochemical, physiological and pharmacological properties of nine members of the multidrug resistance protein (MRP)-related ABCC family (MRP1, MRP2, MRP3, MRP4, MRP5, MRP6, MRP7, ABCC11 and ABCC12) as well as the G family member, ABCG2/BCRP, are summarized. A focus is placed on the structural similarities and differences of these drug transporters as well as the molecular determinants of their substrate specificities and transport activities. Factors that regulate expression of the MRP-related proteins and ABCG2/BCRP are also reviewed.

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724 Another mutant, G34A, in which the Val at position 12 has been replaced with Met (Val12Met), exhibits properties comparable to the wild-type protein. Login to comment

[hide] Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplot... Pharmacogenet Genomics. 2005 Sep;15(9):599-608. Colombo S, Soranzo N, Rotger M, Sprenger R, Bleiber G, Furrer H, Buclin T, Goldstein D, Decosterd L, Telenti A
Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo.
Pharmacogenet Genomics. 2005 Sep;15(9):599-608., [PMID:16041239]

Abstract [show]
OBJECTIVES: The human immunodeficiency virus protease inhibitor nelfinavir is substrate of polyspecific drug transporters encoded by ABCB1 (P-glycoprotein), ABCC1 (MRP1) and ABCC2 (MRP2), and an inhibitor of BCRP, encoded by ABCG2. Genetic polymorphism in these genes may be associated with changes in transport function. METHODS: A comprehensive evaluation of single nucleotide polymorphisms (39 SNPs in ABCB1, 7 in ABCC1, 27 in ABCC2, and 16 in ABCG2), and inferred haplotypes was done to assess possible associations of genetic variants with cellular exposure of nelfinavir in vivo. Analysis used peripheral mononuclear cells from individuals receiving nelfinavir (n=28). Key results were re-examined in a larger sample size (n=129) contributing data on plasma drug levels. RESULTS AND CONCLUSIONS: There was no significant association between cellular nelfinavir area under the curve (AUC) and SNPs or haplotypes at ABCC1, ABCC2, ABCG2. There was an association with cellular exposure for two loci in strong linkage disequilibrium: ABCB1 3435C>T; AUCTT>AUCCT>AUCCC (ratio 2.1, 1.4, 1, Ptrend=0.01), and intron 26 +80T>C; AUCCC> AUCCT > AUCTT (ratio 2.4, 1.3, 1, Ptrend=0.006). Haplotypic analysis using tagging SNPs did not improve the single SNP association values.

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78 - 19346T > A 50 upstream Epidauros bc-v-081 c.19 delG exon 2 p.K7fsX28 Epidauros bc-v-007 c.34G > A exon 2 p.V12M Honjo et al., 2001 bc-v-008 rs2231137 c.71C > T exon 2 p.A24V Epidauros bc-v-009 c.114T > C exon 2 synonymous (p.S38S) Zamber et al., 2003 bc-v-071 rs12721644 IVS 2 + 35 A > G intron 2 Honjo et al., 2001 bc-v-058 rs4148152 IVS 2-12 A > G intron 4 Epidauros bc-v-014 rs2231141 c.421C > A exon 5 p.Q141K Imai et al., 2002 bc-v-015 rs2231142 c.496C > G exon 5 p.Q166E Epidauros bc-v-016 rs1061017 IVS 5 + 14 A > T intron 5 Epidauros bc-v-017 rs2231143 Statistics Association between AUC values and genotypes at single SNP loci was evaluated using a Kruskal-Wallis rank test complemented by a Spearman rank test for trend. Login to comment

[hide] Comprehensive pharmacogenetic analysis of irinotec... J Clin Oncol. 2009 Jun 1;27(16):2604-14. Epub 2009 Apr 6. Innocenti F, Kroetz DL, Schuetz E, Dolan ME, Ramirez J, Relling M, Chen P, Das S, Rosner GL, Ratain MJ
Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics.
J Clin Oncol. 2009 Jun 1;27(16):2604-14. Epub 2009 Apr 6., 2009-06-01 [PMID:19349540]

Abstract [show]
PURPOSE: We aim to identify genetic variation, in addition to the UGT1A1*28 polymorphism, that can explain the variability in irinotecan (CPT-11) pharmacokinetics and neutropenia in cancer patients. PATIENTS AND METHODS: Pharmacokinetic, genetic, and clinical data were obtained from 85 advanced cancer patients treated with single-agent CPT-11 every 3 weeks at doses of 300 mg/m(2) (n = 20) and 350 mg/m(2) (n = 65). Forty-two common variants were genotyped in 12 candidate genes of the CPT-11 pathway using several methodologies. Univariate and multivariate models of absolute neutrophil count (ANC) nadir and pharmacokinetic parameters were evaluated. RESULTS: Almost 50% of the variation in ANC nadir is explained by UGT1A1*93, ABCC1 IVS11 -48C>T, SLCO1B1*1b, ANC baseline levels, sex, and race (P < .0001). More than 40% of the variation in CPT-11 area under the curve (AUC) is explained by ABCC2 -24C>T, SLCO1B1*5, HNF1A 79A>C, age, and CPT-11 dose (P < .0001). Almost 30% of the variability in SN-38 (the active metabolite of CPT-11) AUC is explained by ABCC1 1684T>C, ABCB1 IVS9 -44A>G, and UGT1A1*93 (P = .004). Other models explained 17%, 23%, and 27% of the variation in APC (a metabolite of CPT-11), SN-38 glucuronide (SN-38G), and SN-38G/SN-38 AUCs, respectively. When tested in univariate models, pretreatment total bilirubin was able to modify the existing associations between genotypes and phenotypes. CONCLUSION: On the basis of this exploratory analysis, common polymorphisms in genes encoding for ABC and SLC transporters may have a significant impact on the pharmacokinetics and pharmacodynamics of CPT-11. Confirmatory studies are required.

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115 % of Patients HWE Exact P (white)African American (n ϭ 11) White (n ϭ 67) Other (n ϭ 7) ABCB1 IVS9 -44AϾG 10276036 .012 A/A 45.4 37.3 0 A/G 36.4 34.3 57.1 G/G 18.2 28.4 42.9 ABCB1 1236CϾT 1128503 .012 C/C 45.5 38.8 0 C/T 54.5 34.3 57.1 T/T 0 26.9 42.9 ABCB1 IVS13 ϩ24CϾT 2235033 .027 C/C 27.3 29.9 0 C/T 45.4 35.8 57.1 T/T 27.3 34.3 42.9 ABCB1 IVS14 ϩ38AϾG 2235013 .027 A/A 18.2 29.9 0 A/G 54.5 35.8 57.1 G/G 27.3 34.3 42.9 ABCB1 2677GϾA/T (A893T/S) 2032582 .046 G/G 40.0 36.9 40.0 G/T 60.0 36.9 60.0 T/T 0 26.2 0 ABCB1 3435CϾT 1045642 .212 C/C 36.4 28.4 57.1 C/T 54.5 41.8 42.9 T/T 9.1 29.8 0 ABCG2 34GϾA (V12M) 2231137 .113 G/G 100 92.5 28.6 G/A 0 6.0 57.1 A/A 0 1.5 14.3 ABCG2 421CϾA (Q141K) 2231142 1.000 C/A 9.1 14.9 42.9 C/C 90.9 85.1 57.1 A/A 0 0 0 SLCO1B1*1b 388AϾG (N130D) 2306283 .624 A/A 18.2 31.3 0 A/G 63.6 46.3 71.4 G/G 18.2 22.4 28.6 SLCO1B1*5 521TϾC (V174A) 4149056 1.000 T/T 81.8 65.7 57.1 T/C 18.2 31.3 42.9 C/C 0 3.0 0 NOTE. Alleles for which a * nomenclature has not yet been assigned have been reported according to their genomic position related to the ATG start site. The reference sequences used for genotyping are the following: ABCG2, NM_004827; SLCO1B1, NM_006446; ABCB1, NM_000927; ABCC1, NM_004987; and ABCC2, NM_00039. Login to comment

[hide] Impact of CYP2C8*3 on paclitaxel clearance: a popu... Pharmacogenomics J. 2011 Apr;11(2):113-20. Epub 2010 Apr 6. Bergmann TK, Brasch-Andersen C, Green H, Mirza M, Pedersen RS, Nielsen F, Skougaard K, Wihl J, Keldsen N, Damkier P, Friberg LE, Peterson C, Vach W, Karlsson MO, Brosen K
Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer.
Pharmacogenomics J. 2011 Apr;11(2):113-20. Epub 2010 Apr 6., [PMID:20368717]

Abstract [show]
The primary purpose of this study was to evaluate the effect of CYP2C8*3 and three genetic ABCB1 variants on the elimination of paclitaxel. We studied 93 Caucasian women with ovarian cancer treated with paclitaxel and carboplatin. Using sparse sampling and nonlinear mixed effects modeling, the individual clearance of unbound paclitaxel was estimated from total plasma paclitaxel and Cremophor EL. The geometric mean of clearance was 385 l h(1) (range 176-726 l h(1)). Carriers of CYP2C8*3 had 11% lower clearance than non-carriers, P=0.03. This has not been shown before in similar studies; the explanation is probably the advantage of using both unbound paclitaxel clearance and a population of patients of same gender. No significant association was found for the ABCB1 variants C1236T, G2677T/A and C3435T. Secondarily, other candidate single-nucleotide polymorphisms were explored with possible associations found for CYP2C8*4 (P=0.04) and ABCC1 g.7356253C>G (P=0.04).

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135 This effect on clearance of a 'non-fixed` variable provides a competing and dynamic biological explanation for clearance that certainly should be Table 4 Clearance of unbound paclitaxel as function of observed genotypes Gene/allelea Effectb Reference homozygote Heterozygote Variant homozygote P-valuee SNP IDf Nc CLd (10th-90th) Nc CLd (10th-90th) Nc CLd (10th-90th) Candidate SNPs for confirmative analysis CYP2C8 1196A4G(*3) K399R 74 395 (297-490) 19 350 (238-458) 0.03* (0.04) rs10509681 ABCB1 1236C4T G412G 29 391 (270-569) 45 393 (299-490) 19 359 (291-437) 0.25 (0.25) rs1128503 2677G4T/Ag A893S/T 26 387 (270-490) 42(GT) 396 (299-490) 20(TT) 356 (294-437) 0.20 (0.26) rs2032582 3435C4T I1145I 11 403 (326-548) 44 387 (282-490) 38 378 (297-468) 0.83 (0.43) rs1045642 Candidate SNPs for exploratory analysis CYP2C8 792C4G(*4) I264M 86 391 (297-490) 7 321 (270-374) 0.04* (0.03) rs1058930 15577956G4T (*1B) - 49 395 (298-552) 43 373 (291-478) 1 461 0.75 (0.36) rs7909236 15578055A4C (*1C) - 69 382 (291-478) 24 393 (300-552) 0.48 (0.62) rs17110453 ABCB1 À1A4G - 1 458 29 396 (270-592) 63 379 (297-477) 0.56 (0.3) rs2214102 61A4G N21D 63 384 (282-490) 29 386 (298-478) 1 437 0.52 (0.77) rs9282564 1199G4A S400N 83 385 (291-490) 10 386 (322-461) 0.74 (0.99) rs2229109 CYP3A4 24616372T4C (*1B) - 85 383 (296-490) 7 397 (270-641) 0.67 (0.72) rs2740574 CYP3A5 219-237G4A Frameshift 84 388 (297-490) 9 360 (176-726) 0.30 (0.36) rs776746 SLCO1B3 699G4A M233I 1 326 19 377 (299-481) 73 388 (291-490) 0.99 (0.46) rs7311358 767G4C G256A 67 386 (298-481) 26 383 (291-490) 0.63 (0.89) rs60140950 CYP1B1 1294C4G (*3) V432L 30 389 (270-530) 36 401 (298-490) 27 361 (300-470) 0.77 (0.24) rs1056836 ABCC1 7356253C4G - 65 394 (297-548) 27 368 (291-470) 1 332 0.04* (0.15) rs504348 ABCC2 1249G4A V417I 67 381 (291-490) 24 396 (297-552) 2 415 (368-468) 0.21 (0.39) rs2273697 3563T4A V1188E 87 386 (296-490) 5 370 (176-569) 0.7 (0.7) rs17222723 4544G4A C1515Y 75 389 (296-490) 3 355 (176-569) 0.72 (0.52) rs8187710 ABCG2 421C4A Q141K 61 374 (291-478) 32 408 (315-548) 0.4 (0.09) rs2231142 34G4A V12M 87 385 (291-490) 4 395 (296-726) 0.68 (0.83) rs2231137 ABCC10 2759T4C I920T 46 386 (297-478) 43 386 (291-548) 4 373 (326-467) 0.88 (0.89) rs2125739 Abbreviations: CL, clearance of unbound paclitaxel; SNP, single-nucleotide polymorphism. Login to comment

[hide] Pharmacogenetics of HIV therapy. Pharmacogenet Genomics. 2006 Oct;16(10):693-703. Owen A, Pirmohamed M, Khoo SH, Back DJ
Pharmacogenetics of HIV therapy.
Pharmacogenet Genomics. 2006 Oct;16(10):693-703., [PMID:17001288]

Abstract [show]
Drug treatment in HIV disease is characterized by variable responses, in terms of both efficacy and toxicity. Both genetic and environmental factors are important determinants of this variability, although the relative contributions are unclear and likely to vary with different drugs. Many of the antiretrovirals are metabolized by polymorphically expressed enzymes (cytochrome P450, CYP450; glucuronyl transferase, GT) and/or transported by drug transporters (ABC and SLC families). Initial studies of antiretroviral efficacy have therefore focused on these genes. For example, it has recently been shown that a CYP2B6 genetic variant predicts higher plasma efavirenz exposure and possibly increased central nervous system toxicity. A large number of studies on ABCB1 genetics with antiretrovirals have also been undertaken; however, as in other therapeutic areas, the data have been contradictory, and currently, no firm conclusions can be reached on the effect of ABCB1 variability as a determinant of efficacy. Indeed, this highlights the need for validation of initial association studies in pharmacogenetic research. By contrast, the clearest association between genetic variants and response relates to the hypersensitivity reaction that occurs with abacavir. The identification that the major histocompatibility complex haplotype 57.1 acts as a strong genetic predisposing factor can be regarded as a prime example of how fundamental research can be translated into a pharmacogenetic test. Nevirapine hypersensitivity has also been related to an HLA gene (HLA-DRB1*0101) but the predictive value does not appear to be sufficient to implement in clinical practice. Much more work needs to be done to define the genetic factors determining response to antiretroviral agents. These studies need to be sufficiently powered and utilize a modern genotyping strategy. Most importantly, the phenotype needs to be carefully characterized. We also need to disseminate this information: a pivotal resource for this can be found at www.HIV-pharmacogenomics.org.

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171 Pharmacogenetics of HIV therapy Owen et al. 699 Table 1 Polymorphisms that have been studied within the context of metabolism, transport and toxicity (but not progression and response) along with the reference ID (where available), the genotypic consequence and the observed phenotype for antiretroviral drugs Gene SNP (haplotype) Reference SNP Genotypic consequence Phenotypic consequence Confirmation CYP3A4 A - 392G (CYP3A4*1B) rs2740574 Promoter; altered expression No effect on nelfinavir or efavirenz Yes for nelfinavir; controversial for efavirenz T878C (CYP3A4*18) rs4986909 L293P; altered activity No effect on efavirenz No CYP3A5 A6986G (CYP3A5*3) rs776746 Splice defect No effect on nelfinavir, saquinavir or efavirenz AUC but altered urinary metabolic ratio of saquinavir Yes for efavirenz G14690A (CYP3A5*6) rs10264272 Splice defect No effect on nelfinavir or efavirenz Yes CYP2C19 G681A (CYP2C19*2) rs4244285 Truncated protein Higher nelfinavir AUC and trend toward decreased virological failure; no effect on efavirenz Yes for efavirenz; controversial for nelfinavir CYP2D6 A2549del (CYP2D6*3) NT21914757 Frameshift Trend to higher plasma levels of nelfinavir and efavirenz No G1846A (CYP2D6*4) rs3892097 Splice defect Trend to higher plasma levels of nelfinavir and efavirenz No T1707del (CYP2D6*6) rs5030655 Frameshift Higher plasma nelfinavir concentrations No CYP2B6 G516 T (CYP2B6*6, *7, *9, *13, *19 and *20) rs3745274 Q172H Higher plasma and intracellular efavirenz AUCs and increased neurotoxicity Yes, numerous studies C1459T (CYP2B6*5 and *7) rs3211371 R487C No effect on nelfinavir or efavirenz No ABCB1 IVS1 - 80delG rs3214119 N/A No influence on cellular nelfinavir No A61G rs9282564 N21D No influence on cellular nelfinavir No TAG1 rs3789243 N/A No influence on cellular nelfinavir No G1199A rs2229109 S400N No influence on cellular nelfinavir No TAG5 rs1128503 N/A No influence on cellular nelfinavir No TAG6 rs2235046 N/A No influence on cellular nelfinavir No IVS21 + T49C rs2032583 N/A No influence on cellular nelfinavir No C3435T rs1045642 Synonymous Some evidence of an influence on plasma and intracellular nelfinavir; decreased efavirenz plasma concentrations; currently under debate; increase in HDL cholesterol with efavirenz Controversial G2677T rs2032582 Ala893Ser No effect on efavirenz, ritonavir, nelfinavir, indinavir or viral decay and CD4 count Yes IVS26 + T59G rs2235047 N/A No influence on cellular nelfinavir No IVS26 + T80C rs2235048 N/A Increased intracellular nelfinavir concentrations No TAG11 rs1186746 N/A No influence on cellular nelfinavir No TAG12 rs1186745 N/A No influence on cellular nelfinavir No ABCC1 G816A P272P No influence on cellular nelfinavir No T825C rs246221 V275V No influence on cellular nelfinavir No T1062C rs35587 Synonymous No influence on cellular nelfinavir No IVS9 + A8G rs35588 N/A No influence on cellular nelfinavir No IVS10 + C64T N/A No influence on cellular nelfinavir No ABCC2 C - 24T rs717620 N/A No influence on cellular nelfinavir No G1249A rs2273697 V417I No influence on cellular nelfinavir No C1436G Synonymous No influence on cellular nelfinavir No IVS16 - G47A N/A No influence on cellular nelfinavir No T3563A rs8187694 V1188E No influence on cellular nelfinavir No C4488T rs8187707 Synonymous No influence on cellular nelfinavir No IVS31 + G12A rs8187708 N/A No influence on cellular nelfinavir No IVS31 + C74T N/A No influence on cellular nelfinavir No G4544A rs8187710 C1515Y No influence on cellular nelfinavir No G + 259T N/A No influence on cellular nelfinavir No ABCG2 - 19571_ - 19568delT- CAC rs4148162 Deletion No influence on cellular nelfinavir No A-19541G N/A No influence on cellular nelfinavir No G34A rs2231137 V12M No influence on cellular nelfinavir No IVS2 + 35G rs4148152 N/A No influence on cellular nelfinavir No C421A rs2231142 Q141K No influence on cellular nelfinavir No APOCIII C-482T Pending Promoter Hyperlipidaemia in presence of ritonavir Yes T-455C Pending Promoter Hyperlipidaemia in presence of ritonavir Yes C3238G rs5128 30 UTR variant Hyperlipidaemia in presence of ritonavir Yes APOE 2060T/2198T (APOEe2) rs429358 R112C/R158C Hyperlipidaemia in presence of ritonavir Yes 2060T/2198C (APOEe3) rs7412 R112C/R158R Hyperlipidaemia in presence of ritonavir Yes TNFa G - 238A rs361525 Promoter Rapid development of lipoatrophy Controversial SPINK-1 C112T rs17107315 N34S Associated with risk of pancreatitis Yes, in general population CFTR G1717 - 1A Splice defect Associated with risk of pancreatitis Yes, in general population IVS8 5T Splice defect Associated with risk of pancreatitis Yes, in general population HLA-B HLA-B*57.1 N/A Abacavir hypersensitivity Yes, but not in all populations HLA-DR HLA-DRB1*0101 N/A Nevirapine hypersensitivity No HSPA1L C2437T rs2227956 M493T Abacavir hypersensitivity No UGT1A1 A(TA)7TAA, - 43_ - 42in- sTA (UGT1A1*28) rs8175347 Promoter; insertion at TATA box Gilberts syndrome, hyperbilirubinaemia in presence of atazanavir and indinavir but not saquinavir Yes MT-CO1 C7028T Synonymous Haplogroup T associated with greater incidence of peripheral neuropathy No 700 Pharmacogenetics and Genomics 2006, Vol 16 No The NNRTI nevirapine can also cause a hypersensitivity syndrome characterized by a rash with systemic symptoms; occasionally liver injury may be part of the clinical picture, or alternatively, may actually be the only manifestation. 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[hide] The emerging importance of transporter proteins in... Drug Metab Rev. 2007;39(4):723-46. Wang JS, Newport DJ, Stowe ZN, Donovan JL, Pennell PB, DeVane CL
The emerging importance of transporter proteins in the psychopharmacological treatment of the pregnant patient.
Drug Metab Rev. 2007;39(4):723-46., [PMID:18058331]

Abstract [show]
P-glycoprotein, breast cancer resistance protein, and multidrug resistance proteins have physiological functions in placental tissue. Several antidepressants, antipsychotics, and anti-epileptic drugs have been found to be substrates of P-glycoprotein and other transporters. The extent that drugs pass through the placental barrier is likely influenced by drug transporters. The rational choice of psychoactive drugs to treat mental illness in women of child-bearing age should incorporate knowledge of both drug disposition as well as expected pharmacologic effects. This review summarizes the current data on drug transporters in the placental passage of medications, with a focus on medications used in clinical psychopharmacology.

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124 The two most frequent polymorphisms were the G34A in exon 2 that results in a V12M change, and a C421A transition in exon 5. Login to comment

[hide] Pharmacogenetics of drug transporters in the enter... Pharmacogenomics. 2011 May;12(5):611-31. Stieger B, Meier PJ
Pharmacogenetics of drug transporters in the enterohepatic circulation.
Pharmacogenomics. 2011 May;12(5):611-31., [PMID:21619426]

Abstract [show]
This article summarizes the impact of the pharmacogenetics of drug transporters expressed in the enterohepatic circulation on the pharmacokinetics and pharmacodynamics of drugs. The role of pharmacogenetics in the function of drug transporter proteins in vitro is now well established and evidence is rapidly accumulating from in vivo pharmacokinetic studies, which suggests that genetic variants of drug transporter proteins can translate into clinically relevant phenotypes. However, a large amount of conflicting information on the clinical relevance of drug transporter proteins has so far precluded the emergence of a clear picture regarding the role of drug transporter pharmacogenetics in medical practice. This is very well exemplified by the case of P-glycoprotein (MDR1, ABCB1). The challenge is now to develop pharmacogenetic models with sufficient predictive power to allow for translation into drug therapy. This will require a combination of pharmacogenetics of drug transporters, drug metabolism and pharmacodynamics of the respective drugs.

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94 Gene name Transporter SNP Protein Population size (n) In vitro function Ref. Intestinal uptake transporters SLC15A1 PEPT1 p.P586L 44 Reduced Vmax [81] p.F28Y 247 Increased Km [82] Intestinal efflux transporters ABCB1 MDR1 c.571G>A p.G191R N/A Reduced drug resistance [201] c.1199G>A p.S440N N/A Reduced activity (substrate dependent) [202] c.11199G>A c.1199G>t p.S440N p.S440I N/A N/A Increased drug resistance Reduced drug resistance [203] c.1292-3GT>TG p.C431L N/A Reduced drug resistance [204] c.2005C>T p.R669C N/A Reduced substrate affinity [202] c.2547A>G p.I849M N/A Increased transport activity [202] c.2677G>T p.A893S 60 Lower intracellular digoxin accumulation [205] c.2677G>T c.2677G>A p.A893S p.A893T N/A N/A Unchanged Unchanged [206] c.2677G>T p.A893S 46 No change in rhodamine 123 efflux from peripheral blood lymphocytes [207] c.2667G>T p.A893S N/A Reduced transport function [208] c.2667G>T c.2677G>A p.A893S p.A893T N/A N/A Increased transport function Increased transport function [209] c.2667G>T c.2677G>A p.A893S p.A893T N/A N/A Increased activity (substrate dependent) Increased substrate affinity and transport activity [202] c.2667G>T p.A893S 48 No change in rhodamine 123 efflux activity in peripheral blood mononuclear cells [210] c.2956A>G p.M986V N/A Increased transport activity [202] c.2995G>A p.A999T N/A Increased substrate affinity and transport activity [202] c.3151C>G p.P1051A N/A Increased transport activity (substrate dependent) [202] c.3188G>C p.G1063A N/A Increased transport activity [202] ABCG2 ABCG2 c.34G>A p.V12M N/A Low transport protein expression in vitro [211] c.34G>A p.V12M N/A Unchanged [212] c.34G>A p.V12M N/A No change in HEK-293, lowered transport activity in Sf9 cells in vitro [213] c.34G>A p.V12M N/A Unchanged [214] c.421C>A p.Q141K N/A Lower transport protein expression, normal transport activity [212] c.421C>A p.Q141K N/A Reduced drug resistance and lower ATPase activity [213] c.421C>A p.Q141K N/A Reduced drug extrusion [215] c.421C>A p.Q141K N/A Reduced drug resistance [216] c.421C>A p.Q141K N/A Unchanged [217] c.421C>A p.Q141K N/A No change of intracellular porphyrin accumulation [218] c.421C>A p.Q141K N/A Reduced transport activity [219] c.421C>A p.Q141K N/A Reduced transport activity [55] c.421C>A p.Q141K N/A Increased Km [220] For more information on members of the SLC superfamily of transporters please consult [301] and for more information of ABC transporters please consult [302]. Login to comment

[hide] Xenobiotic, bile acid, and cholesterol transporter... Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26. Klaassen CD, Aleksunes LM
Xenobiotic, bile acid, and cholesterol transporters: function and regulation.
Pharmacol Rev. 2010 Mar;62(1):1-96. Epub 2010 Jan 26., [PMID:20103563]

Abstract [show]
Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

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6588 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/Localization ABCG2 BCRP G34A V12M ↔ Normal/intracellular C376T Gln126STOP N.D. Login to comment

[hide] Genetic polymorphisms of uptake (OATP1B1, 1B3) and... Expert Opin Drug Metab Toxicol. 2009 Jul;5(7):703-29. Ieiri I, Higuchi S, Sugiyama Y
Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs.
Expert Opin Drug Metab Toxicol. 2009 Jul;5(7):703-29., [PMID:19442037]

Abstract [show]
Recent pharmacogenomic/pharmacogenetic studies have disclosed important roles of drug transporters in the pharmacokinetic/pharmacodynamic (PK/PD) profiles of some clinically relevant drugs. It has concurrently been explained that variations in the drug transporter genes are associated with not only inter-individual but also inter-ethnic differences in PK/PD profiles of these drugs. This review focuses on two uptake and two efflux transporters. Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 are uptake transporters, specifically expressed in the liver, and considered important for drugs, particularly as their pharmacological target organ is the liver. Two ATP-binding cassette transporters, multi-drug resistance-associated protein 2 and breast cancer resistance protein, are efflux transporters, expressed in various human tissues, and considered particularly important for intestinal drug absorption and hepatic drug elimination. All 3-hydroxyl-3-methylglutaryl-CoA reductase inhibitors (statins) except fluvastatin are substrates for OATP1B1, but hepatobiliary (canalicular) efflux transporters differ among statins. In this review, we update the pharmacogenomic/pharmacogenetic properties of these transporters and their effects on PK/PD profiles of statins and other clinically relevant drugs. In addition, we describe a physiologically-based pharmacokinetic model for predicting the effects of changes in transporter activities on systemic and hepatic exposure to pravastatin.

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546 Kim HS, Sunwoo YE, Ryu JY, et al. The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment

[hide] Pharmacogenetic pathway analysis of irinotecan. Clin Pharmacol Ther. 2008 Sep;84(3):393-402. Epub 2008 Apr 16. Rosner GL, Panetta JC, Innocenti F, Ratain MJ
Pharmacogenetic pathway analysis of irinotecan.
Clin Pharmacol Ther. 2008 Sep;84(3):393-402. Epub 2008 Apr 16., [PMID:18418374]

Abstract [show]
Irinotecan, a chemotherapeutic agent against various solid tumors, is a prodrug requiring activation to SN-38. Irinotecan's complex pharmacokinetics potentially allow for many genetic sources of variability. We explored relationships between pharmacokinetic pathways and polymorphisms in genes associated with irinotecan's metabolism and transport. We fitted a seven-compartment pharmacokinetic model with enterohepatic recirculation (EHR) to concentrations of irinotecan and metabolites SN-38, SN-38 glucuronide (SN-38G), and aminopentanoic acid (APC). Principal component analysis (PCA) of patient-specific parameter estimates produced measures interpretable along pathways. Nine principal components provided good characterization of the overall variation. Polymorphisms in genes UGT1A1, UGT1A7, and UGT1A9 had strong associations with a component corresponding to the irinotecan-to-SN-38 pathway and SN-38 recirculation and to a component relating to SN-38-to-SN-38G conversion and elimination of SN-38G. The component characterizing irinotecan's compartments was associated with HNF1alpha and ABCC2 polymorphisms. The exploratory analysis with PCA in this pharmacogenetic analysis was able to identify known associations and may have allowed identification of previously uncharacterized functional polymorphisms.

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97 Table 3 Associations between the principal components and polymorphisms Polymorphism PC1 PC2 PC3 PC4 PC5 PC6 PC7 PC8 PC9 UGT1A1, -53A(TA)6>7TAA, PROMOTER 0.086/0.5 0.301/0.2 0.007/4.9 0.019/1.8 0.216/0.2 0.009/3.4 0.314/0.2 0.204/0.2 0.123/0.4 UGT1A1, -3279G>T (UGT1A1*60), PBREM 0.021/1.7 0.056/0.7 0.043/0.9 0.027/1.3 0.588/0.1 0.001/24.8 0.482/0.1 0.527/0.1 0.046/0.8 UGT1A1, -3156G>A, PBREM 0.008/4.2 0.136/0.3 0.014/2.6 0.017/2.0 0.322/0.2 0.005/6.7 0.031/1.1 0.268/0.2 0.083/0.5 UGT1A7, 387G>T (N129K), EXON 1 0.007/4.6 0.139/0.3 0.001/26.7 0.050/0.8 0.050/0.8 0.103/0.4 0.116/0.4 0.186/0.3 0.114/0.4 UGT1A7, 622T>C (W208R), EXON 1 0.000/77.5 0.392/0.2 0.002/17.3 0.019/1.8 0.332/0.2 0.003/11.2 0.289/0.2 0.055/0.7 0.270/0.2 UGT1A9, -118(T)9>10, UGT1A9*1b, PROMOTER 0.003/12.3 0.258/0.2 0.001/36.4 0.017/2.0 0.054/0.7 0.025/1.4 0.067/0.6 0.279/0.2 0.066/0.6 UGT1A9, -2152C>T, PROMOTER 0.809/0.1 0.453/0.1 0.293/0.2 0.703/0.1 0.328/0.2 0.473/0.1 0.615/0.1 0.238/0.2 0.784/0.1 UGT1A9, -275T>A, PROMOTER 0.632/0.1 0.217/0.2 0.297/0.2 0.764/0.1 0.148/0.3 0.583/0.1 0.527/0.1 0.245/0.2 0.944/0.1 HNF1α, 79A>C (I27L), EXON 1 0.625/0.1 0.001/37.3 0.154/0.3 0.434/0.1 0.527/0.1 0.423/0.2 0.517/0.1 0.366/0.2 0.213/0.2 CYP3A4, -392A>G, CYP3A4*1B, 5ʹ-UTR 0.414/0.2 0.556/0.1 0.337/1.2 0.967/0.4 0.721/0.1 0.323/0.2 0.772/0.2 0.487/0.3 0.923/0.1 CYP3A5, 6986A>G, CYP3A5*3, INTRON 3 0.861/0.4 0.179/0.9 0.255/0.5 0.480/0.1 0.124/0.4 0.704/0.1 0.536/0.1 0.822/0.1 0.443/ 0.1 SLCO1B1, 388A>G (N130D), SLCO1B1*1b, EXON 4 0.079/0.5 0.106/0.4 0.023/1.6 0.097/0.4 0.580/0.1 0.379/0.2 0.317/0.2 0.038/1.0 0.269/0.2 SLCO1B1, 521T>C (V174A), SLCO1B1*15, EXON 5 0.878/0.1 0.614/0.6 0.600/0.1 0.433/0.2 0.751/0.2 0.159/0.5 0.942/0.1 0.145/0.3 0.066/0.6 ABCC2, -1549A>G, 5ʹ-Flanking region 0.383/0.2 0.001/47.4 0.301/0.2 0.308/0.2 0.171/0.3 0.749/0.1 0.705/0.1 0.253/0.2 0.643/0.1 ABCC2, -1019A>G, 5ʹ-Flanking region 0.583/0.1 0.002/15.4 0.254/0.2 0.249/0.2 0.398/0.2 0.732/0.1 0.681/0.1 0.226/0.2 0.809/0.1 ABCC2, -24C>T, 5ʹ-UTR 0.985/0.1 0.013/2.7 0.575/0.2 0.950/1.1 0.054/0.9 0.221/0.7 0.402/0.2 0.641/0.1 0.366/0.6 ABCC2, 1249G>A (V417I), EXON 10 0.443/0.1 0.045/0.9 0.934/0.1 0.358/0.2 0.521/0.1 0.329/0.2 0.495/0.1 0.002/14.9 0.706/0.1 ABCC2, -34T>C, INTRON 26 0.469/0.1 0.258/0.2 0.963/0.1 0.167/0.3 0.639/0.1 0.829/0.1 0.049/0.8 0.734/0.1 0.345/0.2 ABCC2, 3972C>T (I1324I), EXON 28 0.250/0.2 0.011/3.1 0.224/0.2 0.103/0.4 0.013/2.5 0.144/0.3 0.175/0.3 0.200/0.3 0.149/0.3 ABCC1, 1062T>C (N354N), EXON 9 0.136/0.3 0.179/0.3 0.221/0.2 0.120/0.4 0.139/0.3 0.684/0.1 0.013/2.3 0.228/0.2 0.082/0.5 ABCC1, -48C>T, INTRON 11 0.302/0.2 0.187/0.3 0.840/0.2 0.175/0.3 0.105/0.4 0.748/0.5 0.577/0.2 0.642/0.1 0.084/0.6 ABCC1, 1684T>C (L562L), EXON 13 0.405/0.2 0.018/2.0 0.414/0.2 0.098/0.4 0.579/0.1 0.436/0.1 0.805/0.1 0.037/1.0 0.233/0.2 ABCC1, -30C>G, INTRON 18 0.188/0.3 0.004/8.0 0.362/0.2 0.155/0.3 0.879/0.1 0.620/0.1 0.526/0.1 0.061/0.6 0.177/0.3 ABCC1, 4002G>A (S1334S), EXON 28 0.001/29.4 0.022/1.7 0.300/0.2 0.195/0.3 0.416/0.2 0.096/0.4 0.184/0.3 0.064/0.6 0.072/0.6 ABCC1, +18A>G, INTRON 30 0.023/1.6 0.198/0.3 0.424/0.2 0.825/0.1 0.365/0.2 0.296/0.2 0.217/0.2 0.403/0.2 0.236/0.2 ABCB1, -129T>C, 5ʹ-UTR 0.559/0.5 0.811/0.1 0.610/0.3 0.977/0.2 0.725/0.9 0.807/0.4 0.163/0.3 0.177/0.3 0.009/3.5 ABCB1, -25G>T, INTRON 4 0.229/0.3 0.774/0.1 0.832/0.5 0.826/1.1 0.635/0.1 0.877/0.2 0.368/0.2 0.661/0.1 0.832/0.1 ABCB1, -44A>G, INTRON 9 0.147/0.3 0.605/0.1 0.618/0.1 0.570/0.1 0.109/0.4 0.156/0.3 0.096/0.4 0.338/0.2 0.051/0.8 ABCB1, 1236C>T (G412G), EXON 12 0.182/0.3 0.437/0.1 0.382/0.2 0.482/0.1 0.090/0.5 0.280/0.2 0.106/0.4 0.376/0.2 0.153/0.3 ABCB1, +24C>T, INTRON 13 0.725/0.1 0.439/0.1 0.491/0.1 0.540/0.1 0.532/0.1 0.076/0.5 0.100/0.4 0.306/0.2 0.016/2.1 ABCB1, +38A>G, INTRON 14 0.627/0.1 0.538/0.1 0.669/0.1 0.540/0.1 0.532/0.1 0.054/0.7 0.100/0.4 0.306/0.2 0.033/1.1 ABCB1, 2677G>A/T (A893T/S), EXON 21 0.302/0.2 0.543/0.1 0.491/0.1 0.962/0.1 0.943/0.1 0.309/0.2 0.210/0.2 0.890/0.1 0.004/6.9 ABCB1, 3435C>T (I1145I), EXON 26 0.319/0.2 0.441/0.1 0.531/0.1 0.631/0.1 0.664/0.1 0.644/0.1 0.402/0.2 0.226/0.2 0.013/2.5 ABCG2, 34G>A (V12M), EXON 2 0.479/0.1 0.828/0.1 0.139/0.3 0.348/0.2 0.588/0.2 0.673/0.1 0.087/0.5 0.219/0.2 0.780/0.1 ABCG2, 421C>A (Q141K), EXON 5 0.565/0.1 0.397/0.2 0.421/0.2 0.435/0.1 0.628/0.1 0.256/0.2 0.708/0.1 0.533/0.1 0.787/0.1 CES2, -363C>G, 5ʹ-UTR 0.999/2.3 0.546/0.2 0.028/1.9 0.624/0.1 0.872/0.1 0.899/0.1 0.379/0.6 0.92/.1 0.586/0.1 CES2, +1361A>G, INTRON 1 0.381/1.0 0.549/0.2 0.616/0.8 0.118/0.4 0.546/0.1 0.629/0.1 0.275/0.3 0.26/0.2 0.352/0.2 Split to SN-38 and SN-38 to bile to gut to SN-38 IRN compartments SN-38 to SN-38G and SN-38G elimination Split to APC from IRN central compartment APC elimination EHR SN-38 recir-- culation without EHR SN-38 elimination IRN elimination The table shows the P values and Bayes factors, respectively, separated by a"/. Login to comment
193 UGT1A1, -53A(TA)6>7TAA, PROMOTER 0.709(6):0.286(7) 0.62(6):0.38(7) 15,32 UGT1A1, -3279G>T (UGT1A1*60), PBREM 0.47(G):0.53(T) 0.85(G):0.15(T) UGT1A1, -3156G>A, PBREM 0.69(G):0.31(A) 0.715(G):0.285(A) UGT1A1, 211G>A (G71R), UGT1A1*6, EXON 1 0(A):1(G) 0(A):1(G) UGT1A1, 686C>A (P229Q), UGT1A1*27, EXON 1 0(A):1(C) 0(A):1(C) UGT1A7, 387G>T (N129K), EXON 1 0.646(G):0.354(T) 0.522(G):0.478(T) Supplementary Data S1 onlinea UGT1A7, 391C>A (R131K), EXON 1 0.646(G):0.354(T) 0.522(G):0.478(T) UGT1A7, 622T>C (W208R), EXON 1 0.521(T):0.479(C) 0.729(T):0.271(C) UGT1A9, -118(T)9>10, UGT1A9*1b, PROMOTER 0.59(9):0.41(10) 0.56(9):0.44(10) 42 UGT1A9, -2152C>T, PROMOTER 0.91(C):0.09(T) Unknownb UGT1A9, -275T>A, PROMOTER 0.91(T):0.09(A) Unknownb HNF1α, 79A>C (I27L), EXON 1 0.75(A):0.25(C) Unknownb Supplementary Data S1 onlinea CYP3A4, -392A>G, CYP3A4*1B, 5ʹ-UTR 0.977(A):0.023(G) 0.321(A):0.679(G) 43 CYP3A5, 6986A>G, CYP3A5*3, INTRON 3 0.023(A):0.977(G) 0.633(A):0.367(G) SLCO1B1, 388A>G (N130D), SLCO1B1*1b, EXON 4 0.396(C):0.604(T) 0.717(C):0.283(T) Supplementary Data S1 onlinea SLCO1B1, 521T>C (V174A), SLCO1B1*15, EXON 5 0.083(C):0.917(T) 0.022(C):0.978(T) ABCC1, 1062T>C (N354N), EXON 9 0.458(C):0.542(T) 0.643(C):0.357(T) 44 ABCC1, +8A>G, INTRON 9 0.643(A):0.357(G) 0.433(A):0.567(G) ABCC1, -48C>T, INTRON 11 0.146(T):0.854(C) 0(T):1.0(C) ABCC1, 1684T>C (L562L), EXON 13 0.917(C):0.083(T) 0.848(C):0.152(T) ABCC1, -30C>G, INTRON 18 0.042(C):0.958(G) 0.217(C):0.783(G) ABCC1, 4002G>A (S1334S), EXON 28 0.688(C):0.312(T) 0.955(C):0.045(T) ABCC1, +18A>G, INTRON 30 0.213(T):0.787(C) 0.042(T):0.958(C) ABCC2, -1549A>G, 5ʹ-Flanking region 0.43(A):0.57(G) 0.485(A):0.515(G) 44 ABCC2, -1019A>G, 5ʹ-Flanking region 0.43(G):0.57(A) 0.365(G):0.635(A) ABCC2, -24C>T, 5ʹ-UTR 0.230(A):0.770(G) 0.06(A):0.940(G) ABCC2, 1249G>A (V417I), EXON 10 0.146(A):0.854(G) 0.239(A):0.761(G) ABCC2, -34T>C, INTRON 26 0.17(C):0.83(T) 0.25(C):0.75(T) ABCC2, 3972C>T (I1324I), EXON 28 0.380(A):0.620(G) 0.280(A):0.720(G) ABCB1, -129T>C, 5ʹ-UTR 0.620(C):0.938(T) 0.043(C):0.957(T) 44 ABCB1, -25G>T, INTRON 4 0.273(T):0.737(G) 0.385(T) :0.615(G) ABCB1, -44A>G, INTRON 9 0.409(C):0.591(T) 0.20(C):0.80(T) ABCB1, 1236C>T (G412G), EXON 12 0.523(C):0.477(T) 0.864(C):0.136(T) ABCB1, +24C>T, INTRON 13 0.50(T):0.50(C) 0.467(T):0.533(C) ABCB1, +38A>G, INTRON 14 0.429(A):0.571(G) 0.389(A):0.611(G) ABCB1, 2677G>A/T (A893T/S), EXON 21 0.614(G):0.386(T) 0.923(G):0.077(T) ABCB1, 3435C>T (I1145I), EXON 26 0.375(C):0.625(T) 0.848(C):0.152(T) ABCG2, 34G>A (V12M), EXON 2 0.017(A):0.983(G) 0.071(A):0.929(G) Supplementary Data S1 onlinea ABCG2, 421C>A (Q141K), EXON 5 0.045(A):0.955(C) 0.023(A):0.977(C) CES2, -363C>G, 5ʹ-UTR 0.810(C):0.190(G) 0.733(C):0.267(G) Supplementary Data S1 onlinea CES2, +1361A>G, INTRON 1 0.143(G):0.857(A) 0.438(G):0.562(A) CES2, 108C>G, 3ʹ-UTR 0.004(G):0.996(C) 0(G):1.0(C) PBREM, phenobarbital-responsive enhancer module; UTR, untranslated region. Login to comment

[hide] Apical/basolateral surface expression of drug tran... Pharm Res. 2005 Oct;22(10):1559-77. Epub 2005 Sep 22. Ito K, Suzuki H, Horie T, Sugiyama Y
Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport.
Pharm Res. 2005 Oct;22(10):1559-77. Epub 2005 Sep 22., [PMID:16180115]

Abstract [show]
It is well known that transporter proteins play a key role in governing drug absorption, distribution, and elimination in the body, and, accordingly, they are now considered as causes of drug-drug interactions and interindividual differences in pharmacokinetic profiles. Polarized tissues directly involved in drug disposition (intestine, kidney, and liver) and restricted distribution to naive sanctuaries (blood-tissue barriers) asymmetrically express a variety of drug transporters on the apical and basolateral sides, resulting in vectorial drug transport. For example, the organic anion transporting polypeptide (OATP) family on the sinusoidal (basolateral) membrane and multidrug resistance-associated protein 2 (MRP2/ABCC2) on the apical bile canalicular membrane of hepatocytes take up and excrete organic anionic compounds from blood to bile. Such vectorial transcellular transport is fundamentally attributable to the asymmetrical distribution of transporter molecules in polarized cells. Besides the apical/basolateral sorting direction, distribution of the transporter protein between the membrane surface (active site) and the intracellular fraction (inactive site) is of practical importance for the quantitative evaluation of drug transport processes. The most characterized drug transporter associated with this issue is MRP2 on the hepatocyte canalicular (apical) membrane, and it is linked to a genetic disease. Dubin-Johnson syndrome is sometimes caused by impaired canalicular surface expression of MRP2 by a single amino acid substitution. Moreover, single nucleotide polymorphisms in OATP-C/SLC21A6 (SLCO1B1) also affect membrane surface expression, and actually lead to the altered pharmacokinetic profile of pravastatin in healthy subjects. In this review article, the asymmetrical transporter distribution and altered surface expression in polarized tissues are discussed.

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210 Mizuarai et al. (120) reported that the V12M SNP mutant exhibited severely impaired apical expression in LLC-PK1 cells. Login to comment
211 The allele frequency of V12M reached as high as 10.3%, and actually 27 and 2 out of the 150 normal healthy Caucasians were hetero-and homozygotes of this SNP, respectively. Login to comment
212 Kondo et al. (119) also examined the cellular localization of a total of seven SNP variants of BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S, and S441N) in LLC-PK1. Login to comment
214 In contrast to the report from Mizuarai et al., V12M was found to be normally localized on the apical membrane of LLC-PK1 cells (119). Login to comment
215 The reason why such a contradictory result was observed while using the same SNP variant of BCRP (V12M) in the same host cell (LLC-PK1) is currently unknown, but the different cell culture conditions in laboratories might be one possible cause. Login to comment

[hide] Intestinal transporters for endogenic and pharmace... J Pharm Pharmacol. 2012 Nov;64(11):1523-48. doi: 10.1111/j.2042-7158.2012.01505.x. Epub 2012 Mar 30. Grandvuinet AS, Vestergaard HT, Rapin N, Steffansen B
Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug-drug interactions.
J Pharm Pharmacol. 2012 Nov;64(11):1523-48. doi: 10.1111/j.2042-7158.2012.01505.x. Epub 2012 Mar 30., [PMID:23058041]

Abstract [show]
Objectives This review provides an overview of intestinal human transporters for organic anions and stresses the need for standardization of the various in-vitro methods presently employed in drug-drug interaction (DDI) investigations. Key findings Current knowledge on the intestinal expression of the apical sodium-dependent bile acid transporter (ASBT), the breast cancer resistance protein (BCRP), the monocarboxylate transporters (MCT) 1, MCT3-5, the multidrug resistance associated proteins (MRP) 1-6, the organic anion transporting polypetides (OATP) 2B1, 1A2, 3A1 and 4A1, and the organic solute transporter alpha/beta (OSTalpha/beta) has been covered along with an overview of their substrates and inhibitors. Furthermore, the many challenges in predicting clinically relevant DDIs from in-vitro studies have been discussed with focus on intestinal transporters and the various methods for deducting in-vitro parameters for transporters (K(m) /K(i) /IC50, efflux ratio). The applicability of using a cut-off value (estimated based on the intestinal drug concentration divided by the K(i) or IC50) has also been considered. Summary A re-evaluation of the current approaches for the prediction of DDIs is necessary when considering the involvement of other transporters than P-glycoprotein. Moreover, the interplay between various processes that a drug is subject to in-vivo such as translocation by several transporters and dissolution should be considered.

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517 Kim HS et al. The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment

[hide] Deletion of abcg2 has differential effects on excr... J Pharmacol Exp Ther. 2012 Nov;343(2):316-24. doi: 10.1124/jpet.112.197046. Epub 2012 Aug 6. Huang L, Be X, Tchaparian EH, Colletti AE, Roberts J, Langley M, Ling Y, Wong BK, Jin L
Deletion of abcg2 has differential effects on excretion and pharmacokinetics of probe substrates in rats.
J Pharmacol Exp Ther. 2012 Nov;343(2):316-24. doi: 10.1124/jpet.112.197046. Epub 2012 Aug 6., [PMID:22869929]

Abstract [show]
This study was designed to characterize breast cancer resistance protein (Bcrp) knockout Abcg2(-/-) rats and assess the effect of ATP-binding cassette subfamily G member 2 (Abcg2) deletion on the excretion and pharmacokinetic properties of probe substrates. Deletion of the target gene in the Abcg2(-/-) rats was confirmed, whereas gene expression was unaffected for most of the other transporters and metabolizing enzymes. Biliary excretion of nitrofurantoin, sulfasalazine, and compound A [2-(5-methoxy-2-((2-methyl-1,3-benzothiazol-6-yl)amino)-4-pyridinyl)-1,5,6,7-tetr ahydro-4H-pyrrolo[3,2-c]pyridin-4-one] accounted for 1.5, 48, and 48% of the dose in the Abcg2(+/+) rats, respectively, whereas it was decreased by 70 to 90% in the Abcg2(-/-) rats. Urinary excretion of nitrofurantoin, a significant elimination pathway, was unaffected in the Abcg2(-/-) rats, whereas renal clearance of sulfasalazine, a minor elimination pathway, was reduced by >90%. Urinary excretion of compound A was minimal. Systemic clearance in the Abcg2(-/-) rats decreased 22, 43 (p < 0.05), and 57%, respectively, for nitrofurantoin, sulfasalazine, and compound A administered at 1 mg/kg and 27% for compound A administered at 5 mg/kg. Oral absorption of nitrofurantoin, a compound with high aqueous solubility and good permeability, was not limited by Bcrp. In contrast, the absence of Bcrp led to a 33- and 11-fold increase in oral exposure of sulfasalazine and compound A, respectively. These data show that Bcrp plays a crucial role in biliary excretion of these probe substrates and has differential effects on systemic clearance and oral absorption in rats depending on clearance mechanisms and compound properties. The Abcg2(-/-) rat is a useful model for understanding the role of Bcrp in elimination and oral absorption.

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24 Several additional SNPs, including V12M, Q126Stop, and P269S, affect expression or activities of the transporter, which may also have clinical implications (Kondo et al., 2004; Mizuarai et al., 2004; Tamura et al., 2006; Lee et al., 2007). Login to comment

[hide] The JR blood group system (ISBT 032): molecular ch... Transfusion. 2012 Oct 15. doi: 10.1111/j.1537-2995.2012.03930.x. Hue-Roye K, Lomas-Francis C, Coghlan G, Zelinski T, Reid ME
The JR blood group system (ISBT 032): molecular characterization of three new null alleles.
Transfusion. 2012 Oct 15. doi: 10.1111/j.1537-2995.2012.03930.x., [PMID:23066723]

Abstract [show]
BACKGROUND: Jr(a) (ISBT 901005) is a high-prevalence antigen unassigned to a blood group system. People lacking this antigen have been found in all populations studied but most commonly in Asians. Two recent reports established that ABCG2-null alleles encode the Jr(a-) phenotype and these studies provided the impetus to study other Jr(a-) individuals. STUDY DESIGN AND METHODS: Blood samples were part of our rare donor-patient collection. DNA was isolated and analyzed by standard techniques. RESULTS: In samples from 13 Jr(a-) study subjects, we found six alleles with nonsense nucleotide changes, three (c.784T, c.1591T, and c.337T) were novel. Twelve of the samples were homozygous for nonsense single-nucleotide polymorphisms (SNPs): eight were c.376T, two were c.706T, one was c.784T, and one was c.1591T. Each of these alleles predicts a truncated ABCG2 product, Gln126Stop, Arg236Stop, Gly262Stop, and Gln531Stop, respectively. One study subject was heterozygous for two nonsense SNPs: c.337C/T (Arg113Stop) and c.736C/T (Arg246Stop). CONCLUSIONS: Jr(a) is the sole antigen in the newly established JR blood group system (ISBT 032001). The previous ISBT designation (901005) is now obsolete. Since ABCG2(null) alleles define the Jr(a-) phenotype, an explanation for why no antithetical low-prevalence antigen to Jr(a) has been found, and also why anti-Jr(a) made by people with any of these JR(null) alleles are mutually compatible has been determined. Based on our findings DNA-based genotyping can be developed to replace the serologic methods that are currently used to identify Jr(a-) blood donors.

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69 Nucleotide and predicted amino acid changes in ABCG2 in 13 serologically defined Jr(a-) samples Proband (D/P) Ethnicity/race Anti-Jra Nucleotide change (exon) Predicted amino acid change 1 (D) Japanese No c.376C>T (4) Gln126Stop 2 (D) Unknown Unknown c.376C>T (4) Gln126Stop 3 (P) Asian Yes c.376C>T (4) Gln126Stop 4 (P) Japanese Yes c.376C>T (4) Gln126Stop 5 (D) Caucasian Yes c.376C>T (4) Gln126Stop 6 (P) Caucasian Yes c.376C>T (4) Gln126Stop 7 (P) Japanese Yes c.376C>T (4) Gln126Stop 8 (P) Chinese Yes c.376C>T (4) Gln126Stop 9 (P) Caucasian Yes c.706C>T (7) Arg236Stop 10 (P) Caucasian Yes c.706C>T (7) Arg236Stop 11 (P) Caucasian Yes c.337C/T† (4) c.736C/T (7) Arg113Stop Arg246Stop 12 (P) Caucasian Yes c.784G>T† (7) Gly262Stop 13 (P) Caucasian Yes c.1591C>T† (13) c.34G>A (2) Gln531Stop Val12 Met † Novel allele. Login to comment

[hide] The contribution of the ABCG2 C421A polymorphism t... BMC Cancer. 2012 Sep 1;12:383. doi: 10.1186/1471-2407-12-383. Chen P, Zhao L, Zou P, Xu H, Lu A, Zhao P
The contribution of the ABCG2 C421A polymorphism to cancer susceptibility: a meta-analysis of the current literature.
BMC Cancer. 2012 Sep 1;12:383. doi: 10.1186/1471-2407-12-383., [PMID:22937733]

Abstract [show]
ABSTRACT: BACKGROUND: ABCG2, also known as BCRP, is a half ATP-binding cassette (ABC) transporter that localizes to plasma membranes. Recently, a number of studies have investigated the relationship between the C421A polymorphism in ABCG2 and cancer risk in multiple populations and various types of cancers; however, this relationship remains unclear. Therefore, we performed a meta-analysis to further explore this association. METHODS: The meta-analysis incorporated 10 studies involving a total of 3593 cases and 5875 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated based on the date extracted from the studies to evaluate the strength of association. We also analyzed the heterogeneity and sensitivity of each report and the publication bias of the studies. RESULTS: Overall, our results showed that there appeared to be a significant association between the ABCG2 C421A polymorphism and decreased cancer susceptibility (heterozygote-AC versus CC: OR = 0.759, 95%CI = 0.620-0.930; dominant effects model-AA/AC versus CC: OR = 0.771, 95%CI = 0.634-0.938; additive effects model-A allele versus C allele: OR = 0.809, 95%CI = 0.687-0.952). Similarly, decreased cancer risk was also found after stratification of the SNP data by cancer type, ethnicity and source of controls in heterozygote model, dominant effects model and additive effects model. CONCLUSIONS: We found that the ABCG2 C421A polymorphism is a protective factor for developing cancer. The same relationship was found when the studies were stratified by cancer type, ethnicity and source of controls.

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31 Researches had shown that there were two frequently polymorphic SNPs in the BCRP gene: one in exon2 (G34A, resulting in a V12M change) and the other in exon5 (C421A, resulting in a Q141K substitution) respectively [15]. Login to comment
24 Researches had shown that there were two frequently polymorphic SNPs in the BCRP gene: one in exon2 (G34A, resulting in a V12M change) and the other in exon5 (C421A, resulting in a Q141K substitution) respectively [15]. Login to comment

[hide] Role of breast cancer resistance protein (BCRP/ABC... Biochem Pharmacol. 2012 Apr 15;83(8):1084-103. Epub 2012 Jan 11. Natarajan K, Xie Y, Baer MR, Ross DD
Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance.
Biochem Pharmacol. 2012 Apr 15;83(8):1084-103. Epub 2012 Jan 11., [PMID:22248732]

Abstract [show]
Since cloning of the ATP-binding cassette (ABC) family member breast cancer resistance protein (BCRP/ABCG2) and its characterization as a multidrug resistance efflux transporter in 1998, BCRP has been the subject of more than two thousand scholarly articles. In normal tissues, BCRP functions as a defense mechanism against toxins and xenobiotics, with expression in the gut, bile canaliculi, placenta, blood-testis and blood-brain barriers facilitating excretion and limiting absorption of potentially toxic substrate molecules, including many cancer chemotherapeutic drugs. BCRP also plays a key role in heme and folate homeostasis, which may help normal cells survive under conditions of hypoxia. BCRP expression appears to be a characteristic of certain normal tissue stem cells termed "side population cells," which are identified on flow cytometric analysis by their ability to exclude Hoechst 33342, a BCRP substrate fluorescent dye. Hence, BCRP expression may contribute to the natural resistance and longevity of these normal stem cells. Malignant tissues can exploit the properties of BCRP to survive hypoxia and to evade exposure to chemotherapeutic drugs. Evidence is mounting that many cancers display subpopulations of stem cells that are responsible for tumor self-renewal. Such stem cells frequently manifest the "side population" phenotype characterized by expression of BCRP and other ABC transporters. Along with other factors, these transporters may contribute to the inherent resistance of these neoplasms and their failure to be cured.

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3631 In another study, the GG genotype of BCRP rs2231137, in relation to the heterozygous (AG) (G34A, encoding V12M) or homozygous (AA) variant genotypes, was significantly associated with a lower rate of complete cytogenetic response to imatinib [197]. Login to comment
3640 With regard to BCRP SNPs, among 145 Korean patients with DLBCL treated with the R-CHOP regimen, there was no influence of BCRP SNPs on clinical characteristics or treatment outcomes, but patients with the Q141K polymorphism (QK or KK), but not the V12M polymorphism discussed above for AML and CML, had more chemotherapy-related diarrhea [201]. Login to comment

[hide] Pharmacogenetic analysis of BR.21, a placebo-contr... J Thorac Oncol. 2012 Feb;7(2):316-22. Liu G, Cheng D, Ding K, Le Maitre A, Liu N, Patel D, Chen Z, Seymour L, Shepherd FA, Tsao MS
Pharmacogenetic analysis of BR.21, a placebo-controlled randomized phase III clinical trial of erlotinib in advanced non-small cell lung cancer.
J Thorac Oncol. 2012 Feb;7(2):316-22., [PMID:22237259]

Abstract [show]
BACKGROUND: BR.21 is a double-blind, placebo-controlled trial of second-/third-line erlotinib in stage IIIB/IV non-small cell lung cancer patients. Predictive and prognostic analyses of epidermal growth factor receptor (EGFR), ABCG2, and AKT1 genetic polymorphisms were performed. METHODS: Two hundred forty-two patients were genotyped for EGFR-216G>T (EGFR216), EGFR-191C>A (EGFR191), EGFR intron 1 CA-dinucleotide-repeat (CADR), ABCG2+421C>A (ABCG2), and AKT1-SNP4G>A (AKT1). Cox proportional hazard and logistic regression models compared genotypes with overall survival (OS), progression-free survival (PFS), and presence/absence of skin toxicity. RESULTS: Prognostic evaluation was based on the placebo arm: patients carrying at least one CADR long allele (>16 repeats) had a trend toward worse PFS: the adjusted hazard ratio was 1.7 (95% confidence interval [CI]: 1.0-3.0; p = 0.07). EGFR216, EGFR191, ABCG2, and AKT1 were not prognostic. Polymorphisms were not predictive for erlotinib effect (OS/PFS): no treatment-polymorphism interactions were demonstrated. Individuals carrying the rare T/T genotype of EGFR216 had an adjusted odds ratio of 8.8 (95% CI: 1.1-72; p = 0.04) of developing skin toxicity; no other significant polymorphic relationships with skin toxicity were found. CONCLUSIONS: In contrast to previous publications, carrying shorter alleles of the EGFR CADR polymorphism was not predictive of OS or PFS. EGFR216 homozygous variants were associated with greater skin toxicity from erlotinib.

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35 We excluded the analysis of the ABCG2 34GϾA (V12M, rs2231137) polymorphism17 because it had a 2% minor allele frequency in our Caucasian-predominant population. Login to comment

[hide] ABCG2 null alleles define the Jr(a-) blood group p... Nat Genet. 2012 Jan 15;44(2):131-2. doi: 10.1038/ng.1075. Zelinski T, Coghlan G, Liu XQ, Reid ME
ABCG2 null alleles define the Jr(a-) blood group phenotype.
Nat Genet. 2012 Jan 15;44(2):131-2. doi: 10.1038/ng.1075., [PMID:22246507]

Abstract [show]
The high-incidence erythrocyte blood group antigen Jr(a) has been known in transfusion medicine for over 40 years. To identify the gene encoding Jr(a), we performed SNP analysis of genomic DNA from six Jr(a-) individuals. All individuals shared a homozygous region of 397,000 bp at chromosome 4q22.1 that contained the gene ABCG2, and DNA sequence analysis showed that ABCG2 null alleles define the Jr(a-) phenotype.

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26 The third ABCG2 null genotype consists of a compound molecular background, with one allele giving rise to a p.Val12Met substitution coupled with a premature stop codon at amino acid 236 and a second allele encoding the p.Val12Met substitution coupled with the normal Arg236 amino acid. Login to comment
37 In studies with polarized LLC-PK1 cells (renal epithelial cells derived from porcine kidneys), cells expressing ABCG2 V12M were ten times more sensitive to topoisomerase inhibitor I than cells transfected with control vectors8, and in vesicles expressing the V12M variant, substrate efflux was also reduced compared with that in control cells transfected with control vectors. Login to comment
38 Further, analysis of ABCG2 V12M localization by immunofluorescence showed that ABCG2 was not present at the apical membrane8. Login to comment
39 In contrast, a previous study did not observe a decrease in urate transport nor a significant difference in the amount of protein in immunoblots of lysates from HEK293 cells expressing the V12M variant5. Login to comment
40 Further investigation of the subject in our study who was homozygous for the mutation encoding p.Val12Met and heterozygous for the one encoding p.Arg236* might have resolved this issue, but, unfortunately, this individual was not available for follow-up studies. Login to comment
42 This finding is not surprising, as the p.Val12Met substitution falls in a region likely to encode a signal peptide. Login to comment
43 Alternatively, it is possible that the p.Val12Met substitution alters the Jra antigenic epitope within the transmembrane domain (amino acids 390-655) of ABCG2. Login to comment
121 Table 1 Nucleotide and predicted protein changes in ABCG2 in six Jr(a-) subjects Subject Ancestrya Nucleotide Protein 1 Caucasian c.736C>T p.Arg246* 2 Caucasian c.736C>T p.Arg246* 3 Asian c.376C>T p.Gln126* 4 Asian c.376C>T p.Gln126* 5 Asian c.376C>T p.Gln126* 6 Asian c.34G>A c.706C>T p.Val12Met p.Arg236* All samples were used with permission under protocols approved by the New York Blood Center and the University of Manitoba`s Health Research Ethics Board. Login to comment

[hide] Functional significance of genetic polymorphisms i... Drug Metab Pharmacokinet. 2012;27(1):85-105. Epub 2011 Nov 29. Ieiri I
Functional significance of genetic polymorphisms in P-glycoprotein (MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2).
Drug Metab Pharmacokinet. 2012;27(1):85-105. Epub 2011 Nov 29., [PMID:22123128]

Abstract [show]
Recent pharmacogenomic/pharmacogenetic (PGx) studies have disclosed important roles for drug transporters in the human body. Changes in the functions of drug transporters due to drug/food interactions or genetic polymorphisms, for example, are associated with large changes in pharmacokinetic (PK) profiles of substrate drugs, leading to changes in drug response and side effects. This information is extremely useful not only for drug development but also for individualized treatment. Among drug transporters, the ATP-binding cassette (ABC) transporters are expressed in most tissues in humans, and play protective roles; reducing drug absorption from the gastrointestinal tract, enhancing drug elimination into bile and urine, and impeding the entry of drugs into the central nervous system and placenta. In addition to PK/pharmacodynamic (PD) issues, ABC transporters are reported as etiologic and prognostic factors (or biomarkers) for genetic disorders. Although a consensus has not yet been reached, clinical studies have demonstrated that the PGx of ABC transporters influences the overall outcome of pharmacotherapy and contributes to the pathogenesis and progression of certain disorders. This review explains the impact of PGx in ABC transporters in terms of PK/PD, focusing on P-glycoprotein and breast cancer resistance protein (BCRP).

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71 Impact of ABCG2 (BCRP) polymorphisms on PK/PD/disorders Gene marker ¤SNPs/haplotype¥ Functional effect of the study Drug Population Disease Ref.Pharmacokinetics Therapeutic efficacy Side effects SNPs assay Others ¤e.g., frequency and susceptibility¥ %15622CgT or ¤1143ChT, %15622ChT¥ haplotype * gefitinib patient NSCLC 68 421ChA * * A771726 HV 223 421ChA ¤141QhK, rs2231142¥ * patient gout 224 421ChA * imatinib patient CML 225 421ChA * patient uric acid 226 421ChA ¤141QhK, rs2231142¥ * patient gout 227 421ChA, 914ChA * methotrexate patient RA 228 421ChA * * sunitinib patient RCC 70 421ChA * rosuvastatin patient myocardial infarction 229 346GhA, 421ChA, 1143ChT, 15994GhA * danusertib patient 230 421ChA * rosuvastatin patient hypercholesterolemia 231 421ChA * patient gout 232 376ChT, 421ChA * gefitinib patient NSCLC 67 421ChA * telatinib patient 233 421ChA * 3 statines HV 234 rs2622604 * irinitecan patient myelosuppression 235 ¤%15622C/T, 1143C/T¥ haplotype * sunitinib patient 127 12VhM, 141QhK * mitoxantrone patient multiple sclerosis 236 421ChA * imatinib patient CML 237 421ChA * sulfasalazine HV 238 421ChA * erlotinib patient SCC 69 421ChA * patient gout 239 421ChA * atorvastatin, rosuvastatin HV 240 12VhM, 141QhK * R-CHOP patient DLBCL 241 12VhM * patient ischemic stroke 242 421ChA * imatinib patient solid malignancies 243 421ChA * patient gout 73 rs2622621, rs1481012 * patient colorectal cancer 244 421ChA * nitrofurantoin HV 245 421ChA * sulfasalazine HV 246 421ChA * doxorubicin patient breast cancer 168 421ChA * sulfasalazine HV 60 Q141K, V12M, Q126X * lamivudine HV 247 34ChA, 421ChA * patient DLBCL 248 421ChA * pitavastatin HV 64 Continued on next page: 141QhK¥ which has been associated with lower BCRP protein expression.52,55¥ Recently, 421ChA was found to greatly affect the stability of BCRP in the endoplasmic reticulum, leading to increased protein degradation via ubiquitination and proteasomal proteolysis.56,57¥ Therefore, 421ChA may lead to increased bioavailability after the oral administration of substrate drugs. Login to comment

[hide] Human ABCG2: structure, function, and its role in ... Int J Biochem Mol Biol. 2012;3(1):1-27. Epub 2011 Mar 30. Mo W, Zhang JT
Human ABCG2: structure, function, and its role in multidrug resistance.
Int J Biochem Mol Biol. 2012;3(1):1-27. Epub 2011 Mar 30., [PMID:22509477]

Abstract [show]
Human ABCG2 is a member of the ATP-binding cassette (ABC) transporter superfamily and is known to contribute to multidrug resistance (MDR) in cancer chemotherapy. Among ABC transporters that are known to cause MDR, ABCG2 is particularly interesting for its potential role in protecting cancer stem cells and its complex oligomeric structure. Recent studies have also revealed that the biogenesis of ABCG2 could be modulated by small molecule compounds. These modulators, upon binding to ABCG2, accelerate the endocytosis and trafficking to lysosome for degradation and effectively reduce the half-life of ABCG2. Hence, targeting ABCG2 stability could be a new venue for therapeutic discovery to sensitize drug resistant human cancers. In this report, we review recent progress on understanding the structure, function, biogenesis, as well as physiological and pathophysiological functions of ABCG2.

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889 The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment
895 The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment

[hide] ABCG2 is a direct transcriptional target of hedgeh... Oncogene. 2011 Dec 8;30(49):4874-86. doi: 10.1038/onc.2011.195. Epub 2011 May 30. Singh RR, Kunkalla K, Qu C, Schlette E, Neelapu SS, Samaniego F, Vega F
ABCG2 is a direct transcriptional target of hedgehog signaling and involved in stroma-induced drug tolerance in diffuse large B-cell lymphoma.
Oncogene. 2011 Dec 8;30(49):4874-86. doi: 10.1038/onc.2011.195. Epub 2011 May 30., [PMID:21625222]

Abstract [show]
Successful treatment of diffuse large B-cell lymphoma (DLBCL) is frequently hindered by the development of resistance to conventional chemotherapy resulting in disease relapse and high mortality. High expression of antiapoptotic and/or drug transporter proteins induced by oncogenic signaling pathways has been implicated in the development of chemoresistance in cancer. Previously, our studies showed that high expression of adenosine triphosphate-binding cassette drug transporter ABCG2 in DLBCL correlated inversely with disease- and failure-free survival. In this study, we have implicated activated hedgehog (Hh) signaling pathway as a key factor behind high ABCG2 expression in DLBCL through direct upregulation of ABCG2 gene transcription. We have identified a single binding site for GLI transcription factors in the ABCG2 promoter and established its functionality using luciferase reporter, site-directed mutagenesis and chromatin-immunoprecipitation assays. Furthermore, in DLBCL tumor samples, significantly high ABCG2 and GLI1 levels were found in DLBCL tumors with lymph node involvement in comparison with DLBCL tumor cells collected from pleural and/or peritoneal effusions. This suggests a role for the stromal microenvironment in maintaining high levels of ABCG2 and GLI1. Accordingly, in vitro co-culture of DLBCL cells with HS-5 stromal cells increased ABCG2 mRNA and protein levels by paracrine activation of Hh signaling. In addition to ABCG2, co-culture of DLBCL cells with HS-5 cells also resulted in increase expression of the antiapoptotic proteins BCL2, BCL-xL and BCL2A1 and in induced chemotolerance to doxorubicin and methotrexate, drugs routinely used for the treatment of DLBCL. Similarly, activation of Hh signaling in DLBCL cell lines with recombinant Shh N-terminal peptide resulted in increased expression of BCL2 and ABCG2 associated with increased chemotolerance. Finally, functional inhibition of ABCG2 drug efflux activity with fumitremorgin C or inhibition of Hh signaling with cyclopamine-KAAD abrogated the stroma-induced chemotolerance suggesting that targeting ABCG2 and Hh signaling may have therapeutic value in overcoming chemoresistance in DLBCL.

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25 One study identified two polymorphisms in ABCG2 gene, G34A (Val12Met) and C421A (Gln141Lys), and associated these polymorphisms with increased risk and poor overall survival of DLBCL (Hu et al., 2007). Login to comment

[hide] ABCG2/BCRP dysfunction as a major cause of gout. Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1117-28. Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, Suzuki H, Hosoya T, Shinomiya N
ABCG2/BCRP dysfunction as a major cause of gout.
Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1117-28., [PMID:22132966]

Abstract [show]
Recent genome-wide association studies showed that serum uric acid (SUA) levels relate to ABCG2/BCRP gene, which locates in a gout-susceptibility locus revealed by a genome-wide linkage study. Together with the ABCG2 characteristics, we hypothesized that ABCG2 transports urate and its dysfunction causes hyperuricemia and gout. Transport assays showed ATP-dependent transport of urate via ABCG2. Kinetic analysis revealed that ABCG2 mediates high-capacity transport of urate (Km: 8.24 +/- 1.44 mM) even under high-urate conditions. Mutation analysis of ABCG2 in 90 Japanese hyperuricemia patients detected six nonsynonymous mutations, including five dysfunctional variants. Two relatively frequent dysfunctional variants, Q126X and Q141K, were then examined. Quantitative trait locus analysis of 739 Japanese individuals showed that Q141K increased SUA as the number of minor alleles of Q141K increased (p = 6.60 x 10(-5)). Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Becuase Q126X and Q141K are assigned to nonfunctional and half-functional haplotypes, respectively, their genotype combinations are divided into four functional groups. The association study with 161 male gout patients and 865 male controls showed that all of those with dysfunctional ABCG2 increased the gout risk, especially those with </=1/4 function (OR, 25.8; 95% CI, 10.3-64.6; p = 3.39 x 10(-21)). These genotypes were found in 10.1% of gout patients, but in only 0.9% of control. Our function-based clinicogenetic (FBCG) analysis showed that combinations of the two dysfunctional variants are major causes of gout, thereby providing a new approach for prevention and treatment of the gout high-risk population.

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38 1119 ABCG2 : ATP binding casse e G2 SNP : single nucleo de polymorphism QTL : quan ta ve trait locus OR : odds ra o ABCG2 as a urate secre on transporter in humans Gene c analysis Func onal analysis ABCG2 muta on analysis of 90 hyperuricemic cases (all coding regions) ABCG2 muta ons (with amino acid altera ons) 6 muta ons c d Func onal analysis of urate transport via wild type ABCG2 (vesicle studies) a Iden fica on of urate transport ac vi es via ABCG2 b Func onal analysis of urate transport via mutated ABCG2 6 mutants e No effect (V12M) g Dysfunc onal genotype combina ons of ABCG2 as major causes of gout q Dysfunc onal SNP with high frequency (>30%) (Q141K) QTL analysis in 739 Japanese individuals h i j n Gout / hyperuricemia with ABCG2 homozygous, n = 2 heterozygous, n = 24 Loss of func on (Q126X, G268R, S441N, F506Sfs) Reduced func on (~50%) (Q141K) f p Genotype combina on analysis 10.1% of gout with ≤1/4 ABCG2 func on OR = 25.8, p = 3.39×10-21 o Haplotype analysis 13.5% of gout with disease haplotype OR = 5.97, p = 4.10×10-12 Associa on analysis of hyperuricemia (Q126X) OR = 3.61, p = 2.91× 10-7 l m Associa on analysis of gout (Q126X) OR = 4.25, p =3.04 × 10-8 Genotyping of nonfunc onal SNP (Q126X) hyperuricemia, n=228 k FIGURE 1 Flowchart for molecular-function-based clinicogenetic (FBCG) analysis of gout patients with ABCG2 polymorphic variants. Login to comment
53 Using the site-directed mutagenesis technique, we constructed ABCG2 mutants (V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment
65 The following six nonsynonymous mutations, including three SNPs, were found: V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4 (Figure 2A). Login to comment
76 Maekawa et al.[17] reported that V12M, Q126X, and Q141K are quite common in the Japanese population, and allele frequencies for these SNPs were 31.9% for Q141K, 19.2% for V12M, and 2.8% for Q126X, respectively. Login to comment
77 Using Hardy-Weinberg equilibrium and these data on a Japanese population reported by Maekawa et al.,[17] we estimated that the frequencies of Japanese individuals with these minor alleles were 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X. Login to comment
80 The V12M variant did not show any changes in urate transport compared to wild-type ABCG2. Login to comment
97 We also found that V12M is exclusively assigned to a nonrisk haplotype. Login to comment

[hide] Identification of ABCG2 dysfunction as a major fac... Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1098-104. Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, Takada Y, Okada C, Sakurai Y, Hosoya T, Kanai Y, Suzuki H, Shinomiya N
Identification of ABCG2 dysfunction as a major factor contributing to gout.
Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1098-104., [PMID:22132963]

Abstract [show]
The ATP-binding cassette, subfamily G, member 2 gene ABCG2/BCRP locates in a gout-susceptibility locus (MIM 138900) on chromosome 4q. Recent genome-wide association studies also showed that the ABCG2 gene relates to serum uric acid levels and gout. Since ABCG2 is also known as a transporter of nucleotide analogs that are structurally similar to urate, and is an exporter that has common polymorphic reduced functionality variants, ABCG2 could be a urate secretion transporter and a gene causing gout. To find candidate mutations in ABCG2, we performed a mutation analysis of the ABCG2 gene in 90 Japanese patients with hyperuricemia and found six non-synonymous mutations. Among the variants, ATP-dependent urate transport was reduced or eliminated in five variants, and two out of the five variants (Q126X and Q141K) were frequently detected in patients. Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. As Q126X and Q141K are a nonfunctional and half-functional haplotype, respectively, their genotype combinations are divided into four estimated functional groups. The association study with 161 male gout patients and 865 male controls showed that all of those who had dysfunctional ABCG2 had an increased risk of gout, and that a remarkable risk was observed in those with </=1/4 function (OR, 25.8; 95% CI, 10.3-64.6; p = 3.39 x 10(-21)). In 2,150 Japanese individuals, the frequency of those with dysfunctional ABCG2 was more than 50%. Our function-based clinicogenetic analysis identified the combinations of dysfunctional variants of ABCG2 as a major contributing factor in Japanese patients with gout.

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36 Using the site-directed mutagenesis technique, we constructed mutants of ABCG2 (V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment
45 The following six non-synonymous mutations, V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4, were found (Figure 1A), and the first three mutations were SNPs. Login to comment
49 Results are expressed as means ± SD. V12M, and 2.8% for Q126X. Login to comment
50 With the Hardy-Weinberg equilibrium and the data reported by Maekawa et al. of the Japanese population,[5] we calculated estimates of the minor allele frequencies of Japanese individuals to be 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X. Login to comment
53 The V12M variant did not show any changes in urate transport relative to wild-type ABCG2. Login to comment
68 Our findings showed that V12M is exclusively assigned to a non-risk haplotype and that the V12M variant does not exhibit altered urate transport activity (Figure 1B). Login to comment
69 These findings may help explain why V12M decreases gout risk (OR, 0.68; 95% CI, 0.49-0.94; p = 0.02). Login to comment

[hide] ABCG2 is a high-capacity urate transporter and its... Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1091-7. Nakayama A, Matsuo H, Takada T, Ichida K, Nakamura T, Ikebuchi Y, Ito K, Hosoya T, Kanai Y, Suzuki H, Shinomiya N
ABCG2 is a high-capacity urate transporter and its genetic impairment increases serum uric acid levels in humans.
Nucleosides Nucleotides Nucleic Acids. 2011 Dec;30(12):1091-7., [PMID:22132962]

Abstract [show]
The ATP-binding cassette, subfamily G, member 2 (ABCG2/BCRP) gene encodes a well-known transporter, which exports various substrates including nucleotide analogs such as 3'-azido-3'-deoxythymidine (AZT). ABCG2 is also located in a gout-susceptibility locus (MIM 138900) on chromosome 4q, and has recently been identified by genome-wide association studies to relate to serum uric acid (SUA) and gout. Becuase urate is structurally similar to nucleotide analogs, we hypothesized that ABCG2 might be a urate exporter. To demonstrate our hypothesis, transport assays were performed with membrane vesicles prepared from ABCG2-overexpressing cells. Transport of estrone-3-sulfate (ES), a typical substrate of ABCG2, is inhibited by urate as well as AZT and ES. ATP-dependent transport of urate was then detected in ABCG2-expressing vesicles but not in control vesicles. Kinetic analysis revealed that ABCG2 is a high-capacity urate transporter that maintained its function even under high-urate concentration. The calculated parameters of ABCG2-mediated transport of urate were a Km of 8.24 +/- 1.44 mM and a Vmax of 6.96 +/- 0.89 nmol/min per mg of protein. Moreover, the quantitative trait locus (QTL) analysis performed in 739 Japanese individuals revealed that a dysfunctional variant of ABCG2 increased SUA as the number of minor alleles of the variant increased (p = 6.60 x 10(-5)). Because ABCG2 is expressed on the apical membrane in several tissues, including kidney, intestine, and liver, these findings indicate that ABCG2, a high-capacity urate exporter, has a physiological role of urate homeostasis in the human body through both renal and extrarenal urate excretion.

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34 With the site-directed mutagenesis technique, we constructed mutants of ABCG2 (V12M, Q126X, and Q141K), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment
47 We found the following six nonsynonymous mutations: V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4, and the first three mutations are SNPs. Login to comment
48 Maekawa et al.[7] reported that these SNPs are quite common in the Japanese population, and allele frequencies for them are 31.9% for Q141K, 19.2% for V12M, and 2.8% for Q126X, respectively. Login to comment
49 Using Hardy-Weinberg equilibrium and these data on a Japanese population reported by Maekawa et al.,[7] the frequencies of Japanese individuals with these minor alleles were estimated to be 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X, respectively. Login to comment

[hide] Hyperuricemia cosegregating with osteogenesis impe... Hum Genet. 2011 Nov;130(5):671-83. Epub 2011 May 19. Kaneko H, Kitoh H, Matsuura T, Masuda A, Ito M, Mottes M, Rauch F, Ishiguro N, Ohno K
Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8.
Hum Genet. 2011 Nov;130(5):671-83. Epub 2011 May 19., [PMID:21594610]

Abstract [show]
Autosomal dominant osteogenesis imperfecta (OI) is caused by mutations in COL1A1 or COL1A2. We identified a dominant missense mutation, c.3235G>A in COL1A1 exon 45 predicting p.G1079S, in a Japanese family with mild OI. As mutations in exon 45 exhibit mild to lethal phenotypes, we tested if disruption of an exonic splicing cis-element determines the clinical phenotype, but detected no such mutations. In the Japanese family, juvenile-onset hyperuricemia cosegregated with OI, but not in the previously reported Italian and Canadian families with c.3235G>A. After confirming lack of a founder haplotype in three families, we analyzed PRPSAP1 and PRPSAP2 as candidate genes for hyperuricemia on chr 17 where COL1A1 is located, but found no mutation. We next resequenced the whole exomes of two siblings in the Japanese family and identified variable numbers of previously reported hyperuricemia-associated SNPs in ABCG2 and SLC22A12. The same SNPs, however, were also detected in normouricemic individuals in three families. We then identified two missense SNVs in ZPBP2 and GPATCH8 on chromosome 17 that cosegregated with hyperuricemia in the Japanese family. ZPBP2 p.T69I was at the non-conserved region and was predicted to be benign by in silico analysis, whereas GPATCH8 p.A979P was at a highly conserved region and was predicted to be deleterious, which made p.A979P a conceivable candidate for juvenile-onset hyperuricemia. GPATCH8 is only 5.8 Mbp distant from COL1A1 and encodes a protein harboring an RNA-processing domain and a zinc finger domain, but the molecular functions have not been elucidated to date.

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182 Amino acid AF dbSNP II-2 II-3 VIII-2 1 AGL 100,336,361 C [ T Syn. 0.7 rs2230306 T/T -/T -/T 4 ABCG2b 89,034,551 G [ A Syn. 0.02 rs35622453 -/- -/- -/A 89,052,323 C [ A Q141K 0.31 rs2231142 -/A A/A -/- 89,061,114 G [ A V12M 0.19 rs2231137 -/A -/- -/A 4 SLC2A9b 9,909,923 C [ T P350L 0.33 rs2280205 -/T -/T -/- 9,922,130 G [ A R294H 0.72 rs3733591 -/A -/- -/A 9,998,440 G [ A Syn. 0.54 rs10939650 -/A A/A -/A 10,022,981 G [ A G25R 0.43 rs2276961 -/A -/A -/- 10,027,542 G [ A A17T 0.06 rs6820230 -/- -/A -/A 11 SLC22A12b 64,359,286 C [ T Syn. 0.21 rs3825016 -/T T/T -/T 64,360,274 C [ T Syn. 0.81 rs11231825 -/T -/- -/T 12 PFKM n.d. 16 UMODb n.d. 17 G6PC n.d. X HPRT1a n.d. X PRPS1a n.d. X MAOA 43,591,036 G [ T Syn. 0.3 rs6323 -/- T/T T/T a The gene is associated with purine metabolism b The gene is associated with renal excretion of urate - symbol represents in the patients` genotypes mean being identical to the reference nucleotides Syn synonymous nucleotide change, AF allelic frequency of the changed nucleotide, n.d. no SNPs are detected Discussion Phenotypic variabilities of OI mutations We identified a heteroallelic c.3235G[A mutation in COL1A1 exon 45 in a Japanese family with mild OI type I. Login to comment

[hide] Prognostic value of the multidrug resistance trans... Eur J Cancer. 2011 Sep;47(13):1990-9. Epub 2011 Apr 29. Wang F, Liang YJ, Wu XP, Chen LM, To KK, Dai CL, Yan YY, Wang YS, Tong XZ, Fu LW
Prognostic value of the multidrug resistance transporter ABCG2 gene polymorphisms in Chinese patients with de novo acute leukaemia.
Eur J Cancer. 2011 Sep;47(13):1990-9. Epub 2011 Apr 29., [PMID:21531129]

Abstract [show]
BACKGROUND: Functional polymorphisms of the ABCG2 gene may contribute to individual variability in drug response and the prognosis of patients. METHODS: In the present study, the genetic polymorphisms and expression of ABCG2 were analysed in blasts cells obtained from 184 Chinese patients with de novo acute leukaemia to investigate their possible association with clinical outcomes. RESULTS: A novel synonymous ABCG2-single nucleotide polymorphism (SNP) at exon 16 (13561218 C/T) and five known SNPs at exon 2 (13608835 G/A), exon 5 (13600044 C/A), intron 10 (13576005 C/T), intron 13 (13564503 C/T) and intron 14 (13563578 A/G) were identified with occurrence rates of 1.1%, 64.1%, 30.4%, 21.2%, 39.7% and 28.8%, respectively. We found that patients with the ABCG2 34GG genotype displayed longer disease free survival (DFS) (P<0.001) and overall survival (OS) (P<0.001) than those with the 34GA/AA genotypes. Furthermore, the DFS and OS were significantly diminished in bone marrow transplantation (BMT) patients with the 34GA/AA genotypes relative to those with the 34GG genotype. CONCLUSIONS: These results suggest that these highly prevalent ABCG2 34GA/AA genotypes are associated with poor prognosis of Chinese patients with acute leukaemia and BMT patients.

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17 In particular, two SNPs of ABCG2, G34A (V12M) in exon 2 and C421A (Q141K) in exon 5, were found to be the most prevalent in Asian population. Login to comment
80 Of the six polymorphisms, the allele frequencies of two published non-synonymous SNPs, G34A (Val12Met; exon 2) and C421A (Gln141Lys; exon 5), were 0.505 and 0.152 in our study. Login to comment
104 Position Location Change % Genotype frequency(n) Allele % Allele frequency NT-016354.18 dbSNP (NCBI) Nucleotide Amino acid Wildtype Heterozygote Homozygote 13608835 rs2231137 Exon 2 TCCCAG/ATGTCA Val12Met 35.9 (66) 27.2 (50) 36.9 (68) A 50.5 13600044 rs2231142 Exon 5 ACTTAC/AAGTTC Gln 141Lys 69.6 (128) 30.4 (56) 0 A 15.2 13561218a N.D. Exon 16 GGCATC/TGATCT Ile619Ile 98.9 (182) 1.1 (2) 0 T 0.5 13576005 rs2231149 Intron10 TCAAGC/TTTATT N/A 78.8 (145) 21.2 (39) 0 T 10.6 13564503 rs2231162 Intron13 TGACTC/TTTAGT N/A 60.3 (111) 39.7 (73) 0 T 19.8 13563578 rs2231164 Intron14 TTCTTA/GAAATT N/A 71.2 (131) 28.8 (53) 0 G 14.4 NCBI, National Cancer Center for Biotechnology Information; N.D., not determined; N/A, not applicable. Login to comment

[hide] ABCG transporters and disease. FEBS J. 2011 Sep;278(18):3215-25. doi: 10.1111/j.1742-4658.2011.08171.x. Epub 2011 Jun 13. Woodward OM, Kottgen A, Kottgen M
ABCG transporters and disease.
FEBS J. 2011 Sep;278(18):3215-25. doi: 10.1111/j.1742-4658.2011.08171.x. Epub 2011 Jun 13., [PMID:21554546]

Abstract [show]
ATP-binding cassette (ABC) transporters form a large family of transmembrane proteins that facilitate the transport of specific substrates across membranes in an ATP-dependent manner. Transported substrates include lipids, lipopolysaccharides, amino acids, peptides, proteins, inorganic ions, sugars and xenobiotics. Despite this broad array of substrates, the physiological substrate of many ABC transporters has remained elusive. ABC transporters are divided into seven subfamilies, A-G, based on sequence similarity and domain organization. Here we review the role of members of the ABCG subfamily in human disease and how the identification of disease genes helped to determine physiological substrates for specific ABC transporters. We focus on the recent discovery of mutations in ABCG2 causing hyperuricemia and gout, which has led to the identification of urate as a physiological substrate for ABCG2.

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59 R L L A A M AT T T R V S G G G F I T Q R R V K K S G E A D RR V V K K L L G E E E I IN NN D H Q Q R V V V V V L L S G F E N M TT QD D S K R V K L L G F P C Y R K S G F P P C N N A V L L S G G G I N A D R K P P S GG G R V VK K KK L L L LL L S S S GG G PPE E IIII N NN M A A A T D D Y N E A I P E S I D L L F T LS G EI MT D I I P FC L R IH A N T T T T T G L D S S K K K L L L S G G G F F F F Q P P I M M A A A A D H G G LS S S V L L L L L R R RQ Q I I Y Y YS S HE E A T V V V V L Q I S F I I II A A L G G Y K F R S S E E I I L G Y YY Y V V K H S P C M M D R T I II L L L F F YV S S P F N T I A Q Q L L L G F Y Y H S S PR W C N M I I A A A L L G F V V K H W T L I F F C C C D D D A A A QQ Q Q Q G G G G G G G G G G FF FF F F FF Y Y Y Y Y V V V V V VVV K KKK KK K K E E E E P P P P R W W TT TT T TT T T NNNN N N N N N M MM M L L L L L L L L LL LL I I I I I I AA A A A A A S S S S S S S S SS L L L L LL L L LL V V F G GCC T Q Q Q Q Y Y Y KK K K K H H EE E E E E EEE E P P P P R R RW N N N II I I I I I I A AAA A A A S SS S S S S L L LL L L L V V V V F F F F F F F G GG G C TT T T T T K K K K KKKK N NN LL D DDD DS S 395 469 565 644 414 450 495 505 584 625 Signature Walker A WalkerBQ EP MI A V V VF FG GTN N NS S S S P F HE V FG CTT K NN LLD SS AAA I V12M N-terminus C-terminus M MM MM T A A A A L F F Y V V S S S F 524476 Y Q126X G268R S441N F506fs Q141K 44 288 PP AA DD Fig. 2. Login to comment

[hide] Drug transport by breast cancer resistance protein... Expert Opin Drug Metab Toxicol. 2010 Nov;6(11):1363-84. Epub 2010 Sep 27. Poguntke M, Hazai E, Fromm MF, Zolk O
Drug transport by breast cancer resistance protein.
Expert Opin Drug Metab Toxicol. 2010 Nov;6(11):1363-84. Epub 2010 Sep 27., [PMID:20873966]

Abstract [show]
IMPORTANCE OF THE FIELD: The ATP-binding cassette transporter ABCG2 is a well-known major mediator of multi-drug resistance in cancers. Beyond multi-drug resistance, experimental and recent clinical studies demonstrate a role for ABCG2 as a determinant of drug pharmacokinetic, safety and efficacy profiles. AREAS COVERED IN THIS REVIEW: The clinical evidence of the role of ABCG2 in pharmacokinetics and pharmacodynamics is reviewed. Key questions that arise from the perspective of preclinical drug evaluation are addressed, including the structure of ABCG2 and mechanisms of drug-transporter interactions, mechanisms responsible for the polyspecificity of ABCG2, methods suitable for studying drug-ABCG2 interactions in vitro and in silico prediction of ABCG2 substrates and inhibitors. WHAT THE READER WILL GAIN: An update on current knowledge of the importance of ABCG2 in drug disposition with special emphasis on drug development. TAKE HOME MESSAGE: The field of drug-ABCG2 interaction is rapidly advancing and beginning to expand into clinical practice. However, the structural understanding of drug binding and transport by ABCG2 is still incomplete. Incorporation of novel concepts of drug-transporter interactions such as electrostatic funneling might help explain the multispecificity of ABCG2 and enable in silico predictions.

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529 The effect of ABCG2 V12M, Q141K and Poguntke, Hazai, Fromm & Zolk Expert Opin. Drug Metab. Toxicol. Login to comment

[hide] Common defects of ABCG2, a high-capacity urate exp... Sci Transl Med. 2009 Nov 4;1(5):5ra11. Matsuo H, Takada T, Ichida K, Nakamura T, Nakayama A, Ikebuchi Y, Ito K, Kusanagi Y, Chiba T, Tadokoro S, Takada Y, Oikawa Y, Inoue H, Suzuki K, Okada R, Nishiyama J, Domoto H, Watanabe S, Fujita M, Morimoto Y, Naito M, Nishio K, Hishida A, Wakai K, Asai Y, Niwa K, Kamakura K, Nonoyama S, Sakurai Y, Hosoya T, Kanai Y, Suzuki H, Hamajima N, Shinomiya N
Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population.
Sci Transl Med. 2009 Nov 4;1(5):5ra11., [PMID:20368174]

Abstract [show]
Gout based on hyperuricemia is a common disease with a genetic predisposition, which causes acute arthritis. The ABCG2/BCRP gene, located in a gout-susceptibility locus on chromosome 4q, has been identified by recent genome-wide association studies of serum uric acid concentrations and gout. Urate transport assays demonstrated that ABCG2 is a high-capacity urate secretion transporter. Sequencing of the ABCG2 gene in 90 hyperuricemia patients revealed several nonfunctional ABCG2 mutations, including Q126X. Quantitative trait locus analysis of 739 individuals showed that a common dysfunctional variant of ABCG2, Q141K, increases serum uric acid. Q126X is assigned to the different disease haplotype from Q141K and increases gout risk, conferring an odds ratio of 5.97. Furthermore, 10% of gout patients (16 out of 159 cases) had genotype combinations resulting in more than 75% reduction of ABCG2 function (odds ratio, 25.8). Our findings indicate that nonfunctional variants of ABCG2 essentially block gut and renal urate excretion and cause gout.

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46 The following six nonsynonymous mutations were found: V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4 (Table 1). Login to comment
48 Maekawa et al. reported that allele frequencies for these SNPs, which are quite common in the Japanese population, were 31.9% for Q141K, 19.2% for V12M, and 2.8% for Q126X, respectively (Table 1) (34). Login to comment
49 Using Hardy-Weinberg equilibrium and these data of a Japanese population reported by Maekawa et al. (34), we calculated estimates of the frequencies of Japanese individuals with these minor alleles to be 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X. Login to comment
55 The V12M variant did not show any changes in urate transport or in protein amounts relative to wild-type ABCG2. Login to comment
77 The call rate, or the ability of the SNP to be reliably decoded, for V12M, Q126X, and LS N N SV FLC S P T AN FK G LM ETS S E V F I P Q G N T N G FV P A A AS LD V S N I C Y R V K K RKPVEKEILSNINGIKPGLNAILGPG GGKSSL LDVLA ARKDP S G T L S G D V L I G A P PR A N F K N S G Y Q D D V V M G T L T V R NE LV VC H Q F S A A A RL L T T TNEKNER HINRVIQELGLDKVADSKVGTQFIRGVG GERR KTSIGME L I T D P S I L F L D E P T T G L D S S T A N A V LL L L K R M S K Q G R I I F S T S I H Q P R Y M S I F K LFDSLTLLASGRLMFHGPAQEALGYFESAGYHCEAN YN T V A L N R E E D F K A T E II E P S K Q D K L I E L A EK I Y V N S S F Y K ETKAELHQLSGGEKKKKITVFKEISYTTSFCHQRWVK SRS AFFLDII N G D S A PD P L F K N LL G N P Q A S A I V G I I T L V A FI I Q V V L G Y AVEFLKNDST G I Q N R A G V L F F L T T Q C F S L V S S N G L S L M L I T P M S F I FV D L R P I C Y W L W Y I Y T Q S R F L NQ S L F P G A H E F Y S Y S E F R G Y I K V K S V Y I H L E V A S S V L M A A M F V A F M S Y M T M F K A T I M L H F I A V K G W I L V C A N L W V A T L M T C F VI F M M I F S G L L VNLTTIASAIAAGQS L S V V LKGL L F N Q L F P S L D Y G Q K V L C Y EEGTCTAYNCPNNGTAN G P G L K L L L K K SYF L Y D L G L M A P K Extracellular Intracellular 50 150 200 300 100 350 395 415 469 450 470 500 525 550 565 585 600 625 608 650 250 655 603 475 644 F506SfsX4 (F506fs) V12M Q126X Q141K S441N G268R V Q F S G Q # C signature Walker B motif Walker A motif C D E 4.0 4.5 5.0 5.5 6.0 C/C C/A A/A Male + female P= 2.02 x 10 -6 5.0 5.5 6.0 6.5 7.0 C/C C/A A/A Male P= 0.0144 Serumuric acid(mg/dl) 4.0 4.5 5.0 5.5 6.0 C/C C/A A/A Female P= 0.0137 (pmol/mgprotein) 0 20 40 60 80 100 120 140 160 180 200 + AMP + ATP B Serumuric acid(mg/dl) Serumuric acid(mg/dl) A [C]Uratetransport 14 G F M C-terminal N-terminal Fig. 2. Login to comment
89 Amino acid change SNP ID dbSNP (NCBI) Exon Type of mutation Number of hyperuricemia patients Allele frequency (%) (in hyperuricemia) Allele frequency* (%) (in Japanese population) Wild-type Heterozygote Homozygote Q141K rs2231142 5 Missense 29 47 14 41.67 31.9 V12M rs2231137 2 Missense 64 23 3 16.11 19.2 Q126X 4 Nonsense 80 10 0 5.56 2.8 G268R 7 Missense 89 1 0 0.56 N.D. S441N 11 Missense 89 1 0 0.56 0.3 F506SfsX4 13 Frameshift 89 1 0 0.56 0.3 * Data from Maekawa et al. (34). Login to comment
90 Q141K was 98.8%, 100%, and 99.2%, respectively. P values for Hardy-Weinberg equilibrium of V12M, Q126X, and Q141K were 0.08, 0.72, and 0.01, respectively. P values that suggested mistyping were not obtained. Login to comment
97 Our findings showed that V12M is exclusively assigned to a nonrisk haplotype (Table 3) and that the V12M variant does not exhibit altered urate transport activity (Fig. 2B). Login to comment
98 These findings may help explain why V12M decreases gout risk (OR, 0.68; 95% CI, 0.49-0.94; P = 0.02) (Table 2). Login to comment
115 Phenotype SNP Genotype* Allele frequency mode Case Control P value P value OR 95% CI 1/1 1/2 2/2 MAF 1/1 1/2 2/2 MAF Q126X 1 21 139 0.071 0 31 840 0.018 1.74 × 10-7 3.04 × 10-8 4.25 2.44-7.38 Gout Q141K 31 87 41 0.469 87 316 462 0.281 5.80 × 10-10 5.54 × 10-11 2.23 1.75-2.87 V12M 3 43 112 0.155 30 306 526 0.212 0.055 0.020 0.68 0.49-0.94 Q126X 2 24 202 0.061 0 31 840 0.018 1.91 × 10-6 2.91 × 10-7 3.61 2.14-6.08 Hyperuricemia Q141K 45 113 68 0.449 87 316 462 0.281 5.32 × 10-10 1.53 × 10-11 2.06 1.67-2.55 V12M 7 55 163 0.153 30 306 526 0.212 0.006 0.005 0.67 0.51-0.89 * Minor allele was referred to as allele 1 and major allele as 2. Login to comment
118 Allele 1 is A and allele 2 is G in V12M. Login to comment
120 Haplotype frequency analysis of V12M, Q126X, and Q141K. Login to comment
123 Allele Frequency P value OR 95% CI V12M Q126X Q141K Gout Control G C A 0.465 0.284 2.26 × 10-13 2.50 1.94-3.20 G T C 0.071 0.018 4.10 × 10-12 5.97 3.39-10.51 G C C 0.306 0.486 - - - A C C 0.155 0.212 - - - of ABCG2, such as rosuvastatin (42) and gefitinib (43), have been reported. Login to comment
181 Using the site-directed mutagenesis technique, we constructed mutants of ABCG2 (V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment

[hide] Structure, function, expression, genomic organizat... Int J Toxicol. 2006 Jul-Aug;25(4):231-59. Choudhuri S, Klaassen CD
Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters.
Int J Toxicol. 2006 Jul-Aug;25(4):231-59., [PMID:16815813]

Abstract [show]
The ATP-binding cassette (ABC) transporters constitute a large family of membrane proteins, which transport a variety of compounds through the membrane against a concentration gradient at the cost of ATP hydrolysis. Substrates of the ABC transporters include lipids, bile acids, xenobiotics, and peptides for antigen presentation. As they transport exogenous and endogenous compounds, they reduce the body load of potentially harmful substances. One by-product of such protective function is that they also eliminate various useful drugs from the body, causing drug resistance. This review is a brief summary of the structure, function, and expression of the important drug resistance-conferring members belonging to three subfamilies of the human ABC family; these are ABCB1 (MDR1/P-glycoprotein of subfamily ABCB), subfamily ABCC (MRPs), and ABCG2 (BCRP of subfamily ABCG), which are expressed in various organs. In the text, the transporter symbol that carries the subfamily name (such as ABCB1, ABCC1, etc.) is used interchangeably with the corresponding original names, such as MDR1P-glycoprotein, MRP1, etc., respectively. Both nomenclatures are maintained in the text because both are still used in the transporter literature. This helps readers relate various names that they encounter in the literature. It now appears that P-glycoprotein, MRP1, MRP2, and BCRP can explain the phenomenon of multidrug resistance in all cell lines analyzed thus far. Also discussed are the gene structure, regulation of expression, and various polymorphisms in these genes. Because genetic polymorphism is thought to underlie interindividual differences, including their response to drugs and other xenobiotics, the importance of polymorphism in these genes is also discussed.

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573 Recently, Kondo et al. (2004) reported the effect of single nucleotide polymorphisms (SNPs) in ABCG2 gene on its localization, expression level, and transport activity of the BCRP protein. The cellular localization was identified using the wild-type and seven different SNP variants of BCRP protein (Val12Met, Gln141Lys, Ala149Pro, Arg163Lys, Gln166Glu, Pro269Ser, and Ser441Asn), following their expression in LLC-PK1 cells. Login to comment
583 SNP analyses of the ABCG2 gene by Morisaki et al. (2005) revealed three nonsynonymous SNPs that resulted in amino acid substitution of the BCRP protein; these were Val12Met, Gln141Lys, and Asp620Asn. Login to comment

[hide] Outcome, clinical prognostic factors and genetic p... Int J Clin Oncol. 2012 Jun;17(3):204-11. Epub 2011 Jun 25. Narita S, Tsuchiya N, Yuasa T, Maita S, Obara T, Numakura K, Tsuruta H, Saito M, Inoue T, Horikawa Y, Satoh S, Habuchi T
Outcome, clinical prognostic factors and genetic predictors of adverse reactions of intermittent combination chemotherapy with docetaxel, estramustine phosphate and carboplatin for castration-resistant prostate cancer.
Int J Clin Oncol. 2012 Jun;17(3):204-11. Epub 2011 Jun 25., [PMID:21706123]

Abstract [show]
OBJECTIVES: Docetaxel-based chemotherapy is effective in patients with castration-resistant prostate cancer (CRPC). This phase II study assessed the outcome and predictive factors for prognosis and toxicity following intermittent chemotherapy with docetaxel, estramustine phosphate, and carboplatin (DEC) in patients with CRPC. METHODS: Thirty-five patients were treated with a DEC regimen that consisted of a 28-day cycle of drugs as follows: docetaxel (60 mg/m(2) on day 1), carboplatin (AUC 5 on day 1) and estramustine phosphate (560 mg daily). Treatment was continued intermittently. The end point was to test the effect of DEC on the response rate and overall survival (OS). Statistical correlations between the outcomes and predictive factors, including clinical parameters and 8 single-nucleotide polymorphisms (SNPs) related to drug metabolism, were assessed. RESULTS: Prostate-specific antigen levels decreased by more than 30% in 65.7% of the patients. The median OS following DEC was 17.8 months, and the median total time of chemotherapy holiday was 7.7 months (range 1.7-35.8). On multivariate analysis, serum lactate dehydrogenase (LDH) was an independent prognostic factor for OS (p = 0.007). On SNP analysis, patients carrying the TT genotype of the ABCB1 C3435T polymorphism showed a significantly more severe leukocytopenia during the first cycle of DEC therapy compared to patients with the CC + CT genotype (p = 0.036). CONCLUSION: Combination chemotherapy with DEC has a potential effect on CRPC with acceptable toxicity. Serum LDH may be a promising predictor of prognosis, and the ABCB1 C3435T polymorphism may be a genetic predictor of the severity of leukocytopenia in patients with CRPC treated with DEC.

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90 Primers Restriction enzyme Forward Reverse MAP4 Intron rs56313601 TGCATGGTTTCCTTTCCCCTA TCTCTGAAACGTGTGTGGCTT BccI MAPT Intron rs3744460 AAAGTGGAGGCGTCCTTGCGA CAGCTTCTTATTAATTATCTGC MnlI ABCG2 V12M rs2231137 GCTTTTCTGTCTGCAGAAAGAT GAAGCTGTCGCGGGGAAGCC TspRI CYP3A5 A6986G rs776746 ATGGAGAGTGGCATAGGAGATA TGTGGTCCAAACAGGGAAGAAATA SspI XRCC1 C194T rs1799782 ATGCTTGGCCAGTTCCGTGTGAAG CACCTGGGGATGTCTTGTTGATCC AluI XRCC1 A399G rs25487 TCCTCCACCTTGTGCTTTCT AGTAGTCTGCTGGCTCTGGG NciI ABCB1 C3435T rs1045642 TTGATGGCAAAGAAATAAAGC CTTACATTAGGCAGTGACTCG MboI ABCB1 Intron rs7779562 TGTTCTGCAATGAGAAGAATAA ATTGTAACACAAATTAATTATC TaqI Genetic variation affecting adverse reaction Next, we explored the association between each genotype and severe leukocytopenia. Login to comment

[hide] Unveiling the role of multidrug resistance protein... Hypertension. 2009 Aug;54(2):210-6. Epub 2009 Jun 15. Delou JM, Lopes AG, Capella MA
Unveiling the role of multidrug resistance proteins in hypertension.
Hypertension. 2009 Aug;54(2):210-6. Epub 2009 Jun 15., [PMID:19528366]

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54 It is well established that age and hypertension are the most powerful risk factors for stroke.66,67 In a very recent cardiovascular health study, in which 74 genetic variants were tested, it was found that a single nucleotide polymorphism of ABCG2 (Val12Met) was associated with increased risk of ischemic stroke in both white and black participants.68 The authors showed that homozygotes of the Val allele of ABCG2 were at higher risk of stroke than carriers of the Met allele. Login to comment

[hide] Association of some rare haplotypes and genotype c... Leuk Res. 2008 Aug;32(8):1214-20. Epub 2008 Feb 19. Semsei AF, Erdelyi DJ, Ungvari I, Kamory E, Csokay B, Andrikovics H, Tordai A, Csagoly E, Falus A, Kovacs GT, Szalai C
Association of some rare haplotypes and genotype combinations in the MDR1 gene with childhood acute lymphoblastic leukaemia.
Leuk Res. 2008 Aug;32(8):1214-20. Epub 2008 Feb 19., [PMID:18243305]

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To investigate their possible roles in disease susceptibility and some disease characteristics we genotyped C3435T and G2677T/A polymorphisms in multidrug resistance-1 (MDR1) gene with a single base extension method and the G34A and C421A polymorphisms of the breast cancer resistance protein gene with an allelic discrimination system in 396 children with acute lymphoblastic leukaemia (ALL) and 192 control patients. While the distribution of individual alleles and genotypes did not differ between patients and controls, there were significant differences in the frequencies of some rare haplotypes and genotype combinations in the MDR1 gene between the two groups.

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29 The two most frequently identified SNPs in the BCRP gene are in exon 2 (G34A, resulting in a V12M change) and exon 5 (C421A, resulting in a Q141K substitution). Login to comment

[hide] Development of lung cancer before the age of 50: t... Carcinogenesis. 2007 Jun;28(6):1287-93. Epub 2007 Jan 27. Gemignani F, Landi S, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Gaborieau V, Gioia-Patricola L, Bellini I, Barale R, Canzian F, Hall J, Boffetta P, Hung RJ, Brennan P
Development of lung cancer before the age of 50: the role of xenobiotic metabolizing genes.
Carcinogenesis. 2007 Jun;28(6):1287-93. Epub 2007 Jan 27., [PMID:17259654]

Abstract [show]
The role of genes coding for xenobiotic metabolizing enzymes (XMEs) and the risk of lung cancer is unclear. Under the assumption that these genes may be more important among people having a diagnosis of lung cancer at younger ages, we have investigated the role of single-nucleotide polymorphisms (SNPs) within phase I and phase II XME genes, and also genes involved in the metabolism of nucleic acids in a series of young onset patients and matched controls. We genotyped 299 lung cancer cases diagnosed before the age of 50 and 317 controls, from six countries of Central and Eastern Europe, by use of an oligonucleotide microarray and arrayed primer extension technique for 45 SNPs in 15 phase I XME genes, 46 SNPs in 17 phase II genes and 9 SNPs in 4 genes related to metabolism of nucleic acids. Heterozygote carriers of SNPs in CYP1A2 1545T>C, -164C>A and -740T>G; CYP2A6 -47A>C; MDR1 3435T>C; NAT1 1088T>A and 1095A>C; GSTA2 S112T; GSTM3 V224I and MTHFR A222V had altered risk of developing lung cancer. Phenotypes reconstructed after haplotype analyses showed that the carriers of the combined NAT1 fast+ NAT2 fast phenotypes were at lower risk when compared with those with the combined NAT1 slow + NAT2 slow acetylator phenotypes. Finally, extensive EPHX1 metabolizers showed an increased risk as compared with the poor metabolizers.

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154 Associations between lung cancer risk and SNPs belonging to genes involved in the phase II of xenobiotic metabolism SNP name rs no. Homozygotes common allele Heterozygotes Homozygotes rarer allele Ptrend Ca Co Ca Co ORa 95% CI Ca Co ORa 95% CI ABCG2: Q141K rs2231142 225 242 44 47 0.99 (0.61-1.63) 1 1 2.77 (0.15-52.00) 0.87 ABCG2: V12M rs2231137 171 190 15 10 1.91 (0.77-4.75) 0 1 - - 0.45 ALDH2: 348T.C-MspI rs440 187 202 94 96 0.94 (0.64-1.37) 9 7 1.18 (0.41-3.42) 0.91 ALDH2: 355G.A rs886205 184 204 99 93 1.04 (0.71-1.52) 10 9 0.99 (0.37-2.68) 0.88 ALDH2: 483T.C-HaeIII rs441 187 209 89 94 0.91 (0.62-1.34) 9 7 1.20 (0.41-3.46) 0.85 ALDH2: 69G.A rs4646777 191 213 89 89 0.98 (0.67-1.44) 10 8 1.07 (0.39-2.95) 0.99 COMT: IVS2-98A.G rs6269 123 125 136 134 1.17 (0.80-1.70) 36 57 0.74 (0.43-1.25) 0.52 COMT: 186C.G-L136L rs4818 123 124 138 135 1.17 (0.80-1.70) 34 50 0.76 (0.44-1.31) 0.64 COMT: H62H rs4633 60 77 151 149 1.14 (0.73-1.77) 80 78 1.04 (0.63-1.71) 0.92 COMT: V158M-472G.A rs4680 83 81 144 146 1.07 (0.70-1.62) 59 75 0.98 (0.60-1.62) 0.97 GSTA2: S112T rs1051739 70 90 74 84 1.19 (0.74-1.92) 63 49 1.88 (1.11-3.17) 0.02 GSTA4: 668C.T rs405729 86 87 129 148 1.04 (0.69-1.57) 74 72 1.12 (0.70-1.81) 0.64 GSTA4: Q117Q rs1802061 251 227 24 40 0.56 (0.31-1.01) 5 1 3.94 (0.43-36.38) 0.36 GSTM1: A/B and null rs1065411 82 97 18 15 1.63 (0.73-3.67) 50 42 1.39 (0.80-2.42) 0.24 GSTM3: 3 bp del-Mnl I rs1799735 113 132 41 39 1.29 (0.74-2.26) 2 5 0.30 (0.04-2.13) 0.88 GSTM3: IVS8À30 rs1537234 76 83 120 112 1.19 (0.76-1.85) 48 63 0.88 (0.52-1.50) 0.74 GSTM3: V224I rs7483 149 132 120 142 0.75 (0.52-1.09) 26 40 0.57 (0.32-1.04) 0.04 GSTP1: 313A.G-I105V rs947894 127 133 118 130 0.98 (0.67-1.43) 27 22 1.29 (0.67-2.49) 0.63 GSTP1: 341C.T-A114V rs1799811 244 265 47 47 1.08 (0.67-1.76) 6 1 8.47 (0.87-82.09) 0.20 GSTT2: 153 bp 3# of STP rs2719 60 72 107 132 1.14 (0.71-1.82) 57 54 1.55 (0.89-2.68) 0.13 GSTT2: M139I rs1622002 275 296 19 16 1.05 (0.50-2.21) 0 0 - - 0.89 MDR1: 2677G.T-S892A rs2032582 97 112 134 117 1.16 (0.78-1.73) 53 67 0.97 (0.60-1.58) 0.97 MDR1: 3435T.C rs1045642 62 86 164 141 1.56 (1.02-2.40) 65 81 1.18 (0.72-1.94) 0.50 MDR1: G411G rs1128503 96 106 134 125 1.03 (0.69-1.54) 46 64 0.82 (0.49-1.35) 0.50 MnSOD2: 1183C.T-V16A rs1799725 80 84 118 117 1.15 (0.75-1.77) 57 63 1.00 (0.60-1.66) 0.94 NAT1: 1088T.A rs1057126 190 180 77 101 0.67 (0.45-0.99) 7 12 0.87 (0.31-2.45) 0.08 NAT1: 1095A.C rs15561 155 140 74 104 0.63 (0.42-0.95) 18 22 0.83 (0.40-1.70) 0.10 NAT1: À344C.T rs4986988 219 219 14 17 0.85 (0.38-1.90) 2 1 1.23 (0.09-16.00) 0.80 NAT1: À40A.T rs4986989 248 256 17 23 0.81 (0.40-1.65) 2 1 1.64 (0.13-21.32) 0.75 NAT1: 445G.A-V149I rs4987076 243 259 18 26 0.75 (0.37-1.49) 3 1 1.85 (0.16-22.03) 0.64 NAT1: 459G.A-T153T rs4986990 245 264 17 25 0.78 (0.39-1.56) 2 1 1.62 (0.12-21.42) 0.65 NAT1: 559C.T-R187Stop rs5030839 227 238 1 2 0.90 (0.08-10.51) 0 0 - - 0.93 NAT1: 560G.A-R187Q rs4986782 270 300 5 3 2.17 (0.46-10.26) 0 0 - - 0.33 NAT2: 282C.T-Y94 rs1041983 135 144 114 120 1.13 (0.77-1.65) 34 33 1.28 (0.72-2.26) 0.36 NAT2: 341T.C-I114T rs1801280 69 73 101 96 1.16 (0.72-1.86) 51 47 1.02 (0.58-1.81) 0.86 NAT2: 481C.T-L161L rs1799929 113 105 127 161 0.73 (0.49-1.06) 43 36 1.07 (0.61-1.89) 0.65 NAT2: 590G.A-R197Q rs1799930 141 156 106 106 1.30 (0.88-1.91) 18 24 0.91 (0.46-1.83) 0.56 NAT2: 803A.G-L268R rs1208 96 88 117 139 0.73 (0.48-1.11) 52 64 0.69 (0.42-1.16) 0.13 NAT2: 857G.A-G286E rs1799931 244 258 15 12 1.34 (0.58-3.13) 0 0 - - 0.49 NQO1-DIA4: P187S rs1800566 202 207 75 97 0.74 (0.50-1.10) 17 11 1.89 (0.81-4.38) 0.96 NQO1-DIA4: R139W rs4986998 274 295 23 21 1.16 (0.59-2.27) 0 0 - - 0.67 SULT1A1: M223V rs1801030 282 302 0 1 - - 0 0 - - - SULT1A1: R213H-HaeII rs4149396 91 95 100 96 0.95 (0.61-1.47) 2 11 0.23 (0.05-1.18) 0.30 SULT1A2: 357 bp 3# of STP C.T rs11401 210 212 64 67 1.11 (0.72-1.71) 11 12 1.20 (0.48-2.98) 0.56 UGT1A7: N129K-R131K N/A 113 117 125 139 0.97 (0.65-1.43) 38 42 1.05 (0.61-1.81) 0.94 UGT1A7: W208R rs1126802 118 111 130 143 0.77 (0.52-1.12) 45 59 0.66 (0.39-1.10) 0.08 Ca, cases; Co, controls. ORa odd-ratio adjusted for age, sex, country and tobacco smoking. In bold, statistically significant results (P , 0.05). Login to comment

[hide] Genetic polymorphisms of drug-metabolising enzymes... Clin Pharmacokinet. 2006;45(3):253-85. Bosch TM, Meijerman I, Beijnen JH, Schellens JH
Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer.
Clin Pharmacokinet. 2006;45(3):253-85., [PMID:16509759]

Abstract [show]
There is wide variability in the response of individuals to standard doses of drug therapy. This is an important problem in clinical practice, where it can lead to therapeutic failures or adverse drug reactions. Polymorphisms in genes coding for metabolising enzymes and drug transporters can affect drug efficacy and toxicity. Pharmacogenetics aims to identify individuals predisposed to a high risk of toxicity and low response from standard doses of anti-cancer drugs. This review focuses on the clinical significance of polymorphisms in drug-metabolising enzymes (cytochrome P450 [CYP] 2C8, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, dihydropyrimidine dehydrogenase, uridine diphosphate glucuronosyltransferase [UGT] 1A1, glutathione S-transferase, sulfotransferase [SULT] 1A1, N-acetyltransferase [NAT], thiopurine methyltransferase [TPMT]) and drug transporters (P-glycoprotein [multidrug resistance 1], multidrug resistance protein 2 [MRP2], breast cancer resistance protein [BCRP]) in influencing efficacy and toxicity of chemotherapy. The most important example to demonstrate the influence of pharmacogenetics on anti-cancer therapy is TPMT. A decreased activity of TPMT, caused by genetic polymorphisms in the TPMT gene, causes severe toxicity with mercaptopurine. Dosage reduction is necessary for patients with heterozygous or homozygous mutation in this gene. Other polymorphisms showing the influence of pharmacogenetics in the chemotherapeutic treatment of cancer are discussed, such as UGT1A1*28. This polymorphism is associated with an increase in toxicity with irinotecan. Also, polymorphisms in the DPYD gene show a relation with fluorouracil-related toxicity; however, in most cases no clear association has been found for polymorphisms in drug-metabolising enzymes and drug transporters, and pharmacokinetics or pharmacodynamics of anti-cancer drugs. The studies discussed evaluate different regimens and tumour types and show that polymorphisms can have different, sometimes even contradictory, pharmacokinetic and pharmacodynamic effects in different tumours in response to different drugs. The clinical application of pharmacogenetics in cancer treatment will therefore require more detailed information of the different polymorphisms in drug-metabolising enzymes and drug transporters. Larger studies, in different ethnic populations, and extended with haplotype and linkage disequilibrium analysis, will be necessary for each anti-cancer drug separately.

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2327 Characteristics of drug transporter genes (with the most important polymorphisms)[167-169] Gene Location Protein Exons Amino Polymorphisms Location Effect (chromosome) acids (exon) ABCB1 7q21 P-gp/MDR1 29 1280 *6 (C3435T) 26 Silent *7 (G2677T/A) 21 A893S *8 (C1236T) 12 Silent G1199A 11 S400N ABCC2 10q24 MRP2 32 1545 C-24T 5'-UTR Unknown C1249A 10 V417I C2302T 18 R768W C2366T 18 S789F T2439+2C 18 Splice site ND 26 W1254Y,A,C,F C3972T 28 Silent A4145G 29 Q1382R G4348A 31 G1440S ABCG2 4q22 BCRP 16 655 G34A 2 V12M C8825A 5 Q141K BCRP = breast cancer resistance protein; MDR1 = multidrug resistance 1; MRP2 = multidrug resistance protein 2; ND = no data; P-gp = P-glycoprotein. Login to comment
2381 [168] Overall, no clinical effects have been observed topoisomerase I inhibitor, of cells expressing V12M for the different MRP2 genotypes and pharmacoki- or Q141K was less than one-tenth compared with netics and pharmacodynamics of anti-cancer drugs. Login to comment
2384 membrane in the V12M clone; however, it is not known if the altered transport function of ABCG2 5.3 Breast Cancer Resistance Protein influences drug transport in vivo. Login to comment
2400 polymorphisms G34A and C8825A, leading to an amino acid change of V12M and Q141K, respec- The levels of ABCG2 mRNA expression in cell tively (see table VII), on the transporter function of lines were found to be significantly correlated with the protein. Login to comment

[hide] Association of genotypes and haplotypes of multi-d... Biomed Pharmacother. 2014 Apr;68(3):343-9. doi: 10.1016/j.biopha.2014.01.009. Epub 2014 Feb 7. Au A, Aziz Baba A, Goh AS, Wahid Fadilah SA, Teh A, Rosline H, Ankathil R
Association of genotypes and haplotypes of multi-drug transporter genes ABCB1 and ABCG2 with clinical response to imatinib mesylate in chronic myeloid leukemia patients.
Biomed Pharmacother. 2014 Apr;68(3):343-9. doi: 10.1016/j.biopha.2014.01.009. Epub 2014 Feb 7., [PMID:24581936]

Abstract [show]
The introduction and success of imatinib mesylate (IM) has become a paradigm shift in chronic myeloid leukemia (CML) treatment. However, the high efficacy of IM has been hampered by the issue of clinical resistance that might due to pharmacogenetic variability. In the current study, the contribution of three common single nucleotide polymorphisms (SNPs) of ABCB1 (T1236C, G2677T/A and C3435T) and two SNPs of ABCG2 (G34A and C421A) genes in mediating resistance and/or good response among 215 CML patients on IM therapy were investigated. Among these patients, the frequency distribution of ABCG2 421 CC, CA and AA genotypes were significantly different between IM good response and resistant groups (P=0.01). Resistance was significantly associated with patients who had homozygous ABCB1 1236 CC genotype with OR 2.79 (95%CI: 1.217-6.374, P=0.01). For ABCB1 G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with variant TT/AT/AA genotype, compared to other genotype groups (OR=0.48, 95%CI: 0.239-0.957, P=0.03). Haplotype analysis revealed that ABCB1 haplotypes (C1236G2677C3435) was statistically linked to higher risk to IM resistance (25.8% vs. 17.4%, P=0.04), while ABCG2 diplotype A34A421 was significantly correlated with IM good response (9.1% vs. 3.9%, P=0.03). In addition, genotypic variant in ABCG2 421C>A was associated with a major molecular response (MMR) (OR=2.20, 95%CI: 1.273-3.811, P=0.004), whereas ABCB1 2677G>T/A variant was associated with a significantly lower molecular response (OR=0.49, 95%CI: 0.248-0.974, P=0.04). However, there was no significant correlation of these SNPs with IM intolerance and IM induced hepatotoxicity. Our results suggest the usefulness of genotyping of these single nucleotide polymorphisms in predicting IM response among CML patients.

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36 Two most common ABCG2 polymorphisms are 34 G>A, which codes for Val12Met and 421 C>A which codes for Glu141Lys (Zamber et al., 2003). Login to comment

[hide] Expression levels of the ABCG2 multidrug transport... PLoS One. 2012;7(11):e48423. doi: 10.1371/journal.pone.0048423. Epub 2012 Nov 15. Kasza I, Varady G, Andrikovics H, Koszarska M, Tordai A, Scheffer GL, Nemeth A, Szakacs G, Sarkadi B
Expression levels of the ABCG2 multidrug transporter in human erythrocytes correspond to pharmacologically relevant genetic variations.
PLoS One. 2012;7(11):e48423. doi: 10.1371/journal.pone.0048423. Epub 2012 Nov 15., [PMID:23166586]

Abstract [show]
We have developed a rapid, simple and reliable, antibody-based flow cytometry assay for the quantitative determination of membrane proteins in human erythrocytes. Our method reveals significant differences between the expression levels of the wild-type ABCG2 protein and the heterozygous Q141K polymorphic variant. Moreover, we find that nonsense mutations on one allele result in a 50% reduction in the erythrocyte expression of this protein. Since ABCG2 polymorphisms are known to modify essential pharmacokinetic parameters, uric acid metabolism and cancer drug resistance, a direct determination of the erythrocyte membrane ABCG2 protein expression may provide valuable information for assessing these conditions or for devising drug treatments. Our findings suggest that erythrocyte membrane protein levels may reflect genotype-dependent tissue expression patterns. Extension of this methodology to other disease-related or pharmacologically important membrane proteins may yield new protein biomarkers for personalized diagnostics.

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67 The most common SNPs in ABCG2 [V12M (c.34G.A, p.12Val.Met in exon 2, SNP database ID: rs2231137) and Q141K (c.421C.A, p.141Gln.Lys in exon 5, SNP database ID: rs2231142] were genotyped using the LightCycler480 (Roche Diagnostics, Basle, Switzerland) allelic discrimination system as described previously in detail [45]. Login to comment
89 For this purpose we quantified the expression of the erythrocyte ABCG2 in 47 unrelated, healthy individuals that were also screened for the presence of two most prevalent ABCG2 polymorphic variants found in the Caucasian population (V12M and Q141K) [29]. Login to comment
102 There was no significant difference between homozygous wild-type individuals and heterozygous V12M carriers, although the number of the carriers of this variant was relatively low. Login to comment
103 As a summary of the ABCG2 polymorphism analysis data, among the 47 donors we found 11 individuals with the heterozygous presence of the DNA sequence coding for the Q141K variant (carrier frequency: 23.4%, allele frequency: 11.766.6%), and 3 individuals with the heterozygous presence of the V12M variant (carrier frequency: 6.4%; allele frequency: 3.263.6%). Login to comment
136 Labels: individuals carrying wild-type ABCG2 (WT), polymorphic (Q141K, V12M) ABCG2 alleles, or a heterozygous stop mutation (STOP). Login to comment

[hide] Computational analysis and predictive modeling of ... Chem Cent J. 2013 Feb 4;7(1):23. doi: 10.1186/1752-153X-7-23. Lee Y, Jana S, Acharya G, Lee CH
Computational analysis and predictive modeling of polymorph descriptors.
Chem Cent J. 2013 Feb 4;7(1):23. doi: 10.1186/1752-153X-7-23., [PMID:23379683]

Abstract [show]
BACKGROUND: A computation approach based on integrating high throughput binding affinity comparison and binding descriptor classifications was utilized to establish the correlation among substrate properties and their affinity to Breast Cancer Resistant Protein (BCRP). The uptake rates of Mitoxantrone in the presence of various substrates were evaluated as an in vitro screening index for comparison of their binding affinity to BCRP.The effects of chemical properties of various chemotherapeutics, such as antiviral, antibiotic, calcium channel blockers, anticancer and antifungal agents, on their affinity to BCRP, were evaluated using HEK (human embryonic kidney) cells in which 3 polymorphs, namely 482R (wild type) and two mutants (482G and 482T) of BCRP, have been identified. The quantitative structure activity relationship (QSAR) model was developed using the sequential approaches of Austin Model 1 (AM1), CODESSA program, heuristic method (HM) and multiple linear regression (MLR) to establish the relationship between structural specificity of BCRP substrates and their uptake rates by BCRP polymorphs. RESULTS: The BCRP mutations may induce conformational changes as manifested by the altered uptake rates of Mitoxantrone by BCRP in the presence of other competitive binding substrates that have a varying degree of affinities toward BCRP efflux. This study also revealed that the binding affinity of test substrates to each polymorph was affected by varying descriptors, such as constitutional, topological, geometrical, electrostatic, thermodynamic, and quantum chemical descriptors. CONCLUSION: Descriptors involved with the net surface charge and energy level of substrates seem to be the common integral factors for defining binding specificity of selected substrates to BCRP polymorph. The reproducible outcomes and validation process further supported the accuracy of the computational model in assessing the correlation among descriptors involved with substrate affinity to BCRP polymorph. A quantitative computation approach will provide important structural insight into optimal designing of new chemotherapeutic agents with improved pharmacological efficacies.

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125 BCRP G34A (Val12Met) and C421A (Gln141Lys) polymorphisms occurred at high frequency in most ethnic populations and have been associated with the expression and activity of BCRP protein [48]. Login to comment
126 It has distinctive features including racial differences; for instance, BCRP V12M, Q141K, P269S and Q126Stop were detected in Korean at frequencies of 23, 28, 0.2 and 1.9%, respectively [49]. Login to comment

[hide] [Transporter-mediated regulation of pharmacokineti... Yakugaku Zasshi. 2013;133(4):451-61. Takada T
[Transporter-mediated regulation of pharmacokinetics of lifestyle-related substances].
Yakugaku Zasshi. 2013;133(4):451-61., [PMID:23546589]

Abstract [show]
Recent studies revealed the importance of transporters in the behaviors of small molecules in the body. In mammals, the presence of a lot of transporters has been suggested, such as ATP-binding cassette (ABC) transporters and solute ligand carrier (SLC) transporters, some of which are clarified to be causative genes for various kinds of genetic disorders. In addition, a lot of transporters are known to mediate cellular import or export of drugs, to contribute to the pharmacokinetics of substrate drugs and to be involved in the interindividual differences of drug responses. In this review, I introduce our recent work on the transporter-mediated regulation of pharmacokinetics of lifestyle-related substances, such as cholesterol and urate.

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24 c3f; ⏚ ᣸ 3fa; c8; e9; f3; b9; dd; fc; bf; fc; ABCG2 Ĳe; SNPs ௼ ad8;c3f;⏚⊈Kc7;fb;Kdb;ba8;ea;b9;af; ˯f;d3b;fd2;᠓Kc5;௼ ௱௺Me5;఑Ĵc;Ĵb; ad8;c3f;⏚⊈Kc7;ఌKdb;ba8;Ĳf;,d05;ca2;Kc5;௼௤௦a00; ℁İc;௢Ĵb;ఐ௦Ĳb;,Pa5;e80;ఌ ad8;d7;ea;f3;bdf;Ĳe;ᤪbdf;Έe;ɏa;Ĳa;௽ Ĳe;Jb0;᛻⌕8e0;Ĳb;d77;8e0;௳Ĵb;௼ὃ௨఑Ĵc;௺௤ıf;İc;,fd1;e74;Ĳe; Ẇa76;Ĳb;ఐĴa;΋a;f1d;ḄĲa;⌕8e0;Ĳe;b58;ᙠఊ̙a;ᖂ௯Ĵc;௺௤ıf;&#ff0e; 2004 e74;,5f0;e7e;Ĳe;Ẇa76;b0;eb;fc;d7;ఐĴa;,d2;c8;b2c; 4 Cd3; ⁐f53;╩ΊĲb;ʠa;Me5;Ĳe;Kdb;ba8;Kc5;8e0;΋a;f1d;b50;İc;b58;ᙠ௳Ĵb;5ef;Pfd;ឋ İc;ᛇȠa;௯Ĵc;ıf;İc;, 26) ᎛Xdc;♚9df;Ĳb;Ĳf;ɏa;İf;Ĳe;΋a;f1d;b50;İc;Ȟb; ĳe;Ĵc;௺İa;Ĵa;,ᐹf53;ḄĲa;Kc5;8e0;΋a;f1d;b50;Ĳf;Ȝc;b9a;௯Ĵc;௺௤Ĳa; İb;௷ıf;&#ff0e;ıd;௭௻,d30;Pde;̳c;e0a;Ĳb;İa;௤௺f38;〈9fa;cea;Ĳe;᣸3fa; Ĳb;fc2;Ĵf;Ĵb; ABCG2/breast cancer resistance protein (BCRP) ΋a;f1d;b50;İc;௭Ĳe;♚9df;Ĳb;b58;ᙠ௳Ĵb;௭௼, ABCG2 Ĳb;Ĳf;a5f;Pfd;᜕4d5;ఔf34;௦ϗb;ea6;Ĳe; ad8;௤΋a;f1d;b50;ɏa;ɂb;İc;b58;ᙠ௳ Ĵb;௭௼,Ae2;Me5;Ĳe;f38;〈9fa;cea;௼Ĳe;bd4;f03;İb;఑c3f;⏚Ĳf; ABCG2 Ĳe;9fa;cea;Ĳb;Ĳa;Ĵa;f97;Ĵb;௼ὃ௨఑Ĵc;ıf;௭௼Ĳa;௽Ĳe;ᳮᵫĲb;ఐ Ĵa;,b46;ὅ఑Ĳf; ABCG2 Ĳb;_a2;௳Ĵb;ʳc;a0e;ఔ⍈ఉıf;(௵Ĳa; ĳf;Ĳb;,ıd;Ĳe;f8c;Ĳe; GWAS Ĳb;İa;௤௺ఊ⊈e05;c3f;⏚ᎠĲe;᜕ 4d5;Ĳb;_a2;⌿௳Ĵb;΋a;f1d;b50;௼௱௺ ABCG2 Ĳf;ᛇȠa;௯Ĵc;௺௤ Ĵb;) &#ff0e; 27&#e30f; 29) ABCG2/BCRP Ĳf;ıd;Ĳe;Ȝd;Ĳe;΅a;Ĵa;,ɏa;ᒐὊឋĲb;_a2;e0e; ௳Ĵb;8e0;b50;௼௱௺˿a;΂b;௯Ĵc;ıf;c8;e9;f3;b9;dd;fc;bf;fc;௻௢Ĵb; İc;,e83;bc4;Ĳa;d44;e54;ᑖe03;௼e83;௤9fa;cea;a8d;b58;ឋఔᨵ௳Ĵb;௭௼ İc;b21;b2c;Ĳb;ʔe;఑İb;௼Ĳa;Ĵa;,Ife;ᙠ௻Ĳf;ɏa;Ed8;Ĳa;⌤Fb9;İb;఑Ẇ a76;İc;⍈ఉ఑Ĵc;௺௤Ĵb;&#ff0e;Ae5;ʠc;eba;Ĳb;İa;௫Ĵb; ABCG2 ΋a;f1d; b50;ɏa;ɂb;Ĳe;a2;ec;eb;ϗb;ea6;Ĳf; ad8;İf;,˿a;Ife;[cf;5ca;ఁa5f;Pfd;᜕ᓄఔ f34;Ĵf;Ĳa;௤ 34G&#ff1e;A(V12M)Ĳf; 19.2%,bf;f3;d1;af;cea; ˿a;Ife;[cf;İc;d04;Ȗa;ᑖĲb;f4e;e0b;௳Ĵb; 421C&#ff1e;A(Q141K)Ĳf; 31.9%,d42;b62;b3;c9;f3;İc;˯f;௲a5f;Pfd;b20;ʀd;௼Ĳa;Ĵb; 376C&#ff1e;T (Q126X)Ĳf; 2.8%௻௢Ĵb;௼ᛇȠa;௯Ĵc;௺௤Ĵb;&#ff0e; 30) ௭Ĵc; ఑Ĳe;௦௵,ϗb;ea6;İc; ad8;İf;a5f;Pfd;f4e;e0b;ఔf34;௦ 421C&#ff1e;A (Q141K)Ĳb;௸௤௺Ĳf;Qe8;e8a;ḄĲb;ఊఐİf;Ẇa76;௯Ĵc;௺İa; Ĵa;,Uac;ᱥ4d5;ɦb;Ĳe;᜕4d5;௼௱௺Ĳf;,b9;eb;d5;a1;b5;e9;b8;f3;Ĳe; d88;ᓄba1;ᔾ5ce;Ĳe;e0a;᧏,ed;b9;d0;b9;bf;c1;f3;ఌd5;eb;d0;b9;bf;c1; f3;Ĳe;d4c;5e3;ᢗe0e;᧲Ĳe; AUC(Uac;ᱥ⊈e2d;fc3;ea6;ߟ᧲╹Bf2;dda; e0b;☢a4d;)ఌ Cmax(ᨬ ad8;⊈e2d;fc3;ea6;)Ĳe;e0a;᧏İc;Yb3;bdf;௯ Ĵc;௺௤Ĵb;&#ff0e;௭Ĳe;ఐ௦Ĳb;,Uac;ᱥc8;e9;f3;b9;dd;fc;bf;fc; ABCG2 Ĳe;Uac;ᱥ4d5;ɦb;ᑴfa1;8e0;b50;௼௱௺Ĳe;[cd;⌕ឋĲf;a8d;b58; ௯Ĵc;௺௤ıf;ఊĲe;Ĳe;,d2;c8;Ĳb;İa;௫Ĵb;˯f;ᳮḄ9fa;cea;ఌ˯f;ᳮ a5f;Pfd;Ĳb;௸௤௺Ĳf;e0d;ʔe;௻௢௷ıf;&#ff0e; ABCG2 Ĳb;ఐĴb;c3f;⏚f38;〈Ĳb;௸௤௺ʳc;a0e;௳Ĵb;ıf;ఉ, ABCG2 ˿a;Ife;d30;Pde;İb;఑abf;Xfd;௱ıf;d30;Pde;̳c;c0f;Pde;ఔᵨ௤ıf; f38;〈b9f; a13;ఔʹc;௷ıf;d50;ʧc;,ABCG2 Ĳf;˯f;ᳮḄfc3;ea6;௻Ĳf; bfd;Ȥc;௱Ĳa;௤ ad8;bb9;[cf;ឋfb;f4e;Yaa;Ȥc;ឋĲe;c3f;⏚f38;〈ఔ>c5;௦௭ ௼İc;ʔe;఑İb;௼Ĳa;௷ıf;(c3f;⏚Ĳe;eb6;Ye3;ea6;Ĳe;bd4;f03;Ḅ ad8;௤ ad8; pH e0b;௻c42;ఉ఑Ĵc;ıf; Km ᎠĲf; 8.24&#b1;1.44 mM ௻௢ Ĵa;,⊈e05;c3f;⏚Ꭰ(f8b;௨௾ 7.0 mg/dL&#ff1d;d04; 420 mM) ௼bd4;ఇ௺Ĳf;Ĵb;İb;Ĳb; ad8;௤) &#ff0e; 31) ĳe;ıf;,᜕ᶒf53;Ye3;᪆Ĳe;d50; ʧc;,ed6;Ĳe;f38;〈9fa;cea;௼Ȝc;Ed8;,c3f;⏚f38;〈Ĳb;İa;௤௺ఊ Q141K ௻Ĳf;a5f;Pfd;İc;Ȗa;e1b;,Q126X ௻Ĳf;a5f;Pfd;İc;d88;ᜫ௳ Ĵb;௭௼İc;̙a;௯Ĵc;ıf;&#ff0e; ௸௹௤௺,Ae5;ʠc;eba;Ĳe;Ꮙeb7;a3a;Aad;5d7;a3a;ὅĲe;b5;f3;d7;eb;ఔ ᵨ௤௺,⊈e05;c3f;⏚Ꭰ௼ ABCG2 ΋a;f1d;b50;ɏa;ɂb;Ĳe;_a2;fc2;Ĳb; ௸௤௺ʳc;a0e;௱ıf;d50;ʧc;,Q141K ᜕ᶒĲe;fdd;ᢝᦪİc;ɏa;௤ ĳb;௽,⊈e05;c3f;⏚Ꭰİc;e0a;᧏௱௺௤ıf;&#ff0e; 31) ĳe;ıf;,cf;d7;ed; bf;a4;d7;ϗb;ea6;Ye3;᪆Ĳb;ఐĴa;,Q126X ௼ Q141K Ĳe;e21;᜕ᶒ 4. Proposed Model of ABCG2-mediated Urate Secretion31) 458 Vol. 133 (2013) Ĳf;Ȝc;௲Cd3;⁐f53;e0a;Ĳb;Ĳf;b58;ᙠ௱Ĳa;௤௭௼İc;̙a;௯Ĵc;ıf;&#ff0e;ıd; ௭௻,e21;᜕ᶒĲe;ϗb;ea6;Ĳb;௸௤௺Ae5;ʠc;eba;ᵱឋĲe;Kdb;ba8;Kc7;f8b; ௼Ꮙe38;ὅ௻bd4;f03;௱ıf;d50;ʧc;,Q126X ௼ Q141K Ĳe;d44;ĳf; ᔠĴf;ıb;İb;఑?a8;b9a;௯Ĵc;Ĵb;c3f;⏚f38;〈d3b;ឋĲe;f4e;e0b;Ĳb;f34;௤, aa;c3;ba;bd4;௻̙a;௯Ĵc;Ĵb;Kdb;ba8;˿a;Kc7;ea;b9;af;İc;♿℉Ĳb; ad8;ĳe;Ĵb; ௭ ௼ İc; ʔe; ఑ İb; ௼ Ĳa; ௷ ıf; &#ff0e; 31) ௭ Ĵc; ఑ Ĳe; d50; ʧc; Ĳf; , ABCG2 İc;˯f;f53;ᑁĲb;İa;௫Ĵb;c3f;⏚Ĳe;f53;᜜ఆĲe;᣸cc4;Ĳb;_a2; e0e;௱௺İa;Ĵa;,ıd;Ĳe;a5f;Pfd;f4e;e0b;Ĳf;⊈e05;c3f;⏚Ꭰ31,32)5ca;ఁKdb; ba8;˿a;Kc7;ea;b9;af;31)Ĳe;e0a;᧏ఔఊıf;఑௳௭௼ఔ̙a;௳ఊĲe;௻ ௢௷ıf;&#ff0e;ABCG2 Ĳf;̩d;Qd3;,̮e;Qd3;,c0f;ῲĲa;௽Ĳe;♊aef;̳c; Ĳb;˿a;Ife;௱,f38;〈9fa;cea;Ĳe;f53;᜜ఆĲe;᣸3fa;Ĳb;fc2;Ĵf;Ĵb;௭௼İc; Me5;఑Ĵc;௺௤Ĵb;௭௼,c3f;⏚Ĳf;c3f;e2d;Ĳe;ĳf;Ĳa;఑ıa;cde;e2d;Ĳb;ఊ ᣸ cc4; ௯ Ĵc; Ĵb; ௭ ௼ İc; ᛇ Ƞa; ௯ Ĵc; ௺ ௤ ıf; ௭ ௼ İb; ఑ , ABCG2 Ĳf;௭Ĵc;఑Ĳe;d44;e54;İb;఑Ĳe;c3f;⏚ᑖccc;Ĳb;_a2;e0e;௱௺ ௤Ĵb;5ef;Pfd;ឋİc;ὃ௨఑Ĵc;ıf;(Fig. 4) &#ff0e; 31) 5-2. Login to comment

[hide] Molecular pharmacology of ABCG2 and its role in ch... Mol Pharmacol. 2013 Nov;84(5):655-69. doi: 10.1124/mol.113.088609. Epub 2013 Sep 10. Stacy AE, Jansson PJ, Richardson DR
Molecular pharmacology of ABCG2 and its role in chemoresistance.
Mol Pharmacol. 2013 Nov;84(5):655-69. doi: 10.1124/mol.113.088609. Epub 2013 Sep 10., [PMID:24021215]

Abstract [show]
The ATP-binding cassette, subfamily G, isoform 2 protein (ABCG2) is an important member of the ABC transporter superfamily, which has been suggested to be involved in multidrug resistance (MDR) in cancer. Its diverse range of substrates includes many common chemotherapeutics such as imatinib, doxorubicin, and mitoxantrone. Physiologically, ABCG2 is highly expressed in areas such as the blood-brain barrier and gastrointestinal tract, where it is thought to play a role in protection against xenobiotic exposure. High ABCG2 expression has also been found in a variety of solid tumors and in hematologic malignancies and has been correlated with poorer clinical outcomes. Furthermore, ABCG2 expression is a characteristic feature of cancer stem cells, which are able to self-renew and differentiate. These cancer stem cells have been postulated to play an important role in MDR, where their inherent ABCG2 expression may allow them to survive chemotherapy and repopulate the tumor after exposure to chemotherapeutics. This observation raises the exciting possibility that by inhibiting ABCG2, cancer stem cells and other cancers may be targeted and eradicated, at which point conventional chemotherapeutics would be sufficient to eliminate the remaining tumor cells. Inhibitors of ABCG2, such as tyrosine kinase inhibitors, phosphodiesterase-5 inhibitors, and the fumitremorgin-type indolyl diketopiperazine, Ko143 [(3S,6S,12aS)-1,2,3,4,6,7,12,12a-octahydro-9-methoxy-6-(2-methylpropyl)-1,4-dioxo pyrazino[1',2':1,6]pyrido[3,4-b]indole-3-propanoic acid 1,1-dimethylethyl ester], could potentially be used for this purpose. However, these agents are still awaiting comprehensive clinical assessment.

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40 The two most frequent polymorphisms identified were the G34A (resulting in V12M) and C421A (resulting in a Q141K substitution) transitions (Fig. 3), found in 18 and 35.5% of the studied population, respectively (Kobayashi et al., 2005). Login to comment

[hide] Association of single nucleotide polymorphisms in ... Med Oncol. 2014 Jan;31(1):802. doi: 10.1007/s12032-013-0802-6. Epub 2013 Dec 13. Zhao J, Li W, Zhu D, Yu Q, Zhang Z, Sun M, Cai S, Zhang W
Association of single nucleotide polymorphisms in MTHFR and ABCG2 with the different efficacy of first-line chemotherapy in metastatic colorectal cancer.
Med Oncol. 2014 Jan;31(1):802. doi: 10.1007/s12032-013-0802-6. Epub 2013 Dec 13., [PMID:24338217]

Abstract [show]
Either oxaliplatin- or irinotecan-containing regimen could receive a good effectiveness in patients with metastatic colorectal cancer as the first-line chemotherapy, but not all patients would benefit from the treatment they have received. This study was to investigate the role of single nucleotide polymorphisms (SNPs) of methylenetetrahydrofolate reductase (MTHFR) and ATP-binding cassette sub-family G member 2 (ABCG2) in selecting the most appropriate treatment for individual patients. Ninety-two metastatic colorectal cancer patients treated with first-line 5-fluoropyrimidine (5-FU), leucovorin, and oxaliplatin (FOLFOX), capecitabine, and oxaliplatin (XELOX) and sixty-two patients receiving 5-FU, leucovorin, and irinotecan (FOLFIRI) were reviewed. The SNPs of MTHFR and ABCG2 were detected using gene sequencing method after DNA PCR amplification, which was extracted from peripheral blood karyocytes. Clinical characteristics and gene polymorphisms were evaluated in univariate and multivariate analysis as predictive factors for response rate (RR) and progression-free survival (PFS). In patients bearing 2-4 genotypes of MTHFR 677C/C, MTHFR 1298 A/C or C/C, ABCG2 34G/G, and ABCG2 421C/A or A/A, those who received oxaliplatin-based chemotherapy achieved a higher RR (41.7 vs. 18.8 %, P = 0.027) and longer median PFS (mPFS) than irinotecan-based therapy [8.9 vs. 7.1 m, FOLFIRI: hazard ratio (HR) = 1.722, 95 % confidence interval (CI) 1.026-2.892, P = 0.040, compared with FOLFOX/XELOX]; on the contrary, patients carrying 0 or 1 above genotype exhibited better outcomes after receiving FOLFIRI chemotherapy (mPFS: 9.3 vs. 6.4 m, FOLFIRI: HR = 0.422, 95 % CI 0.205-0.870, P = 0.019, compared with FOLFOX/XELOX). Combination of SNPs with MTHFR and ABCG2 may play a role in helping clinicians to select first-line chemotherapy for patients with metastatic colorectal cancer.

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32 Genotyping Genomic DNA was isolated from whole blood using the FUJIFILM DNA extraction kit. Based on previous published studies, the single nucleotide polymorphisms selected for testing were MTHFR 677C[T (rs1801133, Ala 222 Val) and 1298A[C (rs1801131, Glu 428 Ala), and ABCG2 34G[A (rs2231137, Val 12 Met) and 421C[A (rs2231142, Gln 141 Lys). Login to comment

[hide] Impact of genetic variability in the ABCG2 gene on... Biochem Biophys Res Commun. 2014 Jan 24;443(4):1211-7. doi: 10.1016/j.bbrc.2013.12.119. Epub 2014 Jan 3. Deppe S, Ripperger A, Weiss J, Ergun S, Benndorf RA
Impact of genetic variability in the ABCG2 gene on ABCG2 expression, function, and interaction with AT1 receptor antagonist telmisartan.
Biochem Biophys Res Commun. 2014 Jan 24;443(4):1211-7. doi: 10.1016/j.bbrc.2013.12.119. Epub 2014 Jan 3., [PMID:24388985]

Abstract [show]
The ATP-binding cassette transporter ABCG2 plays a prominent role in cardiovascular and cancer pathophysiology, is involved in the pathogenesis of gout, and affects pharmacokinetics of numerous drugs. Telmisartan, a widely used AT1 receptor antagonist, inhibits the transport capacity of ABCG2 and may cause drug-drug interactions, especially in individuals carrying polymorphism that facilitate the telmisartan-ABCG2 interaction. Thus, the aim of this study was to identify ABCG2 polymorphisms and somatic mutations with relevance for the telmisartan-ABCG2 interaction. For this purpose, a cellular system for the conditional expression of ABCG2 was established. ABCG2 variants were generated via site-directed mutagenesis. Interaction of telmisartan with these ABCG2 variants was investigated in HEK293-Tet-On cells using the pheophorbide A efflux assay. Moreover, expression of ABCG2 variants was studied in these cells. Importantly, protein levels of the Q141K and F489L variant were significantly reduced, a phenomenon that was partly reversed by pharmacological proteasome inhibition. Moreover, basal pheophorbide A efflux capacity of S248P, F431L, and F489L variants was significantly impaired. Interestingly, inhibition of ABCG2-mediated pheophorbide A transport by telmisartan was almost abolished in cells expressing the R482G variant, whereas it was largely increased in cells expressing the F489L variant. We conclude that the arginine residue at position 482 of the ABCG2 molecule is of major importance for the interaction of telmisartan with this ABC transporter. Furthermore, individuals carrying the F489L polymorphism may be at increased risk of developing adverse drug reactions in multi-drug regimens involving ABCG2 substrates and telmisartan.

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37 Site-directed mutagenesis Non-synonymous ABCG2 single nucleotide polymorphisms (SNPs) G34A (V12M), C421A (Q141K), T742C (S248P), T1291C (F431L), T1465C (F489L) as well as somatic mutation A1444G (R482G) were inserted into the ABCG2 cDNA sequence in the pTRE-Tight-BI-AcGFP1-ABCG2 plasmid using the QuickChange&#d2; Lightning Site-Directed Mutagenesis Kit (Agilent Technologies, Waldbronn, Germany) with specific primers according to the manufacturer`s instructions (Supplemental Fig. 1). Login to comment
91 The average PhA-associated fluorescence in non-induced HEK293-Tet-On cells transiently transfected with the various ABCG2 variants was not significantly different as compared with that observed in HEK293-Tet-On cells transfected with ABCG2 wild-type (wild-type (100 &#b1; 12.1%), V12M (106.7 &#b1; 2.0%), Q141K (97.1 &#b1; 9.3%), S248P (99.1 &#b1; 9.8%), F431L (104.7% &#b1; 10.9%), R482G A B C D Fig. 2. Login to comment
99 PhA-associated fluorescence was similar in doxycycline-induced AcGFP1-positive HEK293-Tet-On cells transfected with the ABCG2 variants V12M (11.8 &#b1; 0.9%), Q141K (17.9 &#b1; 5.8%), and R482G (17.0 &#b1; 2.8%). Login to comment
104 Inhibitory efficacy of telmisartan was not altered by the ABCG2 polymorphisms V12M and Q141K but tended to be lower in the ABCG2 variants S248P and F431L (Fig. 4A and C). Login to comment

[hide] Genetic association analysis of ATP binding casset... PLoS One. 2014 Feb 21;9(2):e89253. doi: 10.1371/journal.pone.0089253. eCollection 2014. Balan S, Bharathan SP, Vellichiramal NN, Sathyan S, Joseph V, Radhakrishnan K, Banerjee M
Genetic association analysis of ATP binding cassette protein family reveals a novel association of ABCB1 genetic variants with epilepsy risk, but not with drug-resistance.
PLoS One. 2014 Feb 21;9(2):e89253. doi: 10.1371/journal.pone.0089253. eCollection 2014., [PMID:24586633]

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Epilepsy constitutes a heterogeneous group of disorders that is characterized by recurrent unprovoked seizures due to widely different etiologies. Multidrug resistance remains a major issue in clinical epileptology, where one third of patients with epilepsy continue to have seizures. Role of efflux transporters in multidrug resistant epilepsy has been attributed to drug-resistant epilepsy although, with discrepant observation in genetic studies. These discrepancies could be attributed to variety of factors such as variable definition of the anti-epileptic drug (AED)-resistance, variable epilepsy phenotypes and ethnicities among the studies. In the present study we inquired the role of multidrug transporters ABCB1 and ABCG2 variants in determining AED-resistance and susceptibility to epilepsy in three well-characterized cohorts comprising of mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) (prototype for AED-resistant epilepsy); juvenile myoclonic epilepsy (JME) (prototype for AED-responsive epilepsy); and healthy non-epileptic controls, in 738 subjects of Malayalam speaking south Indian ancestry. ABCB1 and ABCG2 variants were not found to be associated with drug resistance when AED-resistant and AED-responsive cohorts were compared. However, a significant association was observed between ABCB1 (C3435T) rs1045642 and risk of having epilepsy (MTLE-HS and JME pooled cohort; genotypic p-value = 0.0002; allelic p-value = 0.004). This association was seen persistent with MTLE-HS (genotypic p-value = 0.0008; allelic p-value = 0.004) and also with JME (genotypic p-value = 0.01; allelic p-value = 0.05) cohort individually. In-silico functional prediction indicated that ABCB1 rs1045642 has a deleterious impact on protein coding function and in splicing regulation. We conclude that the ABCB1 and ABCG2 variants do not confer to AED-resistance in the study population. However, ABCB1 rs1045642 increases vulnerability to epilepsy with greater tendency for MTLE-HS in south Indian ancestry from Kerala.

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62 For ABCG2 three functional variants viz: rs2231142 (Gln141Lys; missense), rs72552713 (Gln126Ter; stop gain) and rs2231137 (Val12Met; missense) were screened. Login to comment

[hide] Structure and function of BCRP, a broad specificit... Arch Toxicol. 2014 Jun;88(6):1205-48. doi: 10.1007/s00204-014-1224-8. Epub 2014 Apr 29. Jani M, Ambrus C, Magnan R, Jakab KT, Beery E, Zolnerciks JK, Krajcsi P
Structure and function of BCRP, a broad specificity transporter of xenobiotics and endobiotics.
Arch Toxicol. 2014 Jun;88(6):1205-48. doi: 10.1007/s00204-014-1224-8. Epub 2014 Apr 29., [PMID:24777822]

Abstract [show]
The discovery and characterization of breast cancer resistance protein (BCRP) as an efflux transporter conferring multidrug resistance has set off a remarkable trajectory in the understanding of its role in physiology and disease. While the relevance in drug resistance and general pharmacokinetic properties quickly became apparent, the lack of a characteristic phenotype in genetically impaired animals and humans cast doubt on the physiological importance of this ATP-binding cassette family member, similarly to fellow multidrug transporters, despite well-known endogenous substrates. Later, high-performance genetic analyses and fine resolution tissue expression data forayed into unexpected territories concerning BCRP relevance, and ultimately, the rise of quantitative proteomics allows putting observed interactions into absolute frameworks for modeling and insight into interindividual and species differences. This overview summarizes existing knowledge on the BCRP transporter on molecular, tissue and system level, both in physiology and disease, and describes a selection of experimental procedures that are the most widely applied for the identification and characterization of substrate and inhibitor-type interactions.

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87 Four variants are found with allele frequencies above 3 % in at least one of the studied population (African American, Asian, and Caucasian): Val12Met (V12M), Gln141Lys (Q141K), Phe208Ser (F208S), and Asp590Tyr (N590Y). Login to comment
91 Q141K and V12M are two variants that are much more highly represented across different ethnicities, although the V12M mutation is not known to alter significantly BCRP function or expression (Tamura et al. 2006; Kondo et al. 2004; Honjo et al. 2002). Login to comment
92 More recently, V12M has been associated with acute lymphoblastic leukemia and gefitinib-induced toxicity (Zhai et al. 2012; Tamura et al. 2012). Login to comment
95 Histone deacetylase inhibitors rescue newly synthesized transporter proteins and prevent aggresome targeting by disturbing TableÊf;1ߒߙMajor non-synonymous single-nucleotide polymorphisms found in the ABCG2 coding region Allele frequencies presented in this table do not reflect interethnic differences Mutation Position in BCRP Cellular effects of SNP Allele frequency % References 34G>A, V12M (rs2231137) N-terminus Lower expression, no impact on function 0-29.8 Tamura et al. (2006), Bosch et al. (2005), Mizuarai et al. (2004), Imai et al. (2002), Kobayashi et al. (2005), Backstrom et al. (2003), Honjo et al. (2002), Kondo et al. (2004) 151G>T, G51C N-terminus Slightly overexpressed, decreased transport activity 0.1 Tamura et al. (2006), Yoshioka et al. (2007) 376C>T, Q126X (rs7255271) NBD No expression, no activity 0-1.7 Tamura et al. (2006), Mizuarai et al. (2004), Itoda et al. (2003), Imai et al. (2002), Kobayashi et al. (2005), Kondo et al. (2004) 421C>A, Q141K (rs2231142) NBD Lower expression, decreased transport activity, substrate specificity altered 0-35.7 Tamura et al. (2006), Bosch et al. (2005), Mizuarai et al. (2004), Imai et al. (2002), Kobayashi et al. (2005), Backstrom et al. (2003), Honjo et al. (2002), Kondo et al. (2004) 458C>T, T153 M NBD Slightly lower expression, no impact on function 3.3 Tamura et al. (2006), Mizuarai et al. (2004) 479G>A, R160Q NBD Not determined 0.5 Bosch et al. (2005), Tamura et al. (2006) 496C>G, Q166E (rs1061017) NBD Slightly lower expression, no impact on function 0-1.1 Tamura et al. (2006), Kondo et al. (2004), Yoshioka et al. (2007) 616A>C, I206L (rs12721643) NBD Well expressed, decreased transport activity 0-10.0 Tamura et al. (2006), Zamber et al. (2003), Vethanayagam et al. (2005), Ieiri (2012a) 623T>C, F208 (rs1061018) NBD No expression, no transport activity 0.9-3.9 Tamura et al. (2006) 742T>C, S248P (rs3116448) NBD Well expressed, no transport activity 0.5 Tamura et al. (2006), Yoshioka et al. (2007) 1000G>T, E334X (rs3201997) NBD No expression, no transport activity Not determined Tamura et al. (2006), Ishikawa et al. (2005) 1291T>C F431L ECL1 Lower expression, substrate specificity altered 0.6-0.8 Tamura et al. (2006), Itoda et al. (2003), Yoshioka et al. (2007) 1322G>A, S441 N ECL1 Slightly lower expression, no transport activity 0.5 Tamura et al. (2006), Kobayashi et al. (2005), Kondo et al. (2004) 1465T>C, F489L TM3 Slightly lower expression, no transport activity 0.5-0.8 Tamura et al. (2006), Itoda et al. (2003), Kobayashi et al. (2005) 1515delC, F506S TM4 Not determined 0.5 Itoda et al. (2003), Kobayashi et al. (2005) 1515delC, F507L 1515delC, V508L 1515delC, M509X 1711T>A, F571I (rs9282571) TM5 Well expressed, substrate specificity altered 0.5 Tamura et al. (2006) 1723C>T, R575X TM5 Not determined 0.5 Tamura et al. (2006) 1768A>T, N590Y (rs34264773) ECL3 Slightly overexpressed, substrate specificity altered 0-9.7 Tamura et al. (2006), Mizuarai et al. (2004), Zamber et al. (2003), Vethanayagam et al. (2005) 1858G>A, D620 N (rs34783571) ECL3 Slightly overexpressed, substrate specificity altered 0-11.1 Tamura et al. (2006), Bosch et al. (2005), Honjo et al. (2002), Vethanayagam et al. (2005) the trafficking along microtubules (Basseville et al. 2012). Login to comment

[hide] Functional polymorphisms of the ABCG2 gene are ass... Int J Mol Sci. 2014 May 22;15(5):9149-59. doi: 10.3390/ijms15059149. Zhou D, Liu Y, Zhang X, Gu X, Wang H, Luo X, Zhang J, Zou H, Guan M
Functional polymorphisms of the ABCG2 gene are associated with gout disease in the Chinese Han male population.
Int J Mol Sci. 2014 May 22;15(5):9149-59. doi: 10.3390/ijms15059149., [PMID:24857923]

Abstract [show]
BACKGROUND: Gout is a common type of arthritis that is characterized by hyperuricemia, tophi and joint inflammation. Genetic variations in the ABCG2 gene have been reported to influence serum uric acid levels and to participate in the pathogenesis of gout, but no further data have been reported in the Han Chinese population. METHODS: Peripheral blood DNA was isolated from 352 male patients with gout and 350 gout-free normal male controls. High-resolution melting analysis and Sanger sequencing were performed to identify the genetic polymorphisms V12M, Q141K and Q126X in the ABCG2 gene. Genotype and haplotype analyses were utilized to determine the disease odds ratios (ORs). A prediction model for gout risk using ABCG2 protein function was established based on the genotype combination of Q126X and Q141K. RESULTS: For Q141K, the A allele frequency was 49.6% in the gout patients and 30.9% in the controls (OR 2.20, 95% confidence interval (CI): 1.77-2.74, p=8.99x10(-)(1)(3)). Regarding Q126X, the T allele frequency was 4.7% in the gout patients and 1.7% in the controls (OR 2.91, 95% CI: 1.49-5.68, p=1.57x10(-)(3)). The A allele frequency for V12M was lower (18.3%) in the gout patients than in the controls (29%) (OR 0.55, 95% CI 0.43-0.71, p=2.55x10(-)(6)). In the order of V12M, Q126X and Q141K, the GCA and GTC haplotypes indicated increased disease risk (OR=2.30 and 2.71, respectively). Patients with mild to severe ABCG2 dysfunction accounted for 78.4% of gout cases. CONCLUSION: The ABCG2 126X and 141K alleles are associated with an increased risk of gout, whereas 12M has a protective effect on gout susceptibility in the Han Chinese population. ABCG2 dysfunction can be used to evaluate gout risk.

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5 High-resolution melting analysis and Sanger sequencing were performed to identify the genetic polymorphisms V12M, Q141K and Q126X in the ABCG2 gene. Login to comment
10 The A allele frequency for V12M was lower (18.3%) in the gout patients than in the controls (29%) (OR 0.55, 95% CI 0.43-0.71, p = 2.55 &#d7; 10-6 ). Login to comment
11 In the order of V12M, Q126X and Q141K, the GCA and GTC haplotypes indicated increased disease risk (OR = 2.30 and 2.71, respectively). Login to comment
37 In the present study, we developed an HRM assay to detect three functional SNPs (Q141K, V12M and Q126X) and then assessed the genetic association of those SNPs in the ABCG2 gene with gout to investigate the association between ABCG2 dysfunction and gout risk in a Han Chinese male population. Login to comment
42 The results obtained from the DNA sequencing analysis confirmed the reliability of the HRM assay. The genotype and allelic frequencies of the three SNPs (Q141K, V12M and Q126X) among the cases and controls were in Hardy-Weinberg equilibrium for all of the polymorphisms analyzed. Login to comment
45 The results of the association study, shown in Table 1, demonstrate that 141K and 126X were significantly associated with an increased risk of gout, whereas the frequency of the A allele of V12M appeared to be significantly decreased in gout patients (18.3%) compared with controls (29%) (OR 0.55, 95% CI: 0.43-0.71). Login to comment
48 The three groups are well distinguished: (A) V12M; (B) Q126X; and (C) Q141K. Login to comment
54 SNP Genotype * Allele Frequency Mode Case Control p-Value p-Value OR 95% CI 1/1 1/2 2/2 MAF 1/1 1/2 2/2 MAF Q141K 84 181 87 0.496 33 150 167 0.309 1.18 &#d7; 10-11 8.99 &#d7; 10-13 2.20 1.77-2.74 Q126X 0 33 319 0.047 0 12 338 0.017 1.31 &#d7; 10-3 1.57 &#d7; 10-3 2.91 1.49-5.68 V12M 16 97 239 0.183 35 133 182 0.290 3.67 &#d7; 10-5 2.55 &#d7; 10-6 0.55 0.43-0.71 * The minor allele was referred to as allele 1, and the major allele was referred to as allele 2. Login to comment
56 Allele 1 is A and allele 2 is G in V12M. Login to comment
58 Haplotype Analysis We performed a 3-SNP haplotype analysis (in the order V12M, Q126X and Q141K). Login to comment
63 Haplotype frequency analysis of V12M, Q126X and Q141K. Allele Frequency p-Value OR 95% CI V12M Q126X Q141K Gout Control G C A 0.481 0.289 1.26 &#d7; 10-13 2.30 1.84-2.87 G T C 0.044 0.017 2.97 &#d7; 10-3 2.71 1.37-5.36 G C C 0.292 0.404 8.27 &#d7; 10-6 0.60 0.48-0.75 A C C 0.165 0.271 1.53 &#d7; 10-6 0.53 0.41-0.69 2.3. Login to comment
76 Discussion This study is the first to examine the possible role of ABCG2 variants, which have previously been found to be associated with gout, in terms of their genetic susceptibility to gout in the Han Chinese population. We found that the Q141K, Q126X and V12M alleles were strongly associated with gout in Chinese males. Login to comment
86 Consistent with the genetic susceptibility identified in gout patients in a cohort of Japanese individuals [18], we observed that the rare alleles of both the 141K and 126X SNPs of ABCG2 were associated with an increased risk for gout, whereas the minor A allele in V12M had a protective effect on susceptibility to gout. Login to comment
115 We selected three functional ABCG2 SNPs: V12M, Q126X and Q141K. Login to comment
124 SNP ID SNP Allele Sequence (5'-3') Size V12M A/G ATGGTATGGGCCATTCATTG 250 bp ATGCCTTCAGGTCATTGGAA Q141K A/C ATGTTGTGATGGGCACTCTG 158 bp CCACATTACCTTGGAGTCTG Q126X C/T GCTGCAAGGAAAGATCCAAG 163 bp CAGCCAAAGCACTTACCCAT 4.3. Login to comment

[hide] Determinants of the activity and substrate recogni... Drug Metab Rev. 2014 Nov;46(4):459-74. doi: 10.3109/03602532.2014.942037. Epub 2014 Jul 18. Szafraniec MJ, Szczygiel M, Urbanska K, Fiedor L
Determinants of the activity and substrate recognition of breast cancer resistance protein (ABCG2).
Drug Metab Rev. 2014 Nov;46(4):459-74. doi: 10.3109/03602532.2014.942037. Epub 2014 Jul 18., [PMID:25036722]

Abstract [show]
The xenobiotic transporters are among the most important constituents of detoxification system in living organisms. Breast cancer resistance protein (BCRP/ABCG2) is one of the major transporters involved in the efflux of xenobiotics. To understand its role in chemotherapeutic and multidrug resistance, it is crucial to establish the determinants of its substrate specificity, which obviously is of high relevance for successful therapy of many diseases. This article summarizes the current knowledge about the substrate preferences of BCRP. We overview the factors which determine its activity, inhibition and substrate recognition, focusing on the structural features of the transporter. BCRP substrate specificity is quite low as it interacts with a spectrum of substances with only a few common features: hydrophobic and aromatic regions, possibly a flat conformation and the metal ion-, oxygen- and nitrogen-containing functionalities, most of which may be the donors/acceptors of H-bonds. Several amino acid residues and structural motifs are responsible for BCRP activity and substrate recognition. Thus, the active form of BCRP, at least a dimer or a larger oligomer is maintained by intramolecular disulfide bridge that involves Cys(603) residues. The GXXXG motif in transmembrane helix 1, Cys residues, Arg(482) and Lys(86) are responsible for maintaining the protein structure, which confers transport activity, and the His(457) or Arg(456) residues are directly involved in substrate binding. Arg(482) does not directly bind substrates, but electrostatically interacts with charged molecules, which initiates the conformational changes that transmit the signal from the transmembrane regions to the ABC domain.

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201 To elucidate the significance of this polymorphism for porphyrin transport, a set of 18 variants of BCRP (Val12 Met, Gly51 Cys, Gln126 stop, Gln141 Lys, Thr153 Met, Gln166 Glu, Ile206 Leu, Phe208 Ser, Ser248 Pro, Glu334 stop, Phe431 Leu, Ser441 Asn, Arg482 Gly, Arg482 Thr, Phe489 Leu, Phe571 Ile, Asn590 Tyr and Asp620 Asn) have been expressed in insect cells. Login to comment

[hide] Role of the breast cancer resistance protein (BCRP... AAPS J. 2015 Jan;17(1):65-82. doi: 10.1208/s12248-014-9668-6. Epub 2014 Sep 19. Mao Q, Unadkat JD
Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport--an update.
AAPS J. 2015 Jan;17(1):65-82. doi: 10.1208/s12248-014-9668-6. Epub 2014 Sep 19., [PMID:25236865]

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The human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. It was so named because it was initially cloned from a multidrug-resistant breast cancer cell line where it was found to confer resistance to chemotherapeutic agents such as mitoxantrone and topotecan. Since its discovery in 1998, the substrates of BCRP have been rapidly expanding to include not only therapeutic agents but also physiological substances such as estrone-3-sulfate, 17beta-estradiol 17-(beta-D-glucuronide) and uric acid. Likewise, at least hundreds of BCRP inhibitors have been identified. Among normal human tissues, BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure. As a result, BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition. We published a highly-accessed review article on BCRP in 2005, and much progress has been made since then. In this review, we provide an update of current knowledge on basic biochemistry and pharmacological functions of BCRP as well as its relevance to drug resistance and drug disposition.

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214 Of these SNPs, 34G>A (V12M) and 421C>A (Q141K) occur most frequently in East Asians (~30-60%) and with relatively low allele frequencies in Caucasians and African-American populations (~5-10%). Login to comment
218 V12M resulting from the 34G>A SNP and other variants (e.g., I206L, F208S, N590Y, and D620N) display expression levels and drug resistance profiles comparable to wild-type BCRP (100,101). Login to comment

[hide] Lack of efficacy of mitoxantrone in primary progre... J Neuroimmunol. 2015 Jan 15;278:277-9. doi: 10.1016/j.jneuroim.2014.11.017. Epub 2014 Nov 20. Grey Nee Cotte S, Salmen Nee Stroet A, von Ahsen N, Starck M, Winkelmann A, Zettl UK, Comabella M, Montalban X, Zipp F, Fleischer V, Kruse N, Gold R, Chan A
Lack of efficacy of mitoxantrone in primary progressive Multiple Sclerosis irrespective of pharmacogenetic factors: a multi-center, retrospective analysis.
J Neuroimmunol. 2015 Jan 15;278:277-9. doi: 10.1016/j.jneuroim.2014.11.017. Epub 2014 Nov 20., [PMID:25468777]

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BACKGROUND: Mitoxantrone is used on an off-label basis in primary progressive MS (PPMS). ABC-transporter-genotypes are associated with therapeutic response in relapsing/secondary progressive MS (RP/SPMS). OBJECTIVE: To evaluate potential pharmacogenetic response markers for mitoxantrone in PPMS. METHODS: 41 mitoxantrone-treated PPMS-patients, 155 mitoxantrone-treated RP/SPMS-patients and 43 PPMS-controls were retrospectively assessed for clinical therapy-response and in correlation with four single-nucleotide-polymorphisms in ABCB1- and ABCG2-genes. RESULTS: 53.7% PPMS-patients were mitoxantrone-responders, in comparison to 78.1% of RP/SPMS-patients (p=0.039). There was no association between genotype and treatment response. CONCLUSION: Our data discourages the use of mitoxantrone in PPMS regardless of pharmacogenetic response markers previously described in RP/SPMS.

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16 Patients, material and methods After approval by local ethics committees and informed consent, genotyping for ABCG2 V12M (reference SNP rs2231137) and Q141K (rs2231142) and ABCB1 3435CNT (rs1045642) and 2677GNT (rs2032582) was performed using TaqManࡊ polymerase chain reaction Journal of Neuroimmunology 278 (2015) 277-279 Ìe; Corresponding author at: Department of Neurology, St. Josef-Hospital, Ruhr University Bochum, Gudrunstr. Login to comment

[hide] Investigation of the functional single-nucleotide ... Biomed Rep. 2015 Jan;3(1):105-109. Epub 2014 Nov 11. Sari FM, Yanar HT, Ozhan G
Investigation of the functional single-nucleotide polymorphisms in the transporter and susceptibility to colorectal cancer.
Biomed Rep. 2015 Jan;3(1):105-109. Epub 2014 Nov 11., [PMID:25469257]

Abstract [show]
Breast cancer resistance protein (BCRP) protects tissues by actively transporting xenobiotics and their metabolites out of the cells. BCRP is expressed in the apical membrane of normal intestinal and colonic epithelium. The BCRP substrates include a number of structurally unrelated compounds, such as drugs, pesticides, carcinogens and endogenous compounds. Although the functional and common BCRP alleles, 34G>A and 421C>A, are shown to vary by ethnicity, their potential mechanism has not been adequately described with regards to affecting the susceptibility to colorectal cancer. The present study aimed to evaluate the effects of the BCRP variants on the susceptibility to colorectal cancer and to predict the individual responses to xenobiotics transferred by BCRP. BCRP 421C>A was significantly associated with the colorectal cancer risk (odds ratio, 16.12; P=0.005). These findings are the first results of BCRP allele distributions in the Turkish population and provide an understanding of the correlation between therapeutic approaches and etiology of colorectal cancer.

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20 The BCRP 34G>A variant (rs2231137), resulting in a Val12Met (V12M) substitution, results in apical plasma membrane dislocalization of BCRP and generates a protein with a significantly reduced ability to transport several drugs/xenobiotics. Login to comment

[hide] Sunitinib-induced severe toxicities in a Japanese ... BMC Cancer. 2014 Dec 16;14:964. doi: 10.1186/1471-2407-14-964. Miura Y, Imamura CK, Fukunaga K, Katsuyama Y, Suyama K, Okaneya T, Mushiroda T, Ando Y, Takano T, Tanigawara Y
Sunitinib-induced severe toxicities in a Japanese patient with the ABCG2 421 AA genotype.
BMC Cancer. 2014 Dec 16;14:964. doi: 10.1186/1471-2407-14-964., [PMID:25515134]

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BACKGROUND: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor that acts against receptors for vascular endothelial growth factor and platelet-derived growth factor. Common toxicities of sunitinib treatment include hypertension, hand-foot syndrome, vomiting, and diarrhea, and the proportion of grade 3 or 4 adverse events relating to sunitinib treatment range from 1 to 13% for all categories. It is reported that increased exposure to sunitinib is associated with improved clinical outcomes but also carries an increased risk of adverse effects. CASE PRESENTATION: A 73-year-old Japanese woman with metastatic renal cell carcinoma who received sunitinib at a dose of 50 mg once daily suffered a high-grade fever on day 11 of treatment. Sunitinib treatment was discontinued on day 12; however, severe thrombocytopenia and transaminase elevation occurred and persisted more than a week. Additionally, severe hypoxia due to pleural effusion and pulmonary edema developed despite immediate discontinuation of sunitinib. On day 14, three days after the discontinuation of sunitinib, the plasma concentrations of sunitinib and its major active metabolite N-desethyl sunitinib (SU12662) were extremely high (131.9 ng/mL and 28.4 ng/mL, respectively). By day 25, all toxicities had resolved, and a CT scan revealed marked tumor shrinkage. Genotyping of seven single-nucleotide polymorphisms that are potentially relevant to the pharmacokinetics of sunitinib was performed. The patient's genotype of ABCG2 (ATP-binding cassette, sub-family G (WHITE), member 2) 421C > A was homozygous for the variant allele (AA), which was reported to be associated with high exposure to sunitinib. Therefore, we speculated that the extremely high plasma concentrations of sunitinib and SU12662 caused by the ABCG2 421 AA genotype might have resulted in severe toxicities to the patient. CONCLUSION: The minor allele frequencies of ABCG2 421C > A are approximately three-fold higher in Asians than in Caucasians. Our report suggests that pharmacogenetic factors should be considered when severe and rapid-onset adverse drug reactions occur in Asian patients, including Japanese treated with sunitinib.

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85 Another population pharmacokinetics study also identified ethnic background as a significant covariate for the Table 1 Genotypes of seven SNPs in CYP3A5, ABCB1 and ABCG2 Gene SNP Allele Amino acid Genotype CYP3A5 rs776746 6986A > G Splice Site AG ABCB1 rs1128503 1236C > T G412G CT ABCB1 rs2032582 2677G > T/A A893S/T GT ABCB1 rs1045642 3435C > T I1145I CT ABCG2 rs2231137 34G > A V12M GG ABCG2 rs72552713 376G > A Q126X GG ABCG2 rs2231142 421C > A Q141K AA prediction of oral clearance [16]. Login to comment

[hide] Novel dysfunctional variant in ABCG2 as a cause of... Rheumatology (Oxford). 2016 Jan;55(1):191-4. doi: 10.1093/rheumatology/kev350. Epub 2015 Sep 30. Stiburkova B, Miyata H, Zavada J, Tomcik M, Pavelka K, Storkanova G, Toyoda Y, Takada T, Suzuki H
Novel dysfunctional variant in ABCG2 as a cause of severe tophaceous gout: biochemical, molecular genetics and functional analysis.
Rheumatology (Oxford). 2016 Jan;55(1):191-4. doi: 10.1093/rheumatology/kev350. Epub 2015 Sep 30., [PMID:26428519]

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18 The analysis of ABCG2 revealed eight variants in intron regions, an unpublished heterozygous intron variant c.689+1G>A and two exon variants, synonymous rs35622453 and heterozygous non-synonymous rs22231137 (p.V12M), which had little effect on the expression and urate transport activity of ABCG2 [6]. Login to comment