ABCMdb

ABCC1 p.Ala893Thr

Predicted by SNAP2:	C: N (82%), D: N (82%), E: N (82%), F: N (78%), G: N (87%), H: N (78%), I: N (93%), K: N (93%), L: N (87%), M: N (87%), N: N (93%), P: N (78%), Q: N (93%), R: N (87%), S: N (93%), T: N (93%), V: N (87%), W: N (78%), Y: N (87%),
Predicted by PROVEAN:	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, V: N, W: D, Y: N,

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[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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126 In addition to the possible decrease in expression levels, ATPase activity in the ABCG2 +24 Intron 20 G A +40 Intron 20 C T 2547 Exon 21 A G 849 Ile to Met 2650 Exon 21 C T 884 Syn 2677 Exon 21 G T 893 Ala to Ser 2677# Exon 21 G A 893 Ala to Thr +31 Intron 22 G A 2956 Exon 24 A G 986 Met to Val 2995 Exon 24 G A 999 Ala to Thr 3151 Exon 25 C G 1051 Pro to Ala 3320 Exon 26 A C 1107 Gln to Pro 3322 Exon 26 T C 1108 Trp to Arg 3396 Exon 26 C T 1132 Syn 3421 Exon 26 T A 1141 Ser to Thr 3435** Exon 26 C T 1145 Syn 3751 Exon 28 G A 1251 Val to Ile 3767 Exon 28 C A 1256 Thr to Lys 4030 Exon 28 G C Non-coding 4036 Exon 28 A G Non-coding +21 Intron 28 T C Table 2. Summary of common genetic variants in the ABCB1 gene (continued) *cDNA numbers are relative to the ATG site and based on the cDNA sequence from GenBank accession number M14758 with an A as the reference at position 43. 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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167 For this purpose, we have prepared several variant forms (i.e., N183S, S400N, R492C, R669C, I849M, A893T, M986V, A999T, P1051A, and G1063A) by site‐ directed mutagenesis. 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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312 However, the nonsynonymous mutations of G2677T/A/C, which result in the amino acid changes A893S, A893T and A893P, gave changes in both substrate specificity and ATPase kinetic properties as measured with 41 different test compounds [139]. Login to comment

[hide] Effects of polymorphisms of MDR1, MRP1, and MRP2 g... Biol Pharm Bull. 2002 Oct;25(10):1356-9. Moriya Y, Nakamura T, Horinouchi M, Sakaeda T, Tamura T, Aoyama N, Shirakawa T, Gotoh A, Fujimoto S, Matsuo M, Kasuga M, Okumura K
Effects of polymorphisms of MDR1, MRP1, and MRP2 genes on their mRNA expression levels in duodenal enterocytes of healthy Japanese subjects.
Biol Pharm Bull. 2002 Oct;25(10):1356-9., [PMID:12392094]

Abstract [show]
In the present study, we examined whether polymorphisms in the ATP-binding cassette (ABC) transporter genes, MDR1, MRP1 and MRP2, were associated with their respective mRNA expression levels in duodenal enterocytes of 13 healthy Japanese volunteers. MDR1 genotypes of T-129C, G2677(A,T) and C3435T, MRP1 genotypes of G128C, C218T, G2168A and G3173A, and MRP2 genotypes of C-24T, G1249A, C2302T, C2366T and G4348A were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) or direct sequencing. Mutations T-129C, G2677(A,T) and C3435T of MDRI gene were found at allele frequencies of 2/26, 16/26 and 12/26, respectively. Mutations G2168A of the MRPI gene and C-24T of the MRP2 gene were also found at allele frequencies of 1/26 and 6/26, respectively, whereas other mutations were not detected in MRP1 and MRP2 genes. The relative concentrations (mean +/- S.E.) of MDR1 mRNA to villin mRNA were 0.38 +/- 0.15, 0.56 +/- 0.14 and 1.13 +/- 0.42 in the subjects with C/C3435, C/T(3435) and T/T(3435), respectively, which supported the lower serum concentrations of digoxin after single oral administration in the subjects with the mutant T-allele at position 3435. Genetic collaboration between positions 3435 and 2677 was suggested, and those in G/G2677, G/(A,T)(2677) and T/(A,T)(2677) were 0.16 +/- 0.05, 1.10 +/- 0.40, and 0.63 +/- 0.16, respectively (p = 0.107). However, there was no remarkable effect of the G2168A of the MRP1 gene or of C-24T of the MRP2 gene on the relative MRP1 or MRP2 mRNA concentrations, respectively.

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46 These results suggested that the higher MDR1 expression in the duodenum was associated with the lower plasma concentration of fexofenadine and serum concentration of digoxin after single oral administration in subjects with the mutant T-allele at position 3435.9,10) The silent mutation C3435T has been suggested to be linked with the missense G2677(A,T) producing Ala893Thr and Ala893Ser, respectively.9,11) In the present study, the mutations T-129C, G2677(A,T) and C3435T of the MDR1 gene were found at allele frequencies of 2/26, 16/26 and 12/26, respectively, and 3 of 5 subjects with C/C3435 were accompanied with G/G2677 , and 3 of 4 subjects with T/T3435 were accompanied with T/T2677 , probably due to linkage between positions 3435 and 2677 in the MDR1 gene (Table 1). 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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70 2650C > T exon 21 synonymous (p.L884L) Kim et al., 2001 md-v-110 rs9282563 c.2677G > T exon 21 p.A893S Kim et al., 2001 md-v-031 rs2032582 c.2677G > A exon 21 p.A893T Kim et al., 2001 md-v-109 IVS 21 + 14 - 17 delAATA intron 21 Epidauros md-v-092 IVS 21 + 49 T > C intron 21 Epidauros md-v-042 rs2032583 IVS 21 + 66 T > C intron 21 Epidauros md-v-108 IVS 26 - 156 T > C intron 25 Epidauros md-v-095 IVS 26 - 68 A > G intron 25 Epidauros md-v-164 c.3320A > C exon 26 p.Q1107P Cascorbi et al., 2002 md-v-033 c.3322T > C exon 26 p.W1108R Kroetz et al., 2003 md-v-225 c.3325C > T exon 26 p.L1109F Epidauros md-v-165 c 3364C > T exon 26 synonymous (p.A1132A) Hoffmeyer et al., 2000 md-v-034 c.3321T > A exon 26 p.S1141T Kim et al., 2001 md-v-035 c.3435C > T (Tag8) exon 26 synonymous (p.I1145I) Hoffmeyer et al., 2000 md-v-036 rs1045642 IVS 26 + 59 T > G intron 26 Epidauros md-v-097 rs2235047 IVS 26 + 80 T > C intron 26 Epidauros md-v-040 rs2235048 IVS 26 + 123_24 insCATG intron 26 Epidauros md-v-096 Tag 11 intron 27 Soranzo et al., 2004 rs1186746 Tag 12 intron 27 Soranzo et al., 2004 rs1186745 MRP1 (ABCC1) c.816G > A exon 8 synonymous (p.P272P) Epidauros mr-v-014 c.825T > C exon 8 synonymous (p.V275V) Saito et al., 2002 mr-v-015 rs246221 c.1062T > C exon 9 synonymous (p.N354N) Saito et al., 2002 mr-v-016 rs35587 c.1068G > A exon 9 synonymous (p.T356T) Epidauros mr-v-057 rs8187852 IVS 9 + 8 A > G intron 9 Saito et al., 2002 mr-v-017 rs35588 c.1303G > T exon 10 p.R433S Conrad et al., 2002 mr-v-018 IVS 10 + 64 C > T intron 10 Epidauros mr-v-019 MRP2 (ABCC2) g. Login to comment

[hide] ABCB1 and ABCC1 expression in peripheral mononucle... Biochem Pharmacol. 2009 Jan 1;77(1):66-75. Epub 2008 Sep 21. Rebecchi IM, Rodrigues AC, Arazi SS, Genvigir FD, Willrich MA, Hirata MH, Soares SA, Bertolami MC, Faludi AA, Bernik MM, Dorea EL, Dagli ML, Avanzo JL, Hirata RD
ABCB1 and ABCC1 expression in peripheral mononuclear cells is influenced by gene polymorphisms and atorvastatin treatment.
Biochem Pharmacol. 2009 Jan 1;77(1):66-75. Epub 2008 Sep 21., 2009-01-01 [PMID:18851956]

Abstract [show]
This study investigated the effects of atorvastatin on ABCB1 and ABCC1 mRNA expression on peripheral blood mononuclear cells (PBMC) and their relationship with gene polymorphisms and lowering-cholesterol response. One hundred and thirty-six individuals with hypercholesterolemia were selected and treated with atorvastatin (10 mg/day/4 weeks). Blood samples were collected for serum lipids and apolipoproteins measurements and DNA and RNA extraction. ABCB1 (C3435T and G2677T/A) and ABCC1 (G2012T) gene polymorphisms were identified by polymerase chain reaction-restriction (PCR)-RFLP and mRNA expression was measured in peripheral blood mononuclear cells by singleplex real-time PCR. ABCB1 polymorphisms were associated with risk for coronary artery disease (CAD) (p<0.05). After atorvastatin treatment, both ABCB1 and ABCC1 genes showed 50% reduction of the mRNA expression (p<0.05). Reduction of ABCB1 expression was associated with ABCB1 G2677T/A polymorphism (p=0.039). Basal ABCB1 mRNA in the lower quartile (<0.024) was associated with lower reduction rate of serum low-density lipoprotein (LDL) cholesterol (33.4+/-12.4%) and apolipoprotein B (apoB) (17.0+/-31.3%) when compared with the higher quartile (>0.085: LDL-c=40.3+/-14.3%; apoB=32.5+/-10.7%; p<0.05). ABCB1 substrates or inhibitors did not affect the baseline expression, while ABCB1 inhibitors reversed the effects of atorvastatin on both ABCB1 and ABCC1 transporters. In conclusion, ABCB1 and ABCC1 mRNA levels in PBMC are modulated by atorvastatin and ABCB1 G2677T/A polymorphism and ABCB1 baseline expression is related to differences in serum LDL cholesterol and apoB in response to atorvastatin.

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26 The G2677T/A/C (rs2032582) is a non-synonymous polymorphism in the exon 21 with three distinct amino acid changes (Ala893Ser, Ala893Thr, and Ala893Pro, respectively) that is located at the transmembrane domain of the protein and it has a great impact on both the activity and the substrate specificity of ABCB1 toward different test compounds [10]. 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] Does the A118G polymorphism at the mu-opioid recep... Anesthesiology. 2002 Oct;97(4):814-9. Lotsch J, Zimmermann M, Darimont J, Marx C, Dudziak R, Skarke C, Geisslinger G
Does the A118G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity?
Anesthesiology. 2002 Oct;97(4):814-9., [PMID:12357145]

Abstract [show]
BACKGROUND: Some, but not all, patients with renal dysfunction suffer from side effects after morphine administration because of accumulation of the active metabolite morphine-6-glucuronide (M6G). The current study aims to identify genetic causes that put patients at risk for, or protect them from, opioid side effects related to high plasma M6G. Candidate genetic causes are the single nucleotide polymorphism (SNP) A118G of the mu-opioid-receptor gene (OPRM1), which has recently been identified to result in decreased potency of M6G, and mutations in the MDR1-gene coding P-glycoprotein, of which morphine and M6G might be a substrate. METHODS: Two men, aged 87 and 65 yr, with renal failure (creatinine clearance of 6 and 9 ml/min) received 30 mg/day oral morphine for pain treatment. Both patients had sufficient analgesia from morphine. However, while one patient tolerated morphine well despite high plasma M6G of 1735 nM, in the patient with M6G plasma concentrations of 941 nM it caused severe sleepiness and drowsiness. Patients were genotyped for known SNPs of the OPRM1 and MDR1 genes. RESULTS: The patient who tolerated morphine well despite high plasma M6G was a homozygous carrier of the mutated G118 allele of the mu-opioid-receptor gene, which has been previously related to decreased M6G potency. In contrast, the patient who suffered from side effects was "wild-type" for this mutation. No other differences were found between the OPRM1 and MDR1 genes. CONCLUSIONS: The authors hypothesize that the A118G single nucleotide polymorphism of the mu-opioid-receptor is among the protective factors against M6G-related opioid toxicity. The observation encourages the search for pharmacogenetic reasons that cause interindividual variability of the clinical effects of morphine.

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106 33 T/T T/T MDR1 2 A61G Asn21Asp 11.2 20.6 9 A/G A/G Forward: 5Ј-AGG AGC AAA GAA GAA GAA CTT TTT TAA ACT GAT C-3Ј 9.3 17.6 8 Reverse: 5Ј-GAT TCC AAA GGC TAG CTT GC-3Ј 5 T307C Phe103Leu 0.6 1.2 9 T/T T/T Forward: 5Ј-GTG GTT GCA CAC AGT CAG CA-3Ј Reverse: 5Ј-GGA GGA TGT CTA ATT ACC TGG TCA-3Ј 11 G1199A Ser400Asn 5.5 11.1 9 G/G G/G Forward: 5Ј-CAG CTA TTC GAA GAG TGG GC-3Ј 6.5 12.9 8 Reverse: 5Ј-CCG TGA GAA AAA AAC TTC AAG G-3Ј 21 G2677T Ala893Ser 41.6 49.2 9 T/T T/T Forward: 5Ј-TGC AGG CTA TAG GTT CCA GG-3Ј 63.9 43.4 8 Reverse: 5Ј-GTT TGA CTC ACC TTC CCA G-3Ј 21 G2677A Ala893Thr 0.9 2 9 NA NA Forward: 5Ј-TGC AGG CTA TAG GTT CCA GG-3Ј Reverse: 5Ј-TTT AGT TTG ACT CAC CTT CCC G-3Ј 26 A3320C Gln1107Pro 0.2 0.4 9 A/A A/A 26 C3396T Ala1132Ala 0.3 0.5 8 C/C C/C Forward: 5Ј-ATC TGT GAA CTC TTG TTT TCA GC-3Ј 26 C3435T Ile1145Ile 50.3 47.7 8 T/T T/T Reverse: 5Ј-TCG ATG AAG GCA TGT ATG TTG-3Ј 53.9 50.5 9 - - MRP2 10 G1249A Val417Ile 12.5 20.8 34 G/G G/G Forward: 5Ј-GGG TCC TAA TTT CAA TCC TTA-3Ј Reverse: 5Ј-TAT TCT TCT GGG TGA CTT TTT-3Ј 18 C2302T Arg768Trp 1 2.1 34 C/C C/C Forward: 5Ј-GGA GTA GTG CTT AAT ATG AAT-3Ј 18 C2366T Ser789Phe 1 2.1 34 C/C C/C Reverse: 5Ј-CCC ACC CCA CCT TTA TAT CTT-3Ј 28 C3972T Ile132Ile 21.9 35.4 34 C/T C/T Forward: 5Ј-TGC TAC CCT TCT CCT GTT CTA-3Ј Reverse: 5Ј-ATC CAG GCC TTC CTT CAC TCC-3Ј 31 G4348A Ala1450Thr 1 2.1 34 G/G G/G Forward: 5Ј-AGG AGC TAA CAC ATG GTT GCT-3Ј Reverse: 5Ј-GGG TTA AGC CAT CCG TGT CAA-3Ј † Sequence is not translated. Login to comment

[hide] Genetic polymorphisms of the human MDR1 drug trans... Annu Rev Pharmacol Toxicol. 2003;43:285-307. Epub 2002 Jan 10. Schwab M, Eichelbaum M, Fromm MF
Genetic polymorphisms of the human MDR1 drug transporter.
Annu Rev Pharmacol Toxicol. 2003;43:285-307. Epub 2002 Jan 10., [PMID:12359865]

Abstract [show]
P-glycoprotein is an ATP-dependent efflux pump that contributes to the protection of the body from environmental toxins. It transports a huge variety of structurally diverse compounds. P-glycoprotein is involved in limiting absorption of xenobiotics from the gut lumen, in protection of sensitive tissues (brain, fetus, testis), and in biliary and urinary excretion of its substrates. P-glycoprotein can be inhibited or induced by xenobiotics, thereby contributing to variable drug disposition and drug interactions. Recently, several SNPs have been identified in the MDR1 gene, some of which can affect P-glycoprotein expression and function. Potential implications of MDR1 polymorphisms for drug disposition, drug effects, and disease risk are discussed.

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60 In a Northern Italian population, the extent of linkage disequilibrium TABLE 2 Summary of MDR1 genetic variants in different ethnic groups Location Position Allele Effect Reference promotor 5 flanking/-41a A (28) G exon 1a exon 1a/-145 C (28) G exon 1b exon 1b/-129 T (25, 33) C intron 1 exon 2/-4 C (29) T intron 1 exon 2/-1 G initiation of translation (25, 27, 29) A exon 2 exon 2/61 A Asn21Asp (25-27, 29) G intron 4 exon 5/-35 G (25) C intron 4 exon 5/-25 G (25) T exon 5 exon 5/307 T Phe103Leu (25) C intron 6 exon 6/+139 C (25, 27) T intron 6 exon 6/+145 C (25) T exon 7 exon 7/548 A Asn183Ser (29) G exon 11 exon 11/1199 G Ser400Asn (25, 27, 29) A exon 12 exon 12/1236 C wobble (23, 25, 27, 29) T (Gly412Gly) intron 12 exon 12/+44 C (25, 27) T exon 13 exon 13/1474 C Arg492Cys (29) T intron 16 exon 17/-76 T (25, 27) A intron 17 exon 17/137 A (25) G exon 21 exon 21/2650 C wobble (29) T (Leu884Leu) (Continued ) TABLE 2 (Continued) Location Position Allele Effect Reference exon 21 exon 21/2677 G (22, 23, 27, 29) T Ala893Ser A Ala893Thr exon 24 exon 24/2956 A Met986Val (33) G exon 24 exon 24/2995 G Ala999Thr (22) A exon 26 exon 26/3320 A Gln1107Pro (27) C exon 26 exon 26/3396 C wobble (25) T exon 26 exon 26/3421 T Ser1141Thr (29, 30) A exon 26 exon 26/3435 C wobble (23, 25, 29) T (Ile1145Ile) exon 28 exon 28/4030 G (33) C exon 28 exon 28/4036 A (23, 33) G The positions of the polymorphisms correspond to positions of MDR1 cDNA with the first base of the ATG start codon set to 1 (GenBank accession # M14758). Login to comment

[hide] No effect of MDR1 C3435T variant on loperamide dis... Clin Pharmacol Ther. 2003 Nov;74(5):487-98. Pauli-Magnus C, Feiner J, Brett C, Lin E, Kroetz DL
No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects.
Clin Pharmacol Ther. 2003 Nov;74(5):487-98., [PMID:14586389]

Abstract [show]
BACKGROUND: The MDR1 gene encodes the efflux transporter P-glycoprotein, which is highly expressed in the small intestine and in the blood-brain barrier. A major function of P-glycoprotein is to limit the absorption and central nervous system exposure of numerous xenobiotics. A genetic polymorphism in the MDR1 gene (C3435T) has been associated with changes in the intestinal expression level and function of P-glycoprotein. The aim of this study was to investigate the effect of this polymorphism on disposition and brain entry of the P-glycoprotein substrate loperamide. METHODS: Healthy white volunteers were genotyped for the MDR1 C3435T polymorphism, and a 16-mg oral dose of loperamide was administered to 8 subjects with the 3435TT genotype and 8 subjects with the 3435CC genotype. Plasma levels of loperamide were determined by liquid chromatography-tandem mass spectrometry. Loperamide-induced respiratory depression was detected as the ventilatory response to carbon dioxide and was used as a measure of central nervous system side effects. RESULTS: We found no significant difference in loperamide pharmacokinetics between individuals homozygous for the C and the T alleles in position 3435 of MDR1, as follows: peak plasma drug concentration, 3164 +/- 1053 pg/mL and 3021 +/- 984 pg/mL; area under the concentration-time curve from 0 to 8 hours, 14414 +/- 4756 pg. h/mL and 14923 +/- 6466 pg. h/mL; and time to peak plasma drug concentration, 3.9 +/- 1.4 hours and 3.9 +/- 2.6 hours for the MDR1 3435CC and 3435TT genotypes, respectively (P >.05, for all parameters). Hypercapnic ventilatory response changed only minimally after ingestion of loperamide (the coefficient of variation during the 0- to 8-hour period was 21% +/- 14% for the sample population), and there was no MDR1 3435 genotype-related effect on respiratory response. Carriers of the 2 major MDR1 haplotypes, MDR1*1 and MDR1*13, did not differ in their response to loperamide. CONCLUSION: There was no association between the MDR1 C3435T variation and plasma levels or central nervous system effects of the P-glycoprotein substrate loperamide in a white study population. The MDR1 haplotype structure was quite variable and supports the use of haplotypes instead of single nucleotide polymorphisms in determining clinical consequences of genetic variation.

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168 In the MDR1 3435CC group, 2 individuals had haplotypes encoding P-glycoprotein variants (Ala893Thr and Asn21Asp), and all subjects in the MDR1 3435TT group were at least heterozygous for a haplotype encoding for the P-glycoprotein Ala893Ser variant. Login to comment

[hide] Pharmacogenetics of drug transporters and its impa... Curr Top Med Chem. 2004;4(13):1385-98. Sakaeda T, Nakamura T, Okumura K
Pharmacogenetics of drug transporters and its impact on the pharmacotherapy.
Curr Top Med Chem. 2004;4(13):1385-98., [PMID:15379652]

Abstract [show]
Most drug responses are determined by the interplay of several gene products that influence pharmacokinetics and pharmacodynamics, i.e., drug metabolizing enzymes, drug transporters, and drug targets. With the sequencing of the human genome, it has been estimated that approximately 500-1200 genes code for drug transporters. Concerning the effects of genetic polymorphisms on pharmacotherapy, the best characterized drug transporter is the multidrug resistant transporter P-glycoprotein/MDR1, the gene product of MDR1. Little such information is available on other drug transporters. MDR1 is a glycosylated membrane protein of 170 kDa, belonging to the ATP-binding cassette superfamily, and is expressed mainly in intestines, liver, kidneys and brain. A number of various types of structurally unrelated drugs are substrates for MDR1, and their intestinal absorption, hepatobiliary secretion, renal secretion and brain transport are regulated by MDR1. The first investigation on the effects of MDR1 genotypes on pharmacotherapy was reported in 2000: a silent single nucleotide polymorphism (SNP), C3435T in exon 26, was found to be associated with the duodenal expression of MDR1, and thereby the plasma concentration of digoxin after oral administration. At present, a total of 28 SNPs have been found at 27 positions on the MDR1 gene. Clinical investigations on the association of MDR1 genotypes with the expression and function of MDR1 in tissues, and with pharmacokinetics and pharmacodynamics have mainly focused on C3435T; however, there are still discrepancies in the results, suggesting that the haplotype of the gene should be analyzed instead of a SNP. C3435T is also reported to be a risk factor for a certain class of diseases including the inflammatory bowel diseases, Parkinson's disease and renal epithelial tumor, and this also might be explained by the effects on MDR1 expression and function. In this review, the latest reports on the effects of genetic polymorphisms of MDR1 on pharmacotherapy are summarized, and the pharmacogenetics of other transporters is briefly introduced.

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127 Position Location Effect A1a/-41G intron noncoding C-145G exon 1a noncoding T-129C (T12C) exon 1b noncoding C-4T exon 2 noncoding G-1A exon 2 noncoding A61G G5/-25T G5/-35C exon 2 intron intron Asn21Asp T307C C6/+139T exon 5 intron Phe103Leu A548G exon 7 Asn183Ser G1199A exon 11 Ser400Asn C1236T C12/+44T exon 12 intron silent C1474T T17/-76A A17/+137G exon 13 intron intron Arg492Cys C2650T exon 21 silent G2677(A,T) exon 21 Ala893Thr (G2677A) Ala893Ser (G2677T) A2956G exon 24 Met986Val G2995A exon 24 Ala999Thr A3320C exon 26 Gln1107Pro C3396T exon 26 silent T3421A exon 26 Ser1141Thr C3435T exon 26 silent G4030C exon 28 silent A4036G exon 28 silent The list was based on the reports [67,68,71-74]. Login to comment

[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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84 Other SNPs at exon 21 (G2677T/A) change encoded amino acids (Ala893Ser and Ala893Thr), and at exon 1b, T129C, was associated with altered P-gp expression (Hitzl et al., 2004; Nakamura et al., 2002; Tanabe et al., 2001). 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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721 209 Schaefer M, Roots I, Gerloff T: In-vitro transport characteristics discriminate wild-type ABCB1 (MDR1) from ALA893SER and ALA893THR polymorphisms. 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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6832 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/ Localization ABCB1 MDR1 A61G N21D ↔ N.D. T307C F103L N.D. N.D. G1199A S400N 1↔ Normal C2005T R669C ↔ N.D. G2677T A893S 21↔ Normal G2677A A893T 1↔ Notmal T3421A S1141T 2↔ N.D. C3435T I1145I 2↔ N.D. G3751A V1251I 2 N.D. 2, reduced function; 1, increased function; ↔, no change in function; N.D. not determined. Login to comment
6829 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/ Localization ABCB1 MDR1 A61G N21D ࢒ N.D. T307C F103L N.D. N.D. G1199A S400N 1࢒ Normal C2005T R669C ࢒ N.D. G2677T A893S 21࢒ Normal G2677A A893T 1࢒ Notmal T3421A S1141T 2࢒ N.D. C3435T I1145I 2࢒ N.D. G3751A V1251I 2 N.D. 2, reduced function; 1, increased function; ࢒, no change in function; N.D. not determined. 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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No. Sentence Comment
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] Effect of the mutation (C3435T) at exon 26 of the ... Clin Pharmacol Ther. 2002 Apr;71(4):297-303. Nakamura T, Sakaeda T, Horinouchi M, Tamura T, Aoyama N, Shirakawa T, Matsuo M, Kasuga M, Okumura K
Effect of the mutation (C3435T) at exon 26 of the MDR1 gene on expression level of MDR1 messenger ribonucleic acid in duodenal enterocytes of healthy Japanese subjects.
Clin Pharmacol Ther. 2002 Apr;71(4):297-303., [PMID:11956513]

Abstract [show]
The effect of the C3435T mutation at exon 26 of the MDR1 gene on the expression levels of MDR1 messenger ribonucleic acid (mRNA) was evaluated by means of real-time polymerase chain reaction in 51 biopsy specimens of duodenum obtained from 13 healthy Japanese subjects. The mRNA levels of MDR1 were 0.38 +/- 0.15, 0.56 +/- 0.14, and 1.13 +/- 0.42 (mean value +/- SE) in the subjects with the homozygote of wild-type allele (C/C), compound heterozygote with mutant T allele (C/T), and the homozygote of the mutant allele (T/T), respectively, reasonably explaining the lower digoxin serum concentration after administration of a single oral dose to subjects harboring a mutant T allele. Good correlation (r =.797; P <.01) was observed between the mRNA concentrations of MDR1 and CYP3A4 in the individual biopsy specimens. This finding suggested a lower plasma concentration of the substrates for CYP3A4 in subjects harboring the C3435T mutation of the MDR1 gene.

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81 The C3435T mutation is a silent mutation that does not cause amino acid substitution and is suggested to be linked with a mutation at exon 21, position 2677 [G2677(A,T)], producing Ala893Thr and Ala893Ser, respectively.6,11 The effect of the C3435T mutation may reflect that of G2677(A,T), and there may be racial differences in the relation between C3435T and G2677(A,T). Login to comment

[hide] Emerging new technologies in Pharmacogenomics: rap... Pharmacol Ther. 2010 Apr;126(1):69-81. Epub 2010 Feb 4. Ishikawa T, Sakurai A, Hirano H, Lezhava A, Sakurai M, Hayashizaki Y
Emerging new technologies in Pharmacogenomics: rapid SNP detection, molecular dynamic simulation, and QSAR analysis methods to validate clinically important genetic variants of human ABC Transporter ABCB1 (P-gp/MDR1).
Pharmacol Ther. 2010 Apr;126(1):69-81. Epub 2010 Feb 4., [PMID:20138191]

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, by extension, their overall pharmacological effects. There are an increasing number of reports addressing genetic polymorphisms of drug transporters. A key requirement for the development of individualized medicine or personalized therapy is the ability to rapidly and conveniently test patients for genetic polymorphisms and/or mutations. We have recently developed a rapid and cost-effective method for single nucleotide polymorphism (SNP) detection, named Smart Amplification Process 2 (SmartAmp2), which enables us to detect genetic polymorphisms or mutations in 30 to 45min under isothermal conditions without DNA isolation and PCR amplification. Furthermore, high-speed functional screening, quantitative structure-activity relationship (QSAR) analysis, and molecular dynamic (MD) simulation methods have been developed to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function and substrate specificity. 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. This review addresses such new methods for validating genetic polymorphisms of human ABC transporter ABCB1 (P-gp/MDR1) which is critically involved in the pharmacokinetics of drugs.

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361 (A) The allele frequencies of WT (Ala893), A893S (Ser893), and A893T (Thr893) among different ethnic populations. Login to comment
413 To understand the molecular mechanisms underlying the observed differences in the ATPase activity among ABCB1 WT, A893P, A893S, and A893T (Sakurai et al., 2007), we performed MD simulation based on the homology model of ABCB1. Login to comment
441 The initial three-dimensional structure of each variant protein (A893S, A893T, or A893P) was deduced from the ABCB1 structure template by using the LEAP module in the AMBER (Assisted model building and energy refinement) simulation package. Login to comment
452 Thus, MD calculation was performed to simulate the movement of the intracellular loop located between TM10 and TM11 for each variant protein (A893S, A893T, or A893P) as well as the WT. Login to comment
453 Fig. 4B demonstrates the loop structures of WT, A893S, A893T, or A893P calculated from the trajectory data of MD simulations at 310 K (37˚C) for 3 ns. Login to comment
455 The RMSF value of alpha carbon of each amino acid residue was calculated from the trajectory data for the intracellular loop of WT, A893S, A893T, and A893P. Login to comment
478 To functionally validate the non-synonymous polymorphisms of ABCB1 (P-glycoprotein/MDR1) in vitro, we generated SNP variant forms (i.e., S400N, R492C, R669C, I849M, A893P, A893S, A893T, M986V, A999T, P1051A, and G1063A; refer to Fig. 6) and expressed them in Sf9 cells. Login to comment
480 The effect of test compounds on the ATPase activity of ABCB1 WT, A893P, A893S, and A893T. Login to comment
500 SNP Km Vmax Vmax / Km (µM) (nmol/min/mg protein) WT 5.8±2.3 62.4±7.8 10.8 S400N 5.8±2.8 46.7±5.3⁎⁎ 8.0 R492C 5.6±1.9 49.6±10.0⁎ 8.9 R669C 3.2±1.6⁎ 64.7±6.9 20.1 I849M 1.5±0.7⁎⁎ 80.3±9.5⁎⁎ 51.8 A893P 1.5±0.5⁎⁎ 405.2±16.5⁎⁎ 274.6 A893S 11.1±5.4 43.1±7.1⁎⁎ 3.9 A893T 4.3±1.4 98.9±9.5⁎⁎ 22.9 M986V 5.1±1.1 114.9±13.6⁎⁎ 22.5 A999T 2.0±0.8⁎⁎ 143.1±21.2⁎⁎ 70.9 P1051A 6.2±3.0 52.1±13.6 8.4 G1063A 6.2±3.7 117.9±16.4⁎⁎ 19.0 Data are expressed as mean±S.D., n=6. Login to comment

[hide] A synonymous polymorphism in a common MDR1 (ABCB1)... Biochim Biophys Acta. 2009 May;1794(5):860-71. Epub 2009 Mar 11. Fung KL, Gottesman MM
A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function.
Biochim Biophys Acta. 2009 May;1794(5):860-71. Epub 2009 Mar 11., [PMID:19285158]

Abstract [show]
The MDR1 (ABCB1) gene encodes a membrane-bound transporter that actively effluxes a wide range of compounds from cells. The overexpression of MDR1 by multidrug-resistant cancer cells is a serious impediment to chemotherapy. MDR1 is expressed in various tissues to protect them from the adverse effect of toxins. The pharmacokinetics of drugs that are also MDR1 substrates also influence disease outcome and treatment efficacy. Although MDR1 is a well-conserved gene, there is increasing evidence that its polymorphisms affect substrate specificity. Three single nucleotide polymorphisms (SNPs) occur frequently and have strong linkage, creating a common haplotype at positions 1236C>T (G412G), 2677G>T (A893S) and 3435C>T (I1145I). The frequency of the synonymous 3435C>T polymorphism has been shown to vary significantly according to ethnicity. Existing literature suggests that the haplotype plays a role in response to drugs and disease susceptibility. This review summarizes recent findings on the 3435C>T polymorphism of MDR1 and the haplotype to which it belongs. A possible molecular mechanism of action by ribosome stalling that can change protein structure and function by altering protein folding is discussed.

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153 A recent study by Gow et al. suggested that all of the SNPs they tested (N21D, S400N, R669C, A893S, A893T, S1141T, V1251I) produced small changes which in most cases are not statistically significant [59]. Login to comment
185 The occurrence of 2677GNT (A893S) is far more frequent than G2677A (A893T). Login to comment

[hide] The clinical impact of pharmacogenetics on the tre... Epilepsia. 2009 Jan;50(1):1-23. Epub 2008 Jul 8. Loscher W, Klotz U, Zimprich F, Schmidt D
The clinical impact of pharmacogenetics on the treatment of epilepsy.
Epilepsia. 2009 Jan;50(1):1-23. Epub 2008 Jul 8., [PMID:18627414]

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Drug treatment of epilepsy is characterized by unpredictability of efficacy, adverse drug reactions, and optimal doses in individual patients, which, at least in part, is a consequence of genetic variation. Since genetic variability in drug metabolism was reported to affect the treatment with phenytoin more than 25 years ago, the ultimate goal of pharmacogenetics is to use the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. However, determining the practical relevance of pharmacogenetic variants remains difficult, in part because of problems with study design and replication. This article reviews the published work with particular emphasis on pharmacogenetic alterations that may affect efficacy, tolerability, and safety of antiepileptic drugs (AEDs), including variation in genes encoding drug target (SCN1A), drug transport (ABCB1), drug metabolizing (CYP2C9, CYP2C19), and human leucocyte antigen (HLA) proteins. Although the current studies associating particular genes and their variants with seizure control or adverse events have inherent weaknesses and have not provided unifying conclusions, several results, for example that Asian patients with a particular HLA allele, HLA-B*1502, are at a higher risk for Stevens-Johnson syndrome when using carbamazepine, are helpful to increase our knowledge how genetic variation affects the treatment of epilepsy. Although genetic testing raises ethical and social issues, a better understanding of the genetic influences on epilepsy outcome is key to developing the much needed new therapeutic strategies for individuals with epilepsy.

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60 The synonymous 3435C>T polymorphism is in linkage disequilibrium with a synonymous SNP in exon 13 (1236C>T) and a nonsynonymous SNP in exon 22 (2677G>TA), suggesting that the observed functional differences in Pgp, initially attributed to the exon 27 synonymous SNP, may be the result of the associated nonsynonymous polymorphism in exon 22, which results in amino acid exchanges (Ala893Ser or Ala893Thr) (Marzolini et al., 2004). Login to comment

[hide] Interaction of genes from influx-metabolism-efflux... Pharmacogenet Genomics. 2008 Dec;18(12):1041-9. Sharma S, Das M, Kumar A, Marwaha V, Shankar S, Aneja R, Grover R, Arya V, Dhir V, Gupta R, Kumar U, Juyal RC, B K T
Interaction of genes from influx-metabolism-efflux pathway and their influence on methotrexate efficacy in rheumatoid arthritis patients among Indians.
Pharmacogenet Genomics. 2008 Dec;18(12):1041-9., [PMID:19093297]

Abstract [show]
OBJECTIVE: Methotrexate (MTX) is the drug of choice for rheumatoid arthritis (RA) but is effective only in around 60% of treated patients. Bioavailability of MTX may be a major determinant of response status and this may be governed by variations in MTX receptor and transporter genes and genes responsible for polyglutamation and deconjugation. We investigated the contribution of single nucleotide polymorphisms (SNPs) in RFC, FOLR1, FPGS, GGH and MDR1 genes to MTX response in RA patients from North India. METHODS: RA patients recruited using American College of Rheumatology criteria, were categorized into good and poor responders to MTX, based on disease activity score. A total of 17 SNPs from the above mentioned genes were genotyped and tested for association with MTX response using [chi]2 test; logistic regression along with clinical variables; and gene-gene interaction using multifactor dimensionality reduction (MDR). RESULTS: One novel synonymous SNP Ala324Ala (972 G > A) was identified in RFC gene. The CT genotype of C3435T in MDR1 gene conferred almost twice the risk of poor response [[chi]2 = 5.85, P = 0.01, odds ratio (95% confidence interval) = 1.97 (1.13-3.42)] and was retained in binary logistic regression [B = 0.66, P = 0.025, adjusted odds ratio (95% confidence interval) = 1.93(1.09-3.42)]. Significant interaction between SNPs in GGH and MDR1 genes seems promising. CONCLUSION: Interactions between genes coding for deconjugation and transporter seem to be important determinants of MTX response in RA but replication and functional studies would be confirmatory.

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70 Gene polymorphisms and MTX response in RA Sharma et al. 1043 published single nucleotide polymorphisms One commonly investigated SNP rs1051266 (80 G > A, Arg27His, exon 3) of RFC gene; a total of eight SNPs from MDR1 gene including one promoter SNP rs3213619 ( - 129T > C); three commonly analysed exonic SNPs rs1128503 (1236C > T, Gly411Gly, exon 12); triallelic SNP rs2032582 (2677G> T, G > A, Ala893Ser, Ala893Thr, exon 21); and rs1045642 (3435C > T, Ile1145Ile, exon 26); and four splice variants rs28381943, rs2235064, rs2235044 and rs2235032; three SNPs from GGH gene including one promoter SNP rs3758149 ( - 401C > T); two exonic SNPs rs1800909 (16T > C, Cys6Arg, exon 1); and rs11545078 (452C > T, Thr151Ile, exon 5) and one tag SNP rs1544105 G > A through hapmap database (release #21) in the vicinity of FPGS gene were genotyped in the sample set. Login to comment

[hide] Effect of ABCB1 (MDR1) 3435C >T and 2677G >A,T pol... Pharmacol Rep. 2007 May-Jun;59(3):323-9. Bartnicka L, Kurzawski M, Drozdzik A, Plonska-Gosciniak E, Gornik W, Drozdzik M
Effect of ABCB1 (MDR1) 3435C >T and 2677G >A,T polymorphisms and P-glycoprotein inhibitors on salivary digoxin secretion in congestive heart failure patients.
Pharmacol Rep. 2007 May-Jun;59(3):323-9., [PMID:17652833]

Abstract [show]
The aim of the present study was to evaluate the effects of ABCB1 ( MDR1 ) gene polymorphism on P-glycoprotein model substrate, i.e. digoxin, salivary secretion. The study was carried out in 77 patients diagnosed with congestive heart failure administered digoxin, who were subdivided into two groups: 1) co-administered P-glycoprotein inhibitors and 2) without any known P-glycoprotein inhibitors. The ABCB1 2677G >A,T and 3435C >T polymorphisms were evaluated using PCR-RFLP methods. Steady-state digoxin concentrations were measured in blood serum as well as in unstimulated and stimulated saliva using FPIA method. It was found that values of Pearson's coefficient were significantly higher in patients co-administered P-glycoprotein inhibitors in comparison with subjects who were not administered any inhibitor both for stimulated (Pearson's coefficient r = 0.832, p < 0.01) and unstimulated saliva (r = 0.812, p < 0.01). Evaluation of the impact of ABCB1 2677G >A,T and 3435C >T polymorphism on salivary digoxin secretion revealed significant differences in digoxin stimulated saliva/serum ratio between patients stratified by 2677G >A,T genotype (TT, TA> GT, GA> GG, p < 0.01). The results from the present study suggest that administration of P-glycoprotein inhibitors as well as ABCB1 gene polymorphism may affect salivary digoxin secretion.

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24 The 3435C >T SNP is a silent mutation that does not cause amino acid substitution and is suggested to be linked, in a majority of subjects, with the mutation in exon 21, position 2677 (2677G >T,A), producing Ala893Thr and Ala893Ser, respectively [16]. Login to comment

[hide] Implications of genetic polymorphisms in drug tran... Cancer Lett. 2006 Mar 8;234(1):4-33. Epub 2006 Feb 28. Kerb R
Implications of genetic polymorphisms in drug transporters for pharmacotherapy.
Cancer Lett. 2006 Mar 8;234(1):4-33. Epub 2006 Feb 28., [PMID:16504381]

Abstract [show]
Drug transporters are increasingly recognized as a key determinant of drug disposition and response. It is now widely appreciated that expression of the ATP-dependent efflux transporter, MDR1 (ABCB1, P-glycoprotein), in organs such as the gastrointestinal tract, liver and kidney significantly alters the extent of drug absorption and excretion. Moreover, expression of MDR1 at the level of the blood-brain barrier limits the entry of many drugs into the central nervous system. Given such an important role of MDR1 in the drug disposition process, it is not surprising to see increasing focus on the role of single nucleotide polymorphisms (SNPs) in this transporter as a potential determinant of interindividual variability in drug disposition and pharmacological response. However, drug transport is often the result of the concerted action of efflux and uptake pumps located both in the basolateral and apical membranes of epithelial cells. A growing list of membrane-spanning proteins involved in the in- or outward transport of a large variety of drugs has been recognized and characterized over the past few years in almost all tissues, including organic anion and cation transporters (OAT, OCT, solute carrier family SLC22A), organic anion transport proteins (OATP, solute carrier family SLCO, formerly SLC21A), and MRPs (ABCCs), other members of the ATP-binding cassette family. We are just beginning to appreciate their role for drug delivery and disposition and the contribution of genetic polymorphisms in these transport proteins to interindividual variability in the efficacy and safety for pharmacotherapy. This review summarizes the consequences of inherited differences in drug transport for pharmacotherapy. With the main focus on ABCB1, an update of recent advances is given and clinically relevant examples are used to illustrate how heritable differential drug transport can help to explain individual variability in drug response. The pharmacogenetics of other transporters is briefly introduced.

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78 Clinical investigations of genotype-related function of MDR1 have been performed mainly focusing on the silent 3435COT and a non-synonymous variant, the transversion 2677GOT (Ala893Ser) and 2677GOA (Ala893Thr). Login to comment

[hide] Efflux transporters and their clinical relevance. Mini Rev Med Chem. 2005 Feb;5(2):183-95. Fischer V, Einolf HJ, Cohen D
Efflux transporters and their clinical relevance.
Mini Rev Med Chem. 2005 Feb;5(2):183-95., [PMID:15720288]

Abstract [show]
It is increasingly recognized that efflux transporters play an important role, not only in chemo protection e.g. multi-drug resistance, but also in the absorption, distribution, and elimination of drugs. The modulation of drug transporters through inhibition or induction can lead to significant drug-drug interactions by affecting intestinal absorption, renal secretion, and biliary excretion, thereby changing the systemic or target tissue exposure of the drug. Few clinically significant drug interactions that affect efficacy and safety are due to a single mechanism and there is considerable overlap of substrates, inhibitors, and inducers of efflux transporters and drug metabolizing enzymes, such as CYP3A. As well, genetic polymorphisms of efflux transporters have been correlated with human disease and variability of drug exposure. Accordingly, this review will discuss drug interactions and suitable probe substrates, as well as, the clinical relevance of the variability and modulation of efflux transporters and the exploitation of substrates as diagnostic tools. An update is given on inhibitors, which clinically reverse drug resistance and minimize the risk of metabolic interactions.

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149 The C3435T polymorphism is highly linked with the SNP at exon 21, position 2677 (G2677T/A), which results in amino acid changes Ala893Thr and Ala893Ser, respectively, and with C1236T in exon 12 [70, 83]. Login to comment

[hide] Importance of P-glycoprotein at blood-tissue barri... Trends Pharmacol Sci. 2004 Aug;25(8):423-9. Fromm MF
Importance of P-glycoprotein at blood-tissue barriers.
Trends Pharmacol Sci. 2004 Aug;25(8):423-9., [PMID:15276711]

Abstract [show]
P-glycoprotein is the product of the ABCB1 [also known as multidrug resistance 1 (MDR1)] gene. It translocates a broad variety of xenobiotics out of cells. P-glycoprotein was first described in tumor cells that were resistant to various anticancer agents as a result of P-glycoprotein overexpression. P-glycoprotein is not only expressed in tumor cells but also in a broad variety of normal tissues with excretory function (small intestine, liver and kidney) and at blood-tissue barriers (blood-brain barrier, blood-testis barrier and placenta). In particular, following the generation of P-glycoprotein-deficient mice it became clear that this efflux transporter limits the absorption of orally administered drugs, promotes drug elimination into bile and urine, and protects various tissues (e.g. brain, testis and fetus) from potentially toxic xenobiotics. In humans, a considerable interindividual variability in P-glycoprotein tissue expression is observed, and current research is focused on the potential role of ABCB1 polymorphisms and haplotypes that affect P-glycoprotein tissue expression, plasma concentrations of drugs, the frequency of adverse drug reactions and treatment outcome.

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112 The C3435T polymorphism is in linkage disequilibrium with the G2677T/A polymorphism, which results in amino acid exchanges (Ala893Ser or Ala893Thr) [59,60]. Login to comment

[hide] ABC transporters in human lymphocytes: expression,... Expert Opin Drug Metab Toxicol. 2010 May;6(5):571-89. Giraud C, Manceau S, Treluyer JM
ABC transporters in human lymphocytes: expression, activity and role, modulating factors and consequences for antiretroviral therapies.
Expert Opin Drug Metab Toxicol. 2010 May;6(5):571-89., [PMID:20367109]

Abstract [show]
IMPORTANCE OF THE FIELD: ATP-binding cassette (ABC) transporters are a superfamily of efflux pumps that transport numerous compounds across cell membranes. These transporters are located in various human tissues including peripheral blood cells, in particular lymphocytes, and present a high variability of expression and activity. This variability may affect the intracellular concentrations and efficacy of drugs acting within lymphocytes, such as antiretroviral drugs. AREAS COVERED IN THIS REVIEW: This review focuses on the current knowledge about the expression, activity, roles and variability of ABC drug transporters in human lymphocytes. The identified modulating factors and their impact on the intracellular pharmacokinetics and efficacy of antiretroviral drugs are also detailed. WHAT THE READER WILL GAIN: Controversial data regarding the expression, activity and sources of variability of ABC transporters in lymphocytes are discussed. The modulating factors and their pharmacological consequences regarding antiretroviral therapies are also provided. TAKE HOME MESSAGE: Numerous studies have reported conflicting results regarding the expression and activity of ABC drug transporters in lymphocytes. Despite these discrepancies, which may partly result from heterogeneous analytical methods, ABCC1 appears to have the highest expression in lymphocytes and may thus play a predominant role in the resistance to antiretroviral drugs, particularly to protease inhibitors.

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158 Two polymorphisms have been abundantly studied: one polymorphism at the 2677 position of exon 21 that may result in two distinct amino-acid changes, Ala893Ser (G2677T) and Ala893Thr (G2677A), and one synonymous polymorphism in exon 26 (C3435T). Login to comment