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MDR1 genotype is associated with hepatic cytochrome P450 3A4 basal and induction phenotype
Author(s) -
Lamba Jatinder,
Strom Stephen,
Venkataramanan Raman,
Thummel Kenneth E.,
Lin Yvonne S.,
Liu Wei,
Cheng Cheng,
Lamba Vishal,
Watkins Paul B.,
Schuetz Erin
Publication year - 2006
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2005.11.013
Subject(s) - cyp3a4 , pregnane x receptor , genotype , single nucleotide polymorphism , biology , cytochrome p450 , basal (medicine) , medicine , endocrinology , drug metabolism , allele , microbiology and biotechnology , gene , metabolism , genetics , nuclear receptor , transcription factor , insulin
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 ( MDR1 ), encoding P‐glycoprotein, or the pregnane X receptor (PXR) were associated with basal or inducible CYP3A4 expression. Methods MDR1 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 MDR1 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 hepatocytes had significantly higher testosterone 6β‐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 6β‐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 MDR1 2677 SNP and the PXR 6‐bp deletion influencing CYP3A4 expression ( P = .007). Conclusions Individuals homozygous for the MDR1 2677T allele show enhanced constitutive CYP3A4 expression in the liver and intestine, as compared with those homozygous for the MDR1 2677G allele, particularly in men. Conversely, the magnitude of CYP3A4 induction by rifampin is greater in persons with the MDR1 2677G allele and is inversely related to baseline CYP3A4 expression. MDR1 likely influences basal CYP3A4 expression by limiting the intracellular concentration of an endogenous regulator. MDR1 genotype may be a useful predictor of basal CYP3A4 and the extent of some CYP3A4‐mediated drug interactions in humans. Moreover, the influence of MDR1 genotype on CYP3A4 expression adds additional complexity to determining the relative contribution of the MDR1 alleles to the disposition of substrates shared by CYP3A4 and MDR1/P‐glycoprotein. Clinical Pharmacology & Therapeutics (2006) 79 , 325–338; doi: 10.1016/j.clpt.2005.11.013