MDR1 genotype is associated with hepatic cytochrome P450 3A4 basal and induction phenotype

Objectives. Variant cytochrome P450 (CYP) 3A4 alleles cannot explain human variation in CYP3A4 expression. This study investigated whether common single-nucleotide polymorphisms (SNPs) in multidrug resistance 1 (MDRI), encoding P-glycoprotein, or the pregnane X receptor (PXR) were associated with basal or inducible CYP3A4 expression. Methods: MDRI G2677T and C3435T SNPs and a PXR 6-base pair (bp) deletion were genotyped in the deoxyribonucleic acid from 144 human livers in 3 cohorts each phenotyped for basal or rifampin (INN, rifampicin)-inducible hepatic CYP3A4 expression (or both) and in 57 human small bowel biopsy specimens from 3 cohorts each phenotyped for either basal or rifampin-induced CYP3A4 expression (or both). Results: Hepatic CYP3A4 expression/function was significantly higher in persons homozygous for the MDRI 2677T (Ser893) allele compared with persons homozygous for 2677G (Ala893) in all 3 hepatic cohorts. For example, homozygous MDR1 2677 TT livers had higher midazolam hydroxylase activity than homozygous 2677 GG livers (1831 +/- 1336 pmol (.) min(-1) (.) mg protein(-1) versus 1060 +/- 552 pmol (.) min(-1.) mg protein(-1), P =.03). In 2 of the 3 groups the association was observed in men but not in women. For example, homozygous MDR1 2677 TT male hepatocytcs had significantly higher testosterone 6 beta-hydroxylase activity compared with homozygous 2677 GG livers (0.120 +/- 0.06 pmol (.) min(-1) (.) mg protein(-1) versus 0.069 +/- 0.04 pmol (.) min(-1) (.) mg protein(-1), P =.0002). Conversely, rifampin induction of testosterone 6 beta-hydroxylation in primary human hepatocytes was significantly higher in persons homozygous for 2677G (12.0 +/- 5.7-fold) compared with MDR1 homozygous TT carriers (7.3 +/- 4.6-fold) (P =.01). Suggestive evidence for higher CYP3A4 expression in MDR1 2677T carriers was also observed in human intestines. CYP3A4 expression was also related to a 6-bp deletion in PXR in 2 of the liver cohorts. Two-factor ANOVA analysis revealed a significant interaction between the MDRI 2677 SNP and the PXR 6-bp deletion influencing CYP3A4 expression (P =.007). Conclusions: Individuals homozygous for the MDRI 2677T allele show enhanced constitutive CYP3A4 expression in the liver and intestine, as compared with those homozygous for the MDRI 2677G allele,