Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities

Morita, Naomi; Yasumori, Toshio; Nakayama, Keiichi I.

doi:10.1016/s0006-2952(03)00178-3

Cited by 112 publications

(70 citation statements)

References 37 publications

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“…In healthy Caucasian and AfricanAmerican volunteers, individuals with the 2677GG/3435CC genotypes had higher fexofenadine AUC values than individuals homozygous for the variant alleles in these two positions (2677TT and 3435TT), consistent with increased Pglycoprotein function in individuals with the variant genotypes (21). A similar finding was made when the 2677 and No difference in transport of verapamil, digoxin, viblastine and cyclosporine A [35] 3435 polymorphisms were analyzed separately, with AUC values being highest for individuals carrying the reference alleles. However, in a separate study, the MDR1 C3435T variant had no effect on fexofenadine disposition (43).…”

Section: Impact Of Mdr1 Genetic Polymorphism On Drug Dispositionsupporting

confidence: 67%

“…However, most substrates used in this study were labeled with bulky fluorescent bodipy groups, which might affect the substrate specificity for P-glycoprotein. Both transient and stable expression of the common Ala893Ser variant has failed to identify significant differences in the transport of calcein-AM, verapamil, digoxin, vinblastine, or cyclosporin A relative to the reference protein (22,35). In both of these cases, the nonsynonymous G2677T variant was studied in the context of the C1236T and C3435T variants found in the common MDR1 haplotypes.…”

Section: In Vitromentioning

confidence: 99%

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Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

2004

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The multidrug resistance (MDR1) gene product P-glycoprotein is a membrane protein that functions as an ATP-dependent efflux pump, transporting exogenous and endogenous substrates from the inside of cells to the outside. Physiological expression of P-glycoprotein in tissues with excretory or protective function is a major determinant of drug disposition and provides a cellular defense mechanism against potentially harmful compounds. Therefore, P-glycoprotein has significant impact on therapeutic efficacy and toxicity as it plays a key role in absorption of oral medications from the intestinal tract, excretion into bile and urine, and distribution into protected tissues such as the brain and testes. There is increasing interest in the possible role of genetic variation in MDR1 in drug therapy. Numerous genetic polymorphisms in MDR1 have been described, some of which have been shown to determine Pglycoprotein expression levels and substrate transport. Furthermore, some of these polymorphisms have an impact on pharmacokinetic and pharmacodynamic profiles of drug substrates and directly influence outcome and prognosis of certain diseases. This review will focus on the impact of genetic variation in MDR1 on expression and function of P-glycoprotein and the implications of this variation for drug therapy and disease risk.

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Section: Impact Of Mdr1 Genetic Polymorphism On Drug Dispositionsupporting

confidence: 67%

Section: In Vitromentioning

confidence: 99%

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

2004

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“…In contrast, transport of other substrates such as verapamil, vinblastine, calcein-AM, prazosin, bisantrene, forskolin, digoxin and cyclosporin A was not affected by G2677T/A or C3435T variants of P-glycoprotein; however, for each substrate only one concentration was tested. 31,[42][43] In conclusion our findings suggest that certain ABCB1 SNPs (e.g. C1236T and G2677T) affect the survival of AML patients with normal karyotype after chemotherapy and might provide useful information for treatment strategies and individualized chemotherapy.…”

Section: Discussionmentioning

confidence: 65%

Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype

et al. 2010

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Over expression of the multi-drug transporter P-glycoprotein, encoded by the ABCB1 gene, is a clinically relevant problem in acute myeloid leukemia (AML). Polymorphisms in ABCB1 might contribute to cancer risk and therapeutic response. We therefore investigated the influence of polymorphisms G1199A, C1236T, G2677T/A and C3435T on cancer susceptibility, in vitro cytotoxicity and overall survival in 100 de novo AML patients with normal karyotype. Patients with 1236C/C or 2677G/G genotypes showed poorer survival than patients with other genotypes (P=0.03 and P=0.02, respectively). Both these genotypes were significant factors for survival in multivariate analysis, along with age, NPM1 and FLT3 mutation status. In vitro cytotoxicity studies demonstrated that leukemic cells from 1236T/T and 2677T/T patients were significantly more susceptible to mitoxantrone (P=0.02), and tended to be more susceptible to etoposide and daunorubicin (P=0.07-0.09), but not to cytarabine. No significant difference in allele frequencies were found between patients and healthy volunteers (n=400).

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“…One study showed the 1236C4T-2677G4TA-3435C4T haplotype to be nonsignificantly associated with mRNA expression, 21 but these results were based on extremely low subgroup sizes, and heterozygotes for the haplotype showed even lower levels of expression. Another study failed to show any association with haplotype in transduced cells, 29 whereas Hitzl et al…”

Section: Gd Leschziner Et Almentioning

confidence: 95%

“…36,40 However, one study reported a decrease in intracellular digoxin concentration in human embryonic kidney (HEK)293T cells transfected with the T2677 variant (Po0.002). 27 Haplotype analysis has revealed equally inconsistent results, with the G2677/T3435 haplotype being associated ABCB1 genotype and therapeutic drug response GD Leschziner et al with a higher AUC, 37 no association with transport or efflux in LLC-PK1 transfected cells, 29 and an association between homozygosity for the G2677/C3435 haplotype and decreased C max , decreased oral bioavailability and increased renal clearance. 41 …”

Section: Digoxinmentioning

confidence: 99%

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

et al. 2006

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The product of the ABCB1 gene, P-glycoprotein (PGP), is a transmembrane active efflux pump for a variety of drugs. It is a putative mechanism of multidrug resistance in a range of diseases. It is postulated that ABCB1 polymorphisms contribute to variability in PGP function, and that therefore multidrug resistance is, at least in part, genetically determined. However, studies of ABCB1 genotype or haplotype and PGP expression, activity or drug response have produced inconsistent results. This critical review of ABCB1 genotype and PGP function, including mRNA expression, PGP-substrate drug pharmacokinetics and drug response, highlights methodological limitations of existing studies, including inadequate power, potential confounding by co-morbidity and co-medication, multiple testing, poor definition of disease phenotype and outcomes, and analysis of multiple drugs that might not be PGP substrates. We have produced recommendations for future research that will aid clarification of the association between ABCB1 genotypes and factors related to PGP activity.

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Human MDR1 polymorphism: G2677T/A and C3435T have no effect on MDR1 transport activities

Cited by 112 publications

References 37 publications

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

Functional Implications of Genetic Polymorphisms in the Multidrug Resistance Gene MDR1 (ABCB1)

Association of ABCB1 polymorphisms with survival and in vitro cytotoxicty in de novo acute myeloid leukemia with normal karyotype

ABCB1 genotype and PGP expression, function and therapeutic drug response: a critical review and recommendations for future research

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