Modulation of multidrug resistance P-glycoprotein 1 (ABCB1) expression in human heart by hereditary polymorphisms

Meissner, Konrad; Jedlitschky, Gabriele; Schwabedissen, Henriette E. Meyer zu; Dazert, Peter; Eckel, Lothar; Vogelgesang, Silke; Warzok, R; Böhm, Michael; Lehmann, Christian; Wendt, Michael; Cascorbi, Ingolf; Kroemer, Heyo K.

doi:10.1097/00008571-200406000-00007

Cited by 73 publications

(72 citation statements)

References 15 publications

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“…We found a significant trend of elevated mRNA expression among carriers of the variant genotype 2677T/A (P ¼ 0.02) and 3435T (P ¼ 0.04). A similar tendency was observed before in myocardial tissue 35 and in the intestine of Japanese subjects. 36 Overall ratios from mRNA/18S rRNA did not correlate with protein content neither in noncancerous nor in cancerous tissue.…”

Section: Discussionsupporting

confidence: 89%

Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

et al. 2006

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There is increasing evidence that polymorphisms of the adenosine 5 0 triphosphate membrane transporters ABCB1 (P-glycoprotein, MDR1) may affect expression and function, whereas less information is available about the impact of ABCC2 (multidrug resistance-associated protein (MRP2)) single-nucleotide polymorphisms . Particularly, their role in human kidney for drug elimination and in the etiology of renal cell carcinoma is poorly understood. ABCB1 and ABCC2 mRNA and protein expression levels were determined by real-time polymerase chain reaction or immunohistochemistry in kidney cancer and adjacent unaffected cortex tissue of 82 nephrectomized renal cell cancer (RCC) patients (63 clear-cell RCC (CCRCC), 19 non-CCRCC). The DNA of all patients was genotyped for ABCB1 À2352G4A, À692T4C, 2677G4T/A (Ala893Ser/Thr), and 3435C4T, and ABCC2 À24C4T, 1249G4A (Val417Ile) and 3972C4T. ABCB1 and ABCC2 were less expressed in CCRCC than in normal cortex on mRNA as well as on protein level. Although the overall genotype frequency distribution did not differ between the patients and a matched control group, ABCB1 2677T/ A and 3435T genotypes were associated with higher (P ¼ 0.02 and P ¼ 0.04) and ABCC2 À24 T with lower mRNA levels in normal tissues (0.03). The expression of ABCB1 and ABCC2 was not related to genetic variants in RCC tissue. In a reporter gene assay in HepG2 cells, the ABCC2 À24T construct showed an 18.7% reduced activity (P ¼ 0.003). In conclusion, ABCB1 and ABCC2 genotypes modulate the expression in the unaffected renal cortex of RCC patients, possibly contributing to inter-individual differences in drug and xenobiotics elimination. Their role in RCC cancer susceptibility or chemotherapy resistance needs further elucidation.

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Section: Discussionsupporting

confidence: 89%

Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

et al. 2006

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“…The 1236C>T and 2677G>T/A/C polymorphisms have also been linked to several diseases such as pharmacoresistant epilepsy and Parkinsons disease [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45]. Studies on these polymorphisms have yielded contradictory results, possibly due to small sample sizes and the isolated nature of the study populations.…”

Section: Discussionmentioning

confidence: 99%

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

et al. 2006

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Introduction-The human multi-drug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp), an important membrane-bound efflux transporter known to confer anti-cancer drug resistance as well as affect the pharmacokinetics of many drugs and xenobiotics. A number of single nucleotide polymorphisms (SNPs) have been identified throughout the ABCB1 gene which may have an effect on P-gp expression levels and function. Haplotype as well as genotype analysis of SNPs is becoming increasingly important in identifying genetic variants underlying susceptibility to human disease. Three SNPs, 1236C>T, 2677G>T, and 3435C>T have been repeatedly shown to predict changes in the function of P-gp. The frequencies with which these polymorphisms exist in a population have also been shown to be ethnically related.

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“…18 Two studies have described the opposite association, that is, the T polymorphism associated with increased mRNA expression, but once again these have been either nonsignificant 19 or performed on a very small sample. 20 The majority have failed to find an association, 17,[21][22][23][24][25] although two of these negative studies did show an association with haplotype rather than genotype. 17,21 Most studies of the 2677G4TA polymorphism and mRNA expression levels have also been negative, 17,19,21,[23][24][25] although one study 22 did report an association between the GG2677 genotype and reduced mRNA expression.…”

Section: Effects Of Genotype On Abcb1 Mrna and Protein Expressionmentioning

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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Modulation of multidrug resistance P-glycoprotein 1 (ABCB1) expression in human heart by hereditary polymorphisms

Cited by 73 publications

References 15 publications

Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

Influence of polymorphisms of ABCB1 and ABCC2 on mRNA and protein expression in normal and cancerous kidney cortex

Ethnicity-Related Polymorphisms and Haplotypes in the Human ABCB1 Gene

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

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