ABCMdb

ABCC1 p.Ala893Ser

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] Irinotecan pathway genotype analysis to predict ph... Clin Cancer Res. 2003 Aug 15;9(9):3246-53. Mathijssen RH, Marsh S, Karlsson MO, Xie R, Baker SD, Verweij J, Sparreboom A, McLeod HL
Irinotecan pathway genotype analysis to predict pharmacokinetics.
Clin Cancer Res. 2003 Aug 15;9(9):3246-53., 2003-08-15 [PMID:12960109]

Abstract [show]
PURPOSE: The purpose was to explore the relationships between irinotecan disposition and allelic variants of genes coding for adenosine triphosphate binding cassette transporters and enzymes of putative relevance for irinotecan. EXPERIMENTAL DESIGN: Irinotecan was administered to 65 cancer patients as a 90-min infusion (dose, 200-350 mg/m(2)), and pharmacokinetic data were obtained during the first cycle. All patients were genotyped for variants in genes encoding MDR1 P-glycoprotein (ABCB1), multidrug resistance-associated proteins MRP-1 (ABCC1) and MRP-2 (canalicular multispecific organic anion transporter; ABCC2), breast cancer resistance protein (ABCG2), carboxylesterases (CES1, CES2), cytochrome p450 isozymes (CYP3A4, CYP3A5), UDP glucuronosyltransferase (UGT1A1), and a DNA-repair enzyme (XRCC1), which was included as a nonmechanistic control. RESULTS: Eighteen genetic variants were found in nine genes of putative importance for irinotecan disposition. The homozygous T allele of the ABCB1 1236C>T polymorphism was associated with significantly increased exposure to irinotecan (P = 0.038) and its active metabolite SN-38 (P = 0.031). Pharmacokinetic parameters were not related to any of the other multiple variant genotypes, possibly because of the low allele frequency. The extent of SN-38 glucuronidation was slightly impaired in homozygous variants of UGT1A1*28, although differences were not statistically significant (P = 0.22). CONCLUSIONS: It is concluded that genotyping for ABCB1 1236C>T may be one of the factors assisting with dose optimization of irinotecan chemotherapy in cancer patients. Additional investigation is required to confirm these findings in a larger population and to assess relationships between irinotecan disposition and the rare variant genotypes, especially in other ethnic groups.

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136 Table 4 Genotype and Allele frequencies for the studied genes Polymorphisma Nomenclature Descriptionb Genotype frequenciesc Allele frequencies (95% CI)d Wt Het Var p q r ABCB1 1236 CϾT n/ae G411G 23 15 8 0.66 (0.52-0.78) 0.34 (0.22-0.48) ABCB1 3435 CϾT n/a E1143E 16 35 8 0.57 (0.44-0.69) 0.43 (0.31-0.56) ABCB1 2677 GϾT/A n/a A893S or T 12 23/4 13/1 0.48 (0.35-0.61) 0.47 (0.34-0.60) 0.05 (0.02-0.14) ABCC1 14008 GϾA n/a intron 27 32 27 5 0.71 (0.59-0.81) 0.29 (0.19-0.41) ABCC1 462 CϾT n/a P154P 65 0 0 1.00 0.00 ABCC1 34215 CϾG n/a intron 18 0 20 40 0.17 (0.1-0.28) 0.83 (0.72-0.90) ABCC2 156231 AϾG n/a intron 3 65 0 0 1.00 0.00 ABCG2 623TϾC n/a F208S 63 0 0 1.00 0.00 CES1 1440 AϾT n/a L480F 64 0 0 1.00 0.00 CES1 1525 AϾC n/a N509H 60 1 0 0.99 (0.92-1) 0.01 (0-0.08) CES2 1647 CϾT n/a L549L 56 1 0 0.99 (0.92-1) 0.01 (0-0.08) CYP3A4 -392 AϾG CYP3A4*1B Promoter 46 3 0 0.97 (0.88-0.99) 0.03 (0.01-0.12) CYP3A4 15713 TϾC CYP3A4*2 S222P 39 0 0 1.00 0.00 CYP3A4 23172 TϾC CYP3A4*3 M445T 62 2 0 0.98 (0.91-1) 0.02 (0-0.09) CYP3A5 22893 GϾA CYP3A5*3C Splice variant 56 8 0 0.94 (0.85-0.98) 0.06 (0.02-0.15) CYP3A5 30597 GϾA CYP3A5*6 Splice variant 63 0 0 1.00 0.00 UGT1A1 (TA)n f UGT1A1*28 Promoter 34 22 2 0.78 (0.66-0.87) 0.22 (0.13-0.34) UGT1A1 1456 TϾG UGT1A1*7 Y486D 62 0 0 1.00 0.00 XRCC1 26304 CϾT n/a R194W 35 8 0 0.91 (0.79-0.96) 0.09 (0.04-0.21) XRCC1 27466 GϾA n/a R280H 60 2 0 0.98 (0.91-1) 0.02 (0-0.09) XRCC1 28152 GϾA n/a R399Q 25 27 5 0.68 (0.55-0.79) 0.32 (0.21-0.45) a Number represents position in nucleotide sequence. Login to comment

[hide] Diflomotecan pharmacokinetics in relation to ABCG2... Clin Pharmacol Ther. 2004 Jul;76(1):38-44. Sparreboom A, Gelderblom H, Marsh S, Ahluwalia R, Obach R, Principe P, Twelves C, Verweij J, McLeod HL
Diflomotecan pharmacokinetics in relation to ABCG2 421C>A genotype.
Clin Pharmacol Ther. 2004 Jul;76(1):38-44., [PMID:15229462]

Abstract [show]
OBJECTIVE: The adenosine triphosphate-binding cassette transporter ABCG2 (breast cancer resistance protein [BCRP]) functions as an efflux transporter for many drugs, including the topoisomerase I inhibitor diflomotecan, and is expressed at high levels in the intestine and liver. We performed an exploratory analysis to evaluate the effects of the natural allelic variant ABCG2 421C>A on the pharmacokinetics of diflomotecan. METHODS: The drug was administered to 22 adult white patients with cancer as a 20-minute infusion (dose, 0.10-0.27 mg), followed 2 weeks later by an oral solution (dose, 0.10-0.35 mg). RESULTS: The ABCG2 421C>A genotype significantly affected the pharmacokinetics of diflomotecan; in 5 patients heterozygous for this allele, plasma levels after intravenous drug administration were 299% (P =.015) of those in 15 patients with wild-type alleles, at mean values of 138 ng x h/mL x mg(-1) (95% confidence interval, 11.3-264 ng x h/mL x mg(-1)) versus 46.1 ng x h/mL x mg(-1) (95% confidence interval, 25.6-66.7 ng x h/mL x mg(-1)), respectively. Diflomotecan levels were not significantly influenced by 11 known variants in the ABCB1, ABCC2, cytochrome P450 (CYP) 3A4, and CYP3A5 genes. CONCLUSION: These findings provide the first evidence linking variant ABCG2 alleles to altered drug exposure and suggest that interindividual variability in substrate drug effects might be influenced, in part, by ABCG2 genotype.

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56 Frequencies for studied variant genes and genotype-phenotype relationships Polymorphism and nomenclature Effect Allele frequencies Ratio (q/p) for intravenous AUC Ratio (q/p) for oral AUC p q Value† P value Value† P value ABCG2 421CϾA Q141K 0.88 0.12 2.98 .015 1.15 .74 ABCC2-24CϾT 5'-UTR 0.89 0.11 0.868 .82 0.890 .78 ABCC2 1249GϾA V417I 0.86 0.14 1.06 .92 2.10 .063 ABCC2 156231AϾG Intron 3 1.00 0.00 NA NA NA NA ABCB1 1236CϾT‡ (ABCB1*8§) G411G 0.40 0.60 0.877 .82 0.585 .31 ABCB1 2677GϾA/T࿣ (ABCB1*7§) A893S/T 0.63 0.34/0.03 0.784 .61 1.27 .55 ABCB1 3435CϾT‡ (ABCB1*6§) I1145I 0.45 0.55 0.978 .97 0.955 .93 CYP3A4 -392AϾG (CYP3A4*1B) Promotor 0.91 0.09 0.731 .63 0.834 .75 CYP3A4 15713TϾC‡ (CYP3A4*2) S222P 1.00 0.00 NA NA NA NA CYP3A4 23172TϾC (CYP3A4*3) M445T 1.00 0.00 NA NA NA NA CYP3A5 22893GϾA‡ (CYP3A5*3) Splice Variant 0.86 0.14 0.808 .77 0.813 .76 CYP3A5 30597GϾA (CYP3A5*6) Splice Variant 1.00 0.00 NA NA NA NA AUC, Area under plasma concentration-time curve normalized to dose (ie, observed AUC/dose in milligrams); NA, not available. 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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90 A detailed analysis of the potential functional consequences of different ABCB1 variants has not yet been performed, except for the five most common non-synonymous coding SNPs (i.e., Asn21Asp, Phe103Leu, Ser400Asn, Ala893Ser/Thr, and Ala998Thr) as assessed by a vaccinia virus-based transient expression system [74]. Login to comment
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
93 One of the tested SNPs, the ABCB1 G2677T/A [75], contains a tri-allelic polymorphism (with G at nucleotide 2677 found in the wild-type sequence, and with A or T at that position being the two possible variants), which results in an amino acid change in exon 21 (Ala893Ser/Thr). 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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706 Mickley et al. (1998) discovered 2 non-synonymous SNP, a 2677G>T transversion in exon 21 and a 2995G>A transition in exon 24 of ABCB1 leading to an A893S and A999T exchanges, respectively. Login to comment
732 Since 3435C>T is linked with 2677G>T/A, leading to an A893S/T amino acid exchange, it was speculated whether this SNP could be causal for P-gp activity. Login to comment
737 Very recently, significantly differences of A893S/T- overexpressing membrane vesicles from Sf9 insect cells for vincristin could be observed. Login to comment
761 0.09d c. 61 A>G N21D 0.11d IVS 5-35 G>C intronic 0.006c IVS 5-25 G>T intronic 0.16c IVS 6+139 C>T intronic 0.37d c. 548 A>G N183S 0.01e c. 1199 G>A S400N 0.05d c. 1236 C>T synonymous 0.41d IVS 12+44 C>T intronic 0.05d c. 1474 C>T R492C 0.01e IVS 17-76 T>A intronic 0.46d IVS 17+137 A>G intronic 0.006c c. 2650 C>T synonymous 0.03e c. 2677 G>T/A A893S/T 0.42d /0.02d c. 2956 A>G M986V 0.005b c. 3320 A>C Q1107P 0.002d c. 3396 C>T synonymous 0.03c c. 3421 T>A S1141T 0.00c c. 3435 C>T synonymous 0.54e c. 4030 G >C synonymous 0.005b c. 4036 A>G synonymous 0.30b a Taniguchi et al. (2003). Login to comment
821 In essence, further studies on ABCB1 polymorphisms confirmed these associations for 2677G>T/A (Ala893Ser/ Thr) or special ABCB1 haplotype constellations (Brant et al., 2003; Potocnik et al., 2004; Ho et al., 2006). Login to comment

[hide] Pharmacogenetics/genomics of membrane transporters... Cancer Metastasis Rev. 2007 Mar;26(1):183-201. Huang Y
Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy.
Cancer Metastasis Rev. 2007 Mar;26(1):183-201., [PMID:17323126]

Abstract [show]
Inter-individual variability in drug response and the emergence of adverse drug reactions are main causes of treatment failure in cancer therapy. Recently, membrane transporters have been recognized as an important determinant of drug disposition, thereby affecting chemosensitivity and -resistance. Genetic factors contribute to inter-individual variability in drug transport and targeting. Therefore, pharmacogenetic studies of membrane transporters can lead to new approaches for optimizing cancer therapy. This review discusses genetic variations in efflux transporters of the ATP-binding cassette (ABC) family such as ABCB1 (MDR1, P-glycoprotein), ABCC1 (MRP1), ABCC2 (MRP2) and ABCG2 (BCRP), and uptake transporters of the solute carrier (SLC) family such as SLC19A1 (RFC1) and SLCO1B1 (SLC21A6), and their relevance to cancer chemotherapy. Furthermore, a pharmacogenomic approach is outlined, which using correlations between the growth inhibitory potency of anticancer drugs and transporter gene expression in multiple human cancer cell lines, has shown promise for determining the relevant transporters for any given drugs and predicting anticancer drug response.

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124 Moreover, Letourneau et al. examined 10 non-synonymous ABCC1 SNPs to determine Table 2 Summary of genetic variants in ABC transporters ABCB1, ABCC1, ABCC2 and ABCG2 involved in cancer chemotherapy Variants (location, effect) Phenotype Drug Sample Reference ABCB1 +103T>C (5'flanking, non-coding) Increased transcription Doxorubicin vincristine osteosarcoma Stein et al., 1994 [19] +8T>C (5'flanking, non-coding) Unknown Leukemia Rund et al., 1999 [21] 1236C>T (exon12, synonymous) Higher expression AML blasts Illmer et al., 2002 [47] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Higher exposure Irinotecan, SN-38 Cancer patients Mathijssen et al., 2003 [45] 2677G>T/A (exon21, A893S/T) Lower expression placenta Tanabe et al., 2001 [42] Lower expression placenta Hitzl et al., 2004 [37] Higher expression AML blasts Illmer et al., 2002 [47] Allele specific expression Cell lines, lymphoma Mickley et al., 1998 [22] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Survival leukemia Illmer et al., 2002 [47] Survival leukemia van den Heuvel-Eibrink et al., 2001 [48] Worse survival AML blasts Kim et al., 2006 [10] Higher efficacy Paclitaxel Ovarian cancer Green et al., 2006 [50] 2995G>A (exon24, A999T) None Cell lines, lymphoma Mickley et al., 1998 [22] 3435C>T (exon26, synonymous) Lower expression Duodenal protein Hoffmeyer et al., 2000 [26] Lower expression placenta Hitzl et al., 2004 [37] Higher expression Intestine mRNA Nakamura et al., 2002 [32] Higher expression AML blasts Illmer et al., 2002 [47] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Lower efflux Digoxin CD56+ NK cells Hitzl et al., 2001 [27] Higher plasma level Digoxin Healthy volunteers Hoffmeyer et al., 2000 [26] Higher AUC Cyclosporin transplant patients Bonhomme-Faivre et al., 2004 [36] Lower CNS relapse Cancer patients Stanulla et al., 2005 [46] Better survival leukemia Illmer et al., 2002 [47] Higher efficacy Breast cancer Kafka et al., 2003 [49] Higher activity, worse survival AML Kim et al., 2006 [10] Better survival Platinums Esophageal cancer Wu et al., 2006 [43] No difference Docetaxel patients Puisset et al., 2004 [41] No difference Irinotecan Cancer patients Mathijssen et al., 2004 [39] No difference Vincristine patients Plasschaert et al., 2004 [40] No difference colon Taniguchi et al., 2003 [24] ABCC1 -260G>C (5'flanking, non-coding) Higher activity Transfected cell line Wang et al., 2005 [62] Table 2 (Continued) Variants (location, effect) Phenotype Drug Sample Reference 128G>C (exon2, C43S) Reduced resistance Vincristine, arsenite Transfected cell line Leslie et al., 2003 [60] 1299G>T (exon10, R433S) Reduced transport of LTC4, increased resistance to doxorubicin Leukotriene C4, doxorubicin Transfected cell line Conrad et al., 2002 [59] 2012G>T (exon16, G671V) No change in activityLeukotriene C4 Transfected cell line Conrad et al., 2001 [58] Heart toxicity Doxorubicin nLon-Hodgkin lymphoma Wojnowski et al., 2005 [63] 2965G>A (exon22, A989T) Reduced transport Estradiol 17β-glucuronide Transfected cell line Letourneau et al., 2005 [61] ABCC2 1271A>G (exon10, R421G) Reduced drug elimination, increased nephrotoxicity Methotrexate One lymphoma patient Hulot et al., 2005 [79] 3972C>T (exon28, nonsynonymous) Reduced drug clearance Irinotecan Cancer patients Innocenti et al., 2004 [80] ABCG2 376C>T (exon4, Q126stop) Reduced transport Porphyrin Trensfected cell Tamura et al., 2006 [104] 421C>A (exon5, Q141K) Lower expression Transfected cell lines Imai et al., 2002 [94] Lower expression Transfected cell lines Kondo et al., 2004 [95] Lower expression Placenta Kobayashi et al., 2005 [98] Reduced ATPase activity Trensfected cell lines Mizuarai et al., 2004 [97] Higher plasma levels Diflomotecan patients Sparreboom et al., 2004 [100] Increased bioavailability Topotecan patients Sparreboom et al., 2005 [101] Increased bioavailability 9-Aminocamptothecin patients Zamboni et al., 2006 [81] Increased drug accumulation Imatinib Transfected cell lines Gardner et al., 2006 [96] Increased drug accumulation Topotecan Trensfected cell lines Imai et al., 2002 [94] No difference Imatinib patients Gardner et al., 2006 [96] No difference intestine Zamber et al., 2003 [99] No difference MTX Trensfected cell lines Kondo et al., 2004 [95] the effects on expression and function of this transporter in transfected HEK293T cells [61]. Login to comment
57 2677G>T in exon 21 and 2995G>A/T in exon 24 were reported by Mickley et al. [22], leading to amino acid changes of A893S and A999T, respectively. 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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300 The first SNP reported for human Pgp was the G2677T variant, which is a nonsynonymous SNP resulting in a change in the coding sequence, A893S. Login to comment
303 One common haplotype includes the SNPs C1236T (exon 12, synonymous), G2677T (exon 21, nonsynonymous, A893S) and C3435T (exon 26, synonymous), and is found frequently in European Americans, whereas C1236C-G2677T-C3435C haplotype is common in Africans [135]. Login to comment
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] 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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227 [112] reported that the C3435T, as well as the synonymous C1236T (G411G) and the nonsynonymous G2677T (A893S) polymorphisms were expressed at equivalent levels at the cell surface. Login to comment
228 Similar results for the A893S SNP were reported by Kimchi-Sarfaty et al. Login to comment
229 [113], who showed that HeLa cells transfected with either the wild-type or the ABCB1 polymorphisms A61G (N21D), T307C (F103L), G1199A (S400N), G2677T (A893S) and G2995A (A998T) expressed the transporter at the cell surface. Login to comment
230 Additionally, cells transfected with double mutants (N21D-S400N, N21D-A893S, and S400N-A893S) revealed similar ABCB1 cell surface expression [113]. 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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52 Functional Significance of ABCB1 SNPs Table6.3 Frequency of ABCB1 genetic variants in Caucasians, position on DNA, putative effect, and frequencies (134) Position Amino acid or effect Frequency of the variant allele 5'-Flanking -2903 T>C 0.02a 5'-Flanking -2410 T>C 0.10a 5'-Flanking -2352 G>A 0.28a 5'-Flanking -1910 T>C 0.10a 5'-Flanking -1717 T>C 0.02a 5'-Flanking -1325 A>G 0.02a 5'-Flanking -934 A>G 0.10a 5'-Flanking -692 T>C 0.10a 5'-Flanking -41 A>G 0.09b IVS 1a -145 C>G 0.02b IVS 1b -129 T>C 0.06b IVS 1b 12 T>C 0.06c IVS 2 -1 G>A 0.09d c. 61 A>G N21D 0.11d IVS 5 -35 G>C Intronic 0.006c IVS 5 -25 G>T Intronic 0.16c IVS 6 +139 C>T Intronic 0.37d c. 548 A>G N183S 0.01e c. 1199 G>A S400N 0.05d c. 1236 C>T Synonymous 0.41d IVS 12 +44 C>T Intronic 0.05d c. 1474 C>T R492C 0.01e IVS 17 -76 T>A Intronic 0.46d IVS 17 +137 A>G Intronic 0.006c c. 2650 C>T Synonymous 0.03e c. 2677 G>T/A A893S/T 0.42d /0.02d c. 2956 A>G M986V 0.005b c. 3320 A>C Q1107P 0.002d c. 3396 C>T Synonymous 0.03c c. 3421 T>A S1141T 0.00c c. 3435 C>T Synonymous 0.54d c. 4030 Synonymous 0.005b c. 4036 Synonymous 0.30b References: a [42], b [26], c [25], d [28], e [23] with lower activity or expression in Caucasians. Login to comment
76 Table6.4 Functional significance of ABCB1 genetic variants and relevance for clinical outcome Position Amino acid exchange Effect of variant 5'-Flanking -2410 T>C Decreased mRNAa 5'-Flanking -692 T>C Decreased mRNAa c. 571 G>A G191R Reduced chemotherapy resistanceb c. 1199 G>A S400N Elevated activityc c. 1236 C>T Synonymous Increased imatinib disposition and therapy responsed c. 2677 G>T/A A893S/T In vitro increased vmax ,q no effect on vincristine,e increased imatinib response in CMLd c. 3435 C>T Synonymous Decreased mRNA and protein expression,f, g decreased invitro transport,h no effect on expression and bioavailability of talinolol,i no effect on invitro transport,j, k decreased digoxin bioavailability,l increased etoposid disposition,m no effect on AML or ALL outcome,k better prognosis of multiple myeloma,n better chemotherapy response in breast cancer,o no effect in colon cancerp References: a [42], b [69], c [38], d [53], e [51], f [23], g [64], h [31], i [39], j [135], k [65-67], l [40, 41], m [52], n [68], o [74], p [70, 71], q [36] As mentioned earlier, the first systematic study on ABCB1 genetic variability and its association to expression and bioavailability was the first one, showing an association of 3435C>T with digoxin plasma levels. Login to comment
59 The missense variant 2677G>T/A coding for the three different amino acids A893S/T exhibits altered transport properties in membrane vesicles from Sf9 insect cells, overexpressing human ABCB1. 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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45 There are three single-nucleotide polymorphisms (SNPs) that are common in most ethnic groups and demonstrate strong linkage disequilibrium: the synonymous transition at nucleotide 1236C[T (Gly411Gly) in exon 12, the non-synonymous tri-allelic transition 2677G[T/A (Ala893Ser/ Thr) in exon 21, and the synonymous transition 3435C[T (Ile1145Ile) in exon 26. Login to comment
46 Of these SNPs, only the 2677G[T/ A (Ala893Ser/Thr) transition causes an amino acid change within a structurally important transmembrane domain of the translated protein, and the effects of this transition are controversial and drug-specific [15, 22, 28-30]. Login to comment
82 Many of the recent publications regarding transporter genotyping have utilized restriction fragment length polymorphism (RFLP) analysis or direct sequencing, although several other methods of genotyping are available such as resequencing, allele-specific PCR, TaqMan PCR, Fluorescence Resonance Energy Transfer (FRET), etc. Table 2 includes polymerase chain reaction (PCR) and direct Table 2 Primers used to amplify selected polymorphisms in the ABCB1, ABCG2, OATP1B1, and OATP1B3 genes Transporter polymorphism Forward primer Reverse primer Ref. ABCB1 1236C[T PCR amplification 50 -GGCACAAACCAGATAATATTAAGG-30 50 -TATCCTGTCCATCAACACTGACC-30 # Nested PCR 50 -GTTCACTTCAGTTACCCATCTCG-30 50 -TCCTGTCCATCAACACTGACCTG-30 # Sequencing PCR 50 -GTCAGTTCCTATATCCTGTGTCTG-30 50 -TCGCATGGGTCATCTCACCATC-30 # ABCB1 2677G[T/A (A893S/T) PCR amplification 50 -AGGCTATAGGTTCCAGGCTTGC-30 50 -AGAACAGTGTGAAGACAATGGCC-30 # Nested PCR 50 -CCCATCATTCGAATAGCAGGAG-30 50 -GAACAGTGTGAAGACAATGGCCT-30 # Sequencing PCR 50 -ATCCTTCATCTATGGTTGGCAAC-30 50 -TGAGTCCAAGAACTGGCTTTGC-30 # ABCB1 3435C[T PCR amplification 50 -ATCTCACAGTAACTTGGCAGTTTC-30 50 -AACCCAAACAGGAAGTGTGGCC-30 # Sequencing PCR 50 -GCTGGTCCTGAAGTTGATCTGTG-30 50 -AAACAGGAAGTGTGGCCAGATGC-30 # ABCG2 421C[T PCR amplification 50 -TGGCAAATCCTTGTATGAAGCAG-30 50 -TTCACGTACAACACCACATTGCC-30 # Sequencing PCR 50 -GCAGGTTCATCATTAGCTAGAAC-30 50 -CCTACTTATGCTGATCATGAGC-30 # OATP1B1*1b PCR amplification 50 -GCAAATAAAGGGGAATATTTCTC-30 50 -AGAGATGTAATTAAATGTATAC-30 [45] RFLP enzyme ClaI OATP1B1*5 PCR amplification 50 -GTTAAATTTGTAATAGAAATGC-30 50 -GTAGACAAAGGGAAAGTGATCATA-30 [45] Allele specific PCR primers WT 50 -CATACATGTGGATATATGT-30 N/A [45] MT 50 -CATACATGTGGATATATGC-30 D OATP1B3 334T[G (S112A) PCR amplification 50 -CCTTCACAGTTAAATTACATGGTC-30 50 -TATTCATTTCATATAAAACTGTATACC-30 # Sequencing PCR 50 -GGGCATATTTGCATTCATTTGGG-30 50 -CATGATAAATAAAGAAATACATGATG-30 # OATP1B3 699G[A (M233I) PCR amplification 50 -TCCTTGTATTTAGGTAACGTACAG-30 50 -TCAAGTTTGGTTATTTTGGATCAAG-30 # Sequencing PCR 50 -GATCTACCCTTGAAATAATAATGTC-30 50 GTAAAAGCAAAGTATAAATAGGAGC-30 # OATP1B3 1564G[T (G522C) PCR amplification 50 -ATATACAGAATTTCATACACTAATTTC-30 50 -AATTCTAAGAAAATGCATTCTCAAAG-30 # Sequencing PCR 50 -TATTTTGCCTTCACTATTAAGCAAC-30 50 -AATATGAATTTGAGCTCAAAATACAG-30 # Primers are used for direct sequencing following amplification from genomic DNA, unless otherwise indicated # Denotes previously unpublished primer sequencing PCR primers that are currently used in the field to amplify polymorphic regions of DNA. Login to comment

[hide] ABC drug transporters: hereditary polymorphisms an... Pharmacogenomics. 2001 Feb;2(1):51-64. Kerb R, Hoffmeyer S, Brinkmann U
ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2.
Pharmacogenomics. 2001 Feb;2(1):51-64., [PMID:11258197]

Abstract [show]
Transport by ATP-dependent efflux pumps, such as P-glycoprotein (PGP) and multi-drug resistance related proteins (MRPs), influences bioavailability and disposition of drugs. These efflux pumps serve as defence mechanisms and determine bioavailability and CNS concentrations of many drugs. However, despite the fact that substantial data have been accumulated on the structure, function and pharmacological role of ABC transporters and even though modification of PGP function is an important mechanism of drug interactions and adverse effects in humans, there is a striking lack of data on variability of the underlying genes. This review focuses on the human drug transporter proteins PGP (MDR1) and the multi-drug resistance proteins MRP1 and MRP2. An overview is provided of pharmacologically relevant genetic, structural and functional data as well as on hereditary polymorphisms, their phenotypical consequences and pharmacological implications.

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97 SNP Region N Frequency of SNPs (%) Effect Heterozygous Homozygous Observed Estimated T-12C E1 85 11.8 0 0.4 Non-coding G-1A E2 188 11.2 0 0.4 TL initiation A61G E2 188 17.6 0.5 0.81 Asn21Asp G-25T I4 85 26 3.5 2.3 G-35C I4 85 1.2 0 0.01 # T307C E5 85 1.2 0 0.01 Phe103Leu C+139T I5 85 48.2 16.5 16.8 C+145T I5 85 2.4 0 0.01 G1199A E11 85 12.9 0 0.4 Ser400Asn C1236T E12 188 48.9 13.3 14.4 Gly412Gly # C+44T I12 188 11.7 0 0.4 T-76A I16 85 45.9 22.4 20.3 A+137G I17 85 1.2 0 0.01 G2677T E21 83b 43.4 42.2 38.4 Ala893Ser G2995A E24 36b 11.1 38.4 Ala999Thr C3435T E26 537 47.7 26.4 24.1 Ile1145Ile C3396T E26 188 0.53 0 0.01 Wobble § MDR1 sequences gb:AC002457 and AC005068 are defined as 'wild type`. 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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101 or Ref sequence; locus Frequencies Fold-increase of nelfinavir AUCintracell Significance AA Aa aa Aa2 AA Aa aa Aa2 chi-squared P-value ABCB1 IVS 1 - 80delG rs3214119 27 1 1 1.0 0.03 0.85 c.61A > G (N21D) rs9282564 26 2 1 2.5 3.85 0.05 TAG1 rs3789243 7 17 3 1 0.8 0.6 1.23 0.54 c.1199G > A (S400N) rs2229109 24 2 1 0.9 0.62 0.43 TAG5 rs1128503 4 18 5 1 0.8 1.3 3.33 0.19 TAG6 rs2235046 6 18 3 1 0.6 0.7 4.43 0.11 c.2677G > T (A893S) rs2032582 4 17 5 1 1 1.0 1.7 1.2 6.42 0.09 IVS 21 + 49T > C rs2032583 19 8 1 0.6 3.45 0.06 TAG8, 3435C > T rs1045642 4 18 6 1 1.4 2.1 6.35 0.04 IVS 26 + 59T > G rs2235047 24 2 1 1.0 0.02 0.89 IVS 26 + 80T > C rs2235048 3 17 6 1 1.3 2.4 7.09 0.03 TAG11 rs1186746 16 10 1 1 1.1 0.3 2.46 0.29 TAG12 rs1186745 17 9 1 1 0.7 1.0 0.33 0.85 ABCC1 c.816G > A NM_004996; c.1012G > A 27 1 1 1.5 1.05 0.30 c.825T > C rs246221 13 11 3 1 1.5 0.7 3.99 0.14 c.1062T > C rs35587 13 11 3 1 1.5 0.7 3.02 0.22 IVS 9 + 8A > G rs35588 13 11 3 1 1.5 0.7 3.02 0.22 IVS 10 + 64C > T NC_000016; g.98791C > T 23 3 1 0.4 1.97 0.16 ABCC2 g. Login to comment
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] 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] 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
73 Both polymorphisms, G2677T/A and G2995A, resulting in amino acid exchanges in exon 21 (Ala893Ser/Thr) and exon 24 (Ala999Thr), respectively, are located in the second transmembrane domain, the exon G2995A polymorphism closer to the ABC domain. Login to comment
86 However, a recent publication characterized the functional consequences of five coding SNPs (Asn21Asp, Phe103Leu, Ser400Asn, Ala893Ser, Ala999Thr) using a vaccinia virus-based transient expression system (40a). 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
164 Importantly, the MDR1*13 haplotype encodes the Ala893Ser change in P-glycoprotein. 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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84 Two amino acid substitutions, Gly185Val and Ala893Ser, were detected in MDR1 isolated from normal human adrenal glands, and the latter was suggested to reflect a genetic polymorphism. Login to comment
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
99 It has been confirmed that C3435T is in significant linkage disequilibrium (LD) with C1236T and G2677T, the latter resulting in Ala893Ser [73,74,84-88]. 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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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] P-glycoprotein: tissue distribution, substrates, a... Handb Exp Pharmacol. 2011;(201):261-83. Cascorbi I
P-glycoprotein: tissue distribution, substrates, and functional consequences of genetic variations.
Handb Exp Pharmacol. 2011;(201):261-83., [PMID:21103972]

Abstract [show]
P-glycoprotein (ABCB1, MDR1) belongs to the ABC transporter family transporting a wide range of drugs and xenobiotics from intra- to extracellular at many biological interfaces such as the intestine, liver, blood-brain barrier, and kidney. The ABCB1 gene is highly polymorphic. Starting with the observation of lower duodenal protein expression and elevated digoxin bioavailability in relation to the 3435C>T single nucleotide polymorphism, hundreds of pharmacokinetic and outcome studies have been performed, mostly genotyping 1236C>T, 2677G>T/A, and 3435C>T. Though some studies pointed out that intracellular concentrations of anticancer drugs, for example, within lymphocytes, might be affected by ABCB1 variants resulting in differential outcome, current knowledge of the functional significance genetic variants of ABC membrane transporters does not allow selection of a particular SNP to predict an individual's pharmacokinetics.

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60 These SNPs caused an Ala893Ser and Ala999Thr exchange, respectively. Login to comment
81 Table 2 Frequency of ABCB1 genetic variants in Caucasians, position on DNA, putative effect, and frequencies [according to Cascorbi (2006) and Cascorbi and Haenisch (2010)] Position Amino acid or effect Frequency of the variant allele Association to expression, kinetics or drug response 50 -flanking À2903 T>C 0.02a 50 -flanking À2410 T>C 0.10a Decreased mRNAa 50 -flanking À2352 G>A 0.28a 50 -flanking À1910 T>C 0.10a 50 -flanking À1717 T>C 0.02a 50 -flanking À1325 A>G 0.02a 50 -flanking À934 A>G 0.10a 50 -flanking À692 T>C 0.10a Decreased mRNAa 50 -flanking À41 A>G 0.09b IVS 1a À145 C>G 0.02b IVS 1b À129 T>C 0.06b IVS 1b 12 T>C 0.06c IVS 2 À1 G>A 0.09d c. 61 A>G N21D 0.11d IVS 5 À35 G>C Intronic 0.006c IVS 5 À25 G>T Intronic 0.16c IVS 6 þ139 C>T Intronic 0.37d c. 548 A>G N183S 0.01e c. 571 G>A G191R 0.07f Reduced chemotherapy resistancef c. 1199 G>A S400N 0.05d c. 1199 C>T S400I 0.02g Elevated activityg c. 1236 C>T Synonymous 0.41d Increased imatinib disposition and therapy responseh IVS 12 þ44 C>T Intronic 0.05d c. 1474 C>T R492C 0.01e IVS 17 À76 T>A Intronic 0.46d IVS 17 þ137 A>G Intronic 0.006c c. 2650 C>T Synonymous 0.03e c. 2677 G>T/A A893S/T 0.42d /0.02d In vitro increased vmax,i increased imatinib response in CMLh c. 2956 A>G M986V 0.005b c. 3320 A>C Q1107P 0.002d c. 3396 C>T Synonymous 0.03c c. 3421 T>A S1141T 0.00c c. 3435 C>T Synonymous 0.54d Decreased mRNA and protein expression,e, k decreased in vitro transport,l no effect on expression and bioavailability of talinolol,m no effect on in vitro transport,n, o decreased digoxin (continued) 4.2.1 Digoxin The heart glycoside digoxin is widely accepted as typical P-glycoprotein substrate. Login to comment
75 The missense variant 2677G>T/A coding for the three different amino acids A893S/T exhibits altered transport properties in membrane vesicles from Sf9 insect cells, overexpressing human ABCB1. 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
6892 Consistent with enhanced in vitro transport activity, the Ala893Ser ABCB1 (MDR1) variant is associated with reduced plasma fexofenadine concentrations (Table 19) (Kim et al., 2001). 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
6889 Consistent with enhanced in vitro transport activity, the Ala893Ser ABCB1 (MDR1) variant is associated with reduced plasma fexofenadine concentrations (Table 19) (Kim et al., 2001). Login to comment

[hide] Common variants in ABCB1, ABCC2 and ABCG2 genes an... Gynecol Oncol. 2012 Mar;124(3):575-81. Epub 2011 Nov 21. Tian C, Ambrosone CB, Darcy KM, Krivak TC, Armstrong DK, Bookman MA, Davis W, Zhao H, Moysich K, Gallion H, DeLoia JA
Common variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes among women with advanced stage ovarian cancer treated with platinum and taxane-based chemotherapy: a Gynecologic Oncology Group study.
Gynecol Oncol. 2012 Mar;124(3):575-81. Epub 2011 Nov 21., [PMID:22112610]

Abstract [show]
PURPOSE: Efflux transporters of the ATP-binding cassette (ABC) family are major determinants of chemoresistance in tumor cells. This study examined associations between functional variants in ABCB1, ABCC2 and ABCG2 genes and clinical outcomes in patients with epithelial ovarian/primary peritoneal cancer (EOC/PPC) following platinum and taxane-based chemotherapy. METHODS: Sequenom iPLEXTMGOLD Assay and MALDI-TOF platform were used to genotype the non-synonymous G2677T/A (rs2032582; encoding Ala893Ser/Thr) and synonymous C3435T (rs1045642; encoding Ile1145Ile) variants in ABCB1, the non-synonymous G1249A variant in ABCC2 (rs2273697; encoding Val417Ile), and the non-synonymous C421A variant in ABCG2 (rs2231142; encoding Q141K, Gln141Lys) in normal DNA from up to 511 women in Gynecologic Oncology Group (GOG) phase III trials, GOG-172 or GOG-182. Progression-free survival (PFS) and overall survival (OS) were analyzed in relation to genetic polymorphisms using Kaplan-Meier and Cox proportional hazards model. RESULTS: The C421A variant (CA+AA versus CC) in ABCG2 was associated with a 6-month longer median PFS (22.7 versus 16.8 months, p=0.041). In multivariate analysis, patients with variant genotypes were at a reduced risk of disease progression (hazard ratio [HR]=0.75, 95% confidence interval [CI]=0.59-0.96, p=0.022). The association between C421A and OS was not statistically significant (HR=0.88, 95% CI=0.67-1.15, p=0.356). None of the other variants measured in either ABCB1 or ABCC2 was associated with PFS or OS. CONCLUSION: The C421A variant in ABCG2, previously shown to be associated with enhanced protein degradation and drug sensitivity, was associated with longer PFS in advanced stage EOC/PPC patents treated with platinum+taxane-based chemotherapy. This finding requires further validation.

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124 Of the more than 50 SNPs identified in the ABCB1 gene, G2677T/A is a non-synonymous polymorphism (encoding Ala893Ser/Thr), and C3435T is a synonymous polymorphism (encoding Ile1145Ile) associated with reduced ABCB1 mRNA expression [44]. Login to comment

[hide] Association between ABCC2 gene haplotypes and teno... J Infect Dis. 2006 Dec 1;194(11):1481-91. Epub 2006 Oct 26. Izzedine H, Hulot JS, Villard E, Goyenvalle C, Dominguez S, Ghosn J, Valantin MA, Lechat P, Deray AG
Association between ABCC2 gene haplotypes and tenofovir-induced proximal tubulopathy.
J Infect Dis. 2006 Dec 1;194(11):1481-91. Epub 2006 Oct 26., [PMID:17083032]

Abstract [show]
BACKGROUND: Tenofovir disoproxil fumarate (TDF) may induce renal proximal tubulopathy (rPT). There are no data on pharmacogenomic predictors of rPT in the genes encoding the multidrug-resistance protein (MRP) 2 and MRP4 transporters. METHODS: Mutational screening of the genes for MRP2 (ABCC2) and MRP4 (ABCC4) was performed using genomic DNA from 13 human immunodeficiency virus type 1 (HIV-1)-infected patients (group 1) presenting with TDF-induced rPT. Concomitantly, 17 unrelated HIV-1-infected patients who had received TDF therapy and who did not have rPT (group 2) were included in a case-control analysis, to assess the influence of single-nucleotide polymorphisms (SNPs) identified in ABCC2 and ABCC4. RESULTS: Six SNPs were identified in ABCC2. A significant allelic association between the 1249 G-->A SNP and TDF-induced rPT was observed (odds ratio, 6.11 [95% confidence interval, 1.19-31.15]; P<.02). ABCC2 haplotypes were significantly associated with the onset of TDF-induced rPT--CATC appeared to be a predisposing haplotype, as it was found in 40.9% of the group 1 case patients and in 13.7% of the group 2 control subjects (P<.01), whereas CGAC appeared to be a protective haplotype, as it was not observed in the group 1 case patients but was present in 20.2% of the group 2 control subjects (P<.01). No association was observed between ABCC4 polymorphism and TDF-induced rPT in the present study. CONCLUSION: ABCC2 haplotypes are associated with rPT induced by TDF in HIV-1-infected patients.

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85 (%) P Group 1 (n p 13) Group 2 (n p 17) Exon 28, 3609 GrA (rs11568695) Ala1203Ala Genotype .43 GG 12 (92) 17 (100) GA 1 (8) 0 AA 0 0 Allele G 25 (96.2) 34 (100) A 1 (3.8) 0 ABCB1 Exon 12, 1236CrT (rs1128503) Gly412Gly Genotype .66 CC 7 (54) 6 (35.2) CT 5 (38) 9 (52.9) TT 1 (8) 2 (11.9) Allele C 19 (73.0) 21 (62.8) T 7 (27.0) 13 (38.2) Exon 21, 2677GrT/A (rs2032582) Ala893Ser/Thr Genotype .82 GG 5 (38) 8 (47) GT 5 (38) 7 (41) TT 1 (8) 1 (6) GA 1 (8) 0 AA 0 1 (6) TA 1 (8) 0 Allele G 16 (61.5) 23 (67.8) T 8 (30.8) 9 (26.4) A 2 (7.7) 2 (5.8) Exon 26, 3435CrT (rs1045642) Ile1145Ile Genotype .25 CC 7 (54) 5 (29.4) CT 3 (23) 9 (52.9) TT 3 (23) 3 (17.7) Allele C 17 (65.4) 19 (55.9) T 9 (34.6) 15 (44.1) NOTE. Login to comment

[hide] Expression and function of efflux drug transporter... Pharmacol Ther. 2006 Jan;109(1-2):137-61. Epub 2005 Oct 4. Takano M, Yumoto R, Murakami T
Expression and function of efflux drug transporters in the intestine.
Pharmacol Ther. 2006 Jan;109(1-2):137-61. Epub 2005 Oct 4., [PMID:16209890]

Abstract [show]
A variety of drug transporters expressed in the body control the fate of drugs by affecting absorption, distribution, and elimination processes. In the small intestine, transporters mediate the influx and efflux of endogenous or exogenous substances. In clinical pharmacotherapy, ATP-dependent efflux transporters (ATP-binding cassette [ABC] transporters) expressed on the apical membrane of the intestinal epithelial cells determine oral bioavailability, intestinal efflux clearance, and the site of drug-drug interaction of certain drugs. The expression and functional activity of efflux transporters exhibit marked interindividual variation and are relatively easily modulated by factors such as therapeutic drugs and daily foods and beverages. In this article, we will summarize the recent findings regarding the intestinal efflux transporters, especially P-glycoprotein (P-gp or human multidrug resistance gene [MDR] 1), multidrug resistance-associated protein 2 (MRP2), and breast cancer resistance protein (BCRP).

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1100 Siegmund et al. (2002b) investigated the influence of the hereditary variants C3435T in exon 26 and G2677T/A (Ala893Ser/Thr) in exon 21, as well as the influence of 7 frequent or putative functional single nucleotide polymorphisms (SNPs) on duodenum MDR1 mRNA and P-gp expression and on talinolol disposition after intravenous and oral administration. Login to comment

[hide] Pharmacogenomics of ABC transporters and its role ... Drug Resist Updat. 2003 Apr;6(2):71-84. Sparreboom A, Danesi R, Ando Y, Chan J, Figg WD
Pharmacogenomics of ABC transporters and its role in cancer chemotherapy.
Drug Resist Updat. 2003 Apr;6(2):71-84., [PMID:12729805]

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), ABCC1 (MRP1), ABCC2 (MRP2, cMOAT), and ABCG2 (BCRP, MXR, 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 pharmacogenomics of ABC transporters, and discusses potential implications of genetic variants for the chemotherapeutic treatment of cancer.

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105 One of the tested SNPs, the ABCB1 2677G>T/A (Mickley et al., 1998), contains a tri-allelic polymorphism (with G at nucleotide 2677 found in the wild-type sequence, and with A or T at that position being the two possible variants), which results in an amino acid change in exon 21 (Ala893Ser/Thr). Login to comment

[hide] Single nucleotide polymorphisms in multidrug resis... Adv Drug Deliv Rev. 2002 Nov 18;54(10):1311-31. Suzuki H, Sugiyama Y
Single nucleotide polymorphisms in multidrug resistance associated protein 2 (MRP2/ABCC2): its impact on drug disposition.
Adv Drug Deliv Rev. 2002 Nov 18;54(10):1311-31., [PMID:12406647]

Abstract [show]
Multidrug resistance associated protein 2 (MRP2/ABCC2), expressed on the bile canalicular membrane, plays an important role in the biliary excretion of various kinds of substrates. In addition, MRP2 is also expressed on the apical membrane of epithelial cells such as enterocytes. It is possible that the inter-individual difference in the function of MRP2 affects the drug disposition. In the present article, we will summarize the physiological and pharmacological role of MRP2, particularly focusing on the factors affecting its transport function such as single nucleotide polymorphisms and/or the induction/down regulation of this transporter. Mutations found in patients suffering from the Dubin-Johnson syndrome, along with the amino acid residues which are involved in supporting the transport activity of MRP2, are also summarized.

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32 Moreover, Ala893Ser rabbit and human MRP2 [21,38,40,42-61], as sum- mutation in MDR1 gene results in the reduced oral marized in Refs. [7,23,25,26]. 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] Interplay of pharmacogenetic variations in ABCB1 t... Arch Pharm Res. 2011 Nov;34(11):1817-28. Epub 2011 Dec 3. Yoo HD, Lee YB
Interplay of pharmacogenetic variations in ABCB1 transporters and cytochrome P450 enzymes.
Arch Pharm Res. 2011 Nov;34(11):1817-28. Epub 2011 Dec 3., [PMID:22139683]

Abstract [show]
Interindividual variability in oral drug efficacy and toxicity is commonly observed in all therapeutic areas. Importantly, interindividual variability in drug uptake and metabolism can result in poor drug response, adverse drug reactions, or unfavorable drug-drug interaction. One of the common causes of individual variations in drug response is genetic variation of drug transporters and metabolizing enzymes. Pharmacogenetics are rapidly elucidating the inherited nature of these differences in drug disposition and effects, thereby providing a stronger scientific basis for optimizing drug therapy on the basis of each patient's genetic constitution. Knowledge of the genotype-phenotype correlation and frequency distribution of functional single nucleotide polymorphisms may be a valuable tool for individualizing drug therapy. This information can also be useful for explaining inter-individual and inter-ethnic variations in drug response and/or adverse effects. In this review, we focus on the interplay between efflux transporter (ATP-binding cassette, sub-family B (MDR/TAP), member 1/ABCB1) and cytochrome P450s according to genetic polymorphism.

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43 The silent 3435C > T (exon 26) and the 2677G > T/A (exon 21), which leads to an amino acid exchange (Ala893Ser/Thr), are common ABCB1 polymorphisms. Login to comment

[hide] The permeability P-glycoprotein: a focus on enanti... Expert Opin Drug Metab Toxicol. 2010 Aug;6(8):953-65. Choong E, Dobrinas M, Carrupt PA, Eap CB
The permeability P-glycoprotein: a focus on enantioselectivity and brain distribution.
Expert Opin Drug Metab Toxicol. 2010 Aug;6(8):953-65., [PMID:20504109]

Abstract [show]
IMPORTANCE OF THE FIELD: The permeability glycoprotein (P-gp) is an important protein transporter involved in the disposition of many drugs with different chemical structures, but few studies have examined a possible stereoselectivity in its activity. P-gp can have a major impact on the distribution of drugs in selected organs, including the brain. Polymorphisms of the ABCB1 gene, which encodes for P-gp, can influence the kinetics of several drugs. AREAS COVERED IN THIS REVIEW: A search including publications from 1990 up to 2009 was performed on P-gp stereoselectivity and on the impact of ABCB1 polymorphisms on enantiomer brain distribution. WHAT THE READER WILL GAIN: Despite stereoselectivity not being expected because of the large variability of chemical structures of P-gp substrates, structure-activity relationships suggest different P-gp-binding sites for enantiomers. Enantioselectivity in the activity of P-gp has been demonstrated by in vitro studies and in animal models (preferential transport of one enantiomer or different inhibitory potencies towards P-gp activity between enantiomers). There is also in vivo evidence of an enantioselective drug transport at the human blood-brain barrier. TAKE HOME MESSAGE: The significant enantioselective activity of P-gp might be clinically relevant and must be taken into account in future studies.

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209 Different SNPs were associated with the phenotype of remission, and carriers of the C allele for the rs2032583 genotype had higher odds ratio for remission (7.72, 95% CI 2.8 -- 21.3) at 4 weeks Exon 7 Exon 13 Exon 11Exon 2 Exon 8 Exon 6 Exon 3 Exon 4 Exon 9 Exon 17 Exon 10 Exon 14 Exon 12 Exon 15 Exon 16 Exon 19 Exon 21 Exon 18 Exon 23 Exon 24 Exon 28 Exon 27 Exon 20 Exon 22 A893S Exon 25 Exon 26 Exon 5 N21D N183S N400S Variant (548G, Ser183) MDR1*1 (548A, Asn183) Variant (2677T, Ser893) S1141T ATP-binding domain ATP-binding domain MDR1*1 (2677g, Ala893) R492C A. B. Figure 2. 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
519 As to the most common nonsynonymous SNP 2677GNT (A893S), there are relatively minor effects on predicted ATPase activity, which is consistent with the clinical association data for this SNP. Login to comment

[hide] Expression and function of p-glycoprotein in norma... Methods Mol Biol. 2010;596:199-222. Staud F, Ceckova M, Micuda S, Pavek P
Expression and function of p-glycoprotein in normal tissues: effect on pharmacokinetics.
Methods Mol Biol. 2010;596:199-222., [PMID:19949926]

Abstract [show]
ATP-binding cassette (ABC) drug efflux transporters limit intracellular concentration of their substrates by pumping them out of cell through an active, energy dependent mechanism. Several of these proteins have been originally associated with the phenomenon of multidrug resistance; however, later on, they have also been shown to control body disposition of their substrates. P-glycoprotein (Pgp) is the first detected and the best characterized of ABC drug efflux transporters. Apart from tumor cells, its constitutive expression has been reported in a variety of other tissues, such as the intestine, brain, liver, placenta, kidney, and others. Being located on the apical site of the plasma membrane, Pgp can remove a variety of structurally unrelated compounds, including clinically relevant drugs, their metabolites, and conjugates from cells. Driven by energy from ATP, it affects many pharmacokinetic events such as intestinal absorption, brain penetration, transplacental passage, and hepatobiliary excretion of drugs and their metabolites. It is widely believed that Pgp, together with other ABC drug efflux transporters, plays a crucial role in the host detoxication and protection against xenobiotic substances. On the other hand, the presence of these transporters in normal tissues may prevent pharmacotherapeutic agents from reaching their site of action, thus limiting their therapeutic potential. This chapter focuses on P-glycoprotein, its expression, localization, and function in nontumor tissues and the pharmacological consequences hereof.

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189 An association between synonymous SNP in exon 26 (C3435T) and nonsynonymous SNP in exon 21 (G2677A,T, Ala893Ser) was observed. Login to comment

[hide] Atazanavir pharmacokinetics in genetically determi... J Antimicrob Chemother. 2009 Nov;64(5):1071-9. Epub 2009 Aug 26. Anderson PL, Aquilante CL, Gardner EM, Predhomme J, McDaneld P, Bushman LR, Zheng JH, Ray M, MaWhinney S
Atazanavir pharmacokinetics in genetically determined CYP3A5 expressors versus non-expressors.
J Antimicrob Chemother. 2009 Nov;64(5):1071-9. Epub 2009 Aug 26., [PMID:19710077]

Abstract [show]
OBJECTIVES: The objective of this study was to compare atazanavir pharmacokinetics in genetically determined CYP3A5 expressors versus non-expressors. METHODS: HIV-negative adult volunteers were pre-screened for CYP3A5 *3, *6 and *7 polymorphisms and enrollment was balanced for CYP3A5 expressor status, gender and race (African-American versus non-African-American). Participants received atazanavir 400 mg daily for 7 days followed by atazanavir/ritonavir 300 mg/100 mg daily for 7 days with pharmacokinetic studies on days 7 and 14. Other measures collected were bilirubin, UGT1A1 *28, and ABCB1 1236C > T, 2677G > T/A and 3435C > T genotypes. Data analyses utilized least squares regression. RESULTS: Fifteen CYP3A5 expressors and 16 non-expressors participated. The day 7 atazanavir oral clearance (CL/F) was 1.39-fold faster (0.25 versus 0.18 L/h/kg; P = 0.045) and the C(min) was half (87 versus 171 ng/mL; P = 0.044) in CYP3A5 expressors versus non-expressors. Non-African-American CYP3A5 expressor males had 2.1-fold faster CL/F (P = 0.003) and <20% the C(min) (P = 0.0001) compared with non-African-American non-expressor males. No overall CYP3A5 expressor effects were observed during the ritonavir phase. One or two copies of wild-type ABCB1 haplotype (1236C/2677G/3435C) was predictive of slower atazanavir and ritonavir CL/F compared with zero copies (P < 0.06). Indirect bilirubin increased 1.6- to 2.8-fold more in subjects with UGT1A1 *28/*28 versus *1/*28 or *1/*1. CONCLUSIONS: CYP3A5 expressors had faster atazanavir CL/F and lower C(min) than non-expressors. The effect was most pronounced in non-African-American men. Ritonavir lessened CYP3A5 expressor effects. The wild-type ABCB1 CGC haplotype was associated with slower CL/F and the UGT1A1 *28 genotype was associated with increased bilirubin. Thus, CYP3A5, ABCB1 and UGT1A1 polymorphisms are associated with atazanavir pharmacokinetics and pharmacodynamics in vivo.

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224 However, the T variant in 2677 encodes an Ala893Ser in exon 21, which was associated with increased activity in one in vitro study.41 Another study showed that the T variant in 2677 is associated with higher basal CYP3A4 expression and activity.42 Finally, some investigators raise the possibility that protein folding differences with the variant haplotype (1236T, 2677T, 3435T) could lead to enhanced P-glycoprotein function, depending on the substrate.17 These investigations are consistent with the findings in the present study. 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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152 A study in our lab showed that common polymorphisms of MDR1 at 61ANG (N21D), 307TNC (F103L), 1199GNA (S400N), 2677GNT (A893S) and 2995GNA (A999T) do not change the transport of four MDR1 substrates when expressed at high levels in human cells [66]. Login to comment
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
154 Another study using a yeast host to express human MDR1 SNPs (M89T, L662R, R669C, A893S, W1108R, S1141T) showed increased resistance to anthracyclines, actinomycin D and valinomycin. Login to comment
185 The occurrence of 2677GNT (A893S) is far more frequent than G2677A (A893T). Login to comment

[hide] Analysis of genotype and haplotype effects of ABCB... Drug Metab Pharmacokinet. 2009;24(3):255-60. Vahab SA, Sen S, Ravindran N, Mony S, Mathew A, Vijayan N, Nayak G, Bhaskaranand N, Banerjee M, Satyamoorthy K
Analysis of genotype and haplotype effects of ABCB1 (MDR1) polymorphisms in the risk of medically refractory epilepsy in an Indian population.
Drug Metab Pharmacokinet. 2009;24(3):255-60., [PMID:19571437]

Abstract [show]
The transmembrane P-glycoprotein that functions as a drug-efflux transporter coded by ATP-binding cassette, subfamily B, member 1/Multidrug Resistance 1 (ABCB1/MDR1) gene is considered relevant to drug absorption and elimination, with access to the central nervous system. Effects of three ABCB1 single nucleotide polymorphisms (SNPs) in genotypic and haplotypic combination have been evaluated in a south Indian population for risk of pediatric medically refractory epilepsy. The study included age and sex matched medically refractory (N=113) cases and drug responsive epilepsy patients (N=129) as controls, belonging to the same ethnic population recruited from a tertiary referral centre, of Karnataka, Southern India. The genotype frequencies of SNPs c.1236C>T, c.2677G>T/A, and c.3435C>T were determined from genomic DNA of the cases and controls by PCR- RFLP and confirmatory DNA sequencing. 256 normal population samples of the same ethnicity were genotyped for the three loci to check for population stratification. Results indicate that there was no statistically significant difference between allele and genotype frequencies of refractory and drug responsive epilepsy patients. The predicted haplotype frequencies of the three polymorphisms did not show significant difference between cases and controls. The results confirm earlier observations on absence of association of ABCB1 polymorphisms with medically refractory epilepsy.

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30 These three coding region SNPs- synonymous c.1236CÀT (p.Gly412Gly) and c.3435CÀT (p.Ile1145Ile), as well as the non-synonymous c.2677GÀT/A (p.Ala893Ser/Thr) are in significant linkage disequilibrium and a few of their haplotypes have shown association to phenotypes with over-expression of the protein.7-10) However, for these three SNPs, ethnic differences have been reported in the pattern of linkage disequilibrium with an allele frequency of 45-55% in Whites and 5-10% in African Americans. 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]

Abstract [show]
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] Enaminones: Exploring additional therapeutic activ... J Pharm Sci. 2007 Oct;96(10):2509-31. Edafiogho IO, Kombian SB, Ananthalakshmi KV, Salama NN, Eddington ND, Wilson TL, Alexander MS, Jackson PL, Hanson CD, Scott KR
Enaminones: Exploring additional therapeutic activities.
J Pharm Sci. 2007 Oct;96(10):2509-31., [PMID:17621683]

Abstract [show]
Enaminones, enamines of beta-dicarbonyl compounds, have been known for many years. Their early use has been relegated to serving as synthetic intermediates in organic synthesis and of late, in pharmaceutical development. Recently, the therapeutic potential of these entities has been realized. This review provides the background and current research in this area with emphasis of these agents as potential anticonvulsants, their proposed mechanisms of action, and as potential modulators of multidrug resistance (MDR).

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92 The most commonly identified linked MDR1 SNPs (linkage disequilibrium) in P-gp are the synonymous 1236 (exon 12, C > T, Glu 412 Glu) and 3435 (exon 26, C > T, Ile 1145 Ile) and the nonsynonymous 2677 (exon 21, G > T/A, Ala 893 Ser/Thr [less frequent]113 ) plymorphisms.102,114-118 To date, discrepancies in the outcomes of genotype-phenotype studies are attributed to the emphasis on studying single SNPs rather than haplotypes, racial variation in allele fre- quencies119 and the number of haplotype combinations,120 the use of P-gp substrates which are affected by other transporters or metabolizing enzymes, and other interfering factors (route of administration and applied dose, steady state versus single-dose kinetics, environmental and experimental factors). 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] P-glycoprotein in the placenta: expression, locali... Reprod Toxicol. 2006 Oct;22(3):400-10. Epub 2006 Mar 24. Ceckova-Novotna M, Pavek P, Staud F
P-glycoprotein in the placenta: expression, localization, regulation and function.
Reprod Toxicol. 2006 Oct;22(3):400-10. Epub 2006 Mar 24., [PMID:16563694]

Abstract [show]
Detailed understanding of the mechanisms employed in transfer of drugs across the placenta is essential for optimization of pharmacotherapy during pregnancy. Disclosure of drug efflux transporters as an "active component" of the placental barrier has brought new important insights into the field of transplacental pharmacokinetics. P-glycoprotein (P-gp, MDR1) is the first discovered and so far the best characterized of drug efflux transporters, whose role in the regulation of drug disposition to the fetus has been extensively studied. Expression of P-gp in the placental trophoblast layer was confirmed at the mRNA and protein levels in all phases of pregnancy, and several in vitro and in vivo studies demonstrated functional activity of the transporter in materno-fetal drug transport. P-gp is able to actively pump drugs and other xenobiotics from trophoblast cells back to the maternal circulation, providing thus protection to the fetus. This review summarizes the current knowledge on the expression, localization and function of P-gp in the placenta. In addition, we include the latest data concerning transcriptional regulation of placental P-gp expression and polymorphisms of the MDR1 gene. Clinical significance of placental P-gp and its future perspectives for pharmacotherapy during pregnancy are also discussed.

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1527 Kim et al. subsequently demonstrated linkage disequilibrium (though not complete) between the synonymous SNP in exon 26 (C3435T) and nonsynonymous SNP in exon 21 (G2677T, Ala893Ser), which can be associated with altered transporter expression or function [110]. Login to comment

[hide] Role for drug transporters beyond tumor resistance... J Clin Oncol. 2006 Sep 10;24(26):4225-7. Epub 2006 Aug 8. Kroetz DL
Role for drug transporters beyond tumor resistance: hepatic functional imaging and genotyping of multidrug resistance transporters for the prediction of irinotecan toxicity.
J Clin Oncol. 2006 Sep 10;24(26):4225-7. Epub 2006 Aug 8., [PMID:16895999]

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27 The current study reported by Michael et al suggests that UGT1A1 genotype alone may not be sufficient to identify patients who would benefit from a lower starting dose of irinotecan.16 They also genotyped for three common coding region variants of ABCB1, two synonymous changes, and a nonsynonymous change resulting in the Ala893Ser variant of Pgp. Login to comment

[hide] Searching for polymorphisms that affect gene expre... AAPS J. 2006 Aug 18;8(3):E515-20. Wang D, Sadee W
Searching for polymorphisms that affect gene expression and mRNA processing: example ABCB1 (MDR1).
AAPS J. 2006 Aug 18;8(3):E515-20., [PMID:17025270]

Abstract [show]
Cis-acting genetic variations can affect the amount and structure of mRNA/protein. Genomic surveys indicate that polymorphisms affecting transcription and mRNA processing, including splicing and turnover, may account for the main share of genetic factors in human phenotypic variability; however, most of these polymorphisms remain yet to be discovered. We use allelic expression imbalance (AEI) as a quantitative phenotype in the search for functional cis-acting polymorphisms in many genes, including ABCB1 (multidrug resistance 1 gene, MDR1, Pgp). Previous studies have shown that ABCB1 activity correlates with a synonymous polymorphism, C3435T; however, the functional polymorphism and molecular mechanism underlying this clinical association remained unknown. Analysis of allele-specific expression in liver autopsy samples and in vitro expression experiments showed that C3435T represents a main functional polymorphism, accounting for 1.5- to 2-fold changes in mRNA levels. The mechanism appears to involve increased mRNA turnover, probably as a result of different folding structures calculated for mRNA with the Mfold program. Other examples of the successful application of AEI analysis for studying functional polymorphism include 5-HTT (serotonin transporter, SLC6A4) and OPRM1 (mu opioid receptor). AEI is therefore a powerful approach for detecting cis-acting polymorphisms affecting gene expression and mRNA processing.

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48 Indeed, C3435T is in linkage disequilibrium with G2677T (Ala893Ser). 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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64 R. Kerb / Cancer Letters 234 (2006) 4-338 naturally-occurring polymorphisms in the human ABCB1 gene reported was the amino acid substitution Gly185Val [89], and more recently Ala893Ser and Met986Val [90]. Login to comment
76 Table 3 Overview of the 15 most common ABCB1 (MDR1) genetic variants Position Location Effect Allelic frequency (%) CA AS AA K129TOC 50 UTR Non-coding 5 4 7 K1GOA 50 UTR Non-coding 8 5 0 61AOG Exon 2 Asn21Asp 8 2 2.5 Exon 5-25GOT Intron 4 16 7 30 Exon 10-44AOG Exon 10 Intron 9 45 69 26 1199GOA Exon 11 Ser400Asn 2.5 0 !1 1236COT Exon 12 Synonymous 46 69 21 Exon 11C44COT Intron 12 5 0 17 Exon 12C24COT Intron 13 52 54 54 Exon 13C38AOG Intron 14 50 68 54 Exon 19C24GOA Intron 20 12 7 15 2677GOT/A Exon 21 Ala893Ser/Thr 46/2 45/7 O1 3421TOA Exon 26 Ser1141Thr 0 0 10 3435COT Exon 26 Synonymous 56 40 10 IVSC21TOC Intron 28 0 8 0 AA, African American; AS, Asian; CA, Caucasian. Login to comment
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
169 It should be noted that, in the majority of subjects, this synonymous 3435COT polymorphism is linked to the nonsynonymous exon 21 2677GOT/A polymorphism, which results in Ala893Ser/Thr, as well as another conservative SNP, 1236COT [47]. 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] An interethnic comparison of polymorphisms of the ... Drug Metab Rev. 2005;37(2):327-78. Chowbay B, Zhou S, Lee EJ
An interethnic comparison of polymorphisms of the genes encoding drug-metabolizing enzymes and drug transporters: experience in Singapore.
Drug Metab Rev. 2005;37(2):327-78., [PMID:15931768]

Abstract [show]
Much of the interindividual variability in drug response is attributable to the presence of single nucleotide polymorphisms (SNPs) in genes encoding drug-metabolizing enzymes and drug transporters. In recent years, we have investigated the polymorphisms in a number of genes encoding phase I and II drug-metabolizing enzymes including CYPIA1, CYP3A4, CYP3A5, GSTM1, NAT2, UGT1A1, and TPMT and drug transporter (MDR1) in three distinct Asian populations in Singapore, namely the Chinese, Malays, and Indians. Significant differences in the frequencies of common alleles encoding these proteins have been observed among these three ethnic groups. For example, the frequency of the variant A2455G polymorphism of CYP1A1 was 28% in Chinese and 31% in Malays, but only 18% in Indians. CYP3A4*4 was detected in two of 110 Chinese subjects, but absent in Indians and Malays. Many Chinese and Malays (61-63%) were homozygous for the GSTM1*0 null genotype compared with 33% of Indians. The frequency of the UGTIA1*28 allele was highest in the Indian population (35%) compared to similar frequencies that were found in the Chinese (16%) and Malay (19%) populations. More importantly, our experience over the years has shown that the pharmacogenetics of these drug-metabolizing enzymes and MDR1 in the Asian populations are different from these in the Caucasian and African populations. For example, the CYP3A4*1B allele, which contains an A-290G substitution in the promoter region of CYP3A4, is absent in all three Asian populations of Singapore studied, but occurs in more than 54% of Africans and 5% of Caucasians. There were no difference in genotype and allelic variant frequencies in exon 12 of MDR1 between the Chinese, Malay, and Indian populations. When compared with other ethnic groups, the distribution of the wild-type C allele in exon 12 in the Malays (34.2%) and Indians (32.8%) was relatively high and similar to the Japanese (38.55%) and Caucasians (41%) but different from African-Americans (15%). The frequency of wild-type TT genotype in Asians (43.5% to 52.1%) and Japanese (61.5%) was much higher than those found in Caucasians (13.3%). All the proteins we studied represent the primary hepatic or extrahepatic enzymes, and their polymorphic expression may be implicated in disease risk and the disposition of drugs or endogenous substances. As such, dose requirements of certain drugs may not be optimal for Asian populations, and a second look at the factors responsible for this difference is necessary.

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427 Kim et al. (2001) indicated that cells transduced with a variant MDR1 containing Ser893 showed reduced intracellular accumulation of [3 H]-digoxin compared with cells with the wild-type Ala893 , suggesting enhanced efflux by the polymorphism of Ala893Ser (G2677T). 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] Impact of drug transporter studies on drug discove... Pharmacol Rev. 2003 Sep;55(3):425-61. Epub 2003 Jul 17. Mizuno N, Niwa T, Yotsumoto Y, Sugiyama Y
Impact of drug transporter studies on drug discovery and development.
Pharmacol Rev. 2003 Sep;55(3):425-61. Epub 2003 Jul 17., [PMID:12869659]

Abstract [show]
Drug transporters are expressed in many tissues such as the intestine, liver, kidney, and brain, and play key roles in drug absorption, distribution, and excretion. The information on the functional characteristics of drug transporters provides important information to allow improvements in drug delivery or drug design by targeting specific transporter proteins. In this article we summarize the significant role played by drug transporters in drug disposition, focusing particularly on their potential use during the drug discovery and development process. The use of transporter function offers the possibility of delivering a drug to the target organ, avoiding distribution to other organs (thereby reducing the chance of toxic side effects), controlling the elimination process, and/or improving oral bioavailability. It is useful to select a lead compound that may or may not interact with transporters, depending on whether such an interaction is desirable. The expression system of transporters is an efficient tool for screening the activity of individual transport processes. The changes in pharmacokinetics due to genetic polymorphisms and drug-drug interactions involving transporters can often have a direct and adverse effect on the therapeutic safety and efficacy of many important drugs. To obtain detailed information about these interindividual differences, the contribution made by transporters to drug absorption, distribution, and excretion needs to be taken into account throughout the drug discovery and development process.

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1866 The G2677T transversion in exon 21 resulted in an alteration in the encoded protein (Ala893Ser). Login to comment

[hide] Effect of levothyroxine administration on intestin... Clin Pharmacol Ther. 2002 Sep;72(3):256-64. Siegmund W, Altmannsberger S, Paneitz A, Hecker U, Zschiesche M, Franke G, Meng W, Warzok R, Schroeder E, Sperker B, Terhaag B, Cascorbi I, Kroemer HK
Effect of levothyroxine administration on intestinal P-glycoprotein expression: consequences for drug disposition.
Clin Pharmacol Ther. 2002 Sep;72(3):256-64., [PMID:12235446]

Abstract [show]
OBJECTIVE: Thyroid function alters the pharmacokinetics of many drugs; one example is the cardiac glycoside digoxin. Because digoxin disposition is affected by intestinal expression of P-glycoprotein, we hypothesized that thyroid hormones may regulate P-glycoprotein and influence disposition of P-glycoprotein substrates. METHODS: Duodenal expression of P-glycoprotein measured by reverse transcriptase-polymerase chain reaction of MDR1 messenger ribonucleic acid (mRNA) and by immunohistochemical examination was studied in 8 healthy volunteers (4 men and 4 women; age range, 22-29 years; body weight, 59-89 kg) before and after coadministration with levothyroxine (200 microg orally for 17 days), which resulted in suppression of thyroid-stimulating hormone. The pharmacokinetics of the P-glycoprotein substrate talinolol was assessed after intravenous (30 mg) and oral (100 mg) administration. RESULTS: Duodenal MDR1 mRNA expression and immunoreactive P-glycoprotein were increased 1.4-fold (not significant; P =.078) and 3.8-fold (P <.01), respectively, after administration of levothyroxine. The changes in P-glycoprotein expression were associated with minor alterations in talinolol half-life after both oral and intravenous administration. CONCLUSIONS: Expression of intestinal P-glycoprotein in humans appears to be influenced by thyroid hormones. The functional consequences need to be addressed in patients with hyperthyroidism.

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111 However, there was a significant trend toward higher intestinal MDR1 mRNA but not protein levels in subjects with the polymorphism G2677T (Ala893Ser) in exon 21, which has been shown to have an allelic frequency of 41.6% in German white subjects. 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

[hide] Genetic variability in the multidrug resistance as... Ann Oncol. 2013 Jun;24(6):1513-25. doi: 10.1093/annonc/mdt008. Epub 2013 Feb 7. Vulsteke C, Lambrechts D, Dieudonne A, Hatse S, Brouwers B, van Brussel T, Neven P, Belmans A, Schoffski P, Paridaens R, Wildiers H
Genetic variability in the multidrug resistance associated protein-1 (ABCC1/MRP1) predicts hematological toxicity in breast cancer patients receiving (neo-)adjuvant chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC).
Ann Oncol. 2013 Jun;24(6):1513-25. doi: 10.1093/annonc/mdt008. Epub 2013 Feb 7., [PMID:23396606]

Abstract [show]
BACKGROUND: To assess the impact of single-nucleotide polymorphisms (SNPs) on predefined severe adverse events in breast cancer (BC) patients receiving (neo-)adjuvant 5-fluorouracil (FU), epirubicin and cyclophosphamide (FEC) chemotherapy. PATIENTS AND METHODS: Twenty-six SNPs in 16 genes of interest, including the drug transporter gene ABCC1/MRP1, were selected based on a literature survey. An additional 33 SNPs were selected in these genes, as well as in 12 other genes known to be involved in the metabolism of the studied chemotherapeutics. One thousand and twelve female patients treated between 2000 and 2010 with 3-6 cycles of (neo-)adjuvant FEC were genotyped for these SNPs using Sequenom MassARRAY. Severe adverse events were evaluated through an electronic chart review for febrile neutropenia (FN, primary end point), FN first cycle, prolonged grade 4 or deep (<100/microl) neutropenia, anemia grade 3-4, thrombocytopenia grade 3-4 and non-hematological grade 3-4 events (secondary end points). RESULTS: Carriers of the rs4148350 variant T-allele in ABCC1/MRP1 were associated with FN relative to homozygous carriers of the G-allele [P = 0.0006; false discovery rate (FDR) = 0.026]. Strong correlations with secondary end points such as prolonged grade 4 neutropenia (P = 0.002, FDR = 0.046) were also observed. Additionally, two other SNPs in ABCC1/MRP1 (rs45511401 and rs246221) correlated with FN (P = 0.007 and P = 0.01, respectively; FDR = 0.16 and 0.19), as well as two SNPs in UGT2B7 and FGFR4 (P = 0.024 and P = 0.04; FDR = 0.28 and 0.38). CONCLUSION: Genetic variability in ABCC1/MRP1 was associated with severe hematological toxicity of FEC.

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114 Overview of 33 additional SNPs located in genes involved in the pharmacokinetics (PK) or pharmacodynamics (PD) of the 5-fluorouracil (5-FU), epirubicin and cyclophosphamide (FEC) regimen Genes Name Function of the gene product Variant allele (rs number, position, amino acid change) PK or PD effect ABCBI/ MDR1 Multidrug resistance 1 Drug transporter implicated in energy-dependent transport of cytotoxic agents out of the cell rs2032582 c.2677G>T/A Ala893Ser/Thr Selected because missense mutations are likely to affect gene function. Login to comment