Sex-dependent genetic markers of CYP3A4 expression and activity in human liver microsomes.

OBJECTIVE

To find genetic markers of the individual cytochrome P450 (CYP)3A expression.

METHODS

A large collection of liver samples phenotyped for CYP3A expression and activity was genotyped for CYP3A variants. Data were analyzed for associations between CYP3A phenotypes and genotypes, and for evidence of recent selection.

RESULTS

We report associations between the hepatic CYP3A4 protein expression level, as well as its enzymatic activity, measured as verapamil N-dealkylation, and genetic polymorphisms from two regions within the CYP3A gene cluster. One region is defined by several variants, mostly located within CYP3A7, the other by a single nucleotide polymorphism in intron 7 of CYP3A4. The effects of these single nucleotide polymorphisms are sex-dependent. For example, female carriers of T alleles of the single nucleotide polymorphism rs4646437C>T in CYP3A4 intron 7 have, respectively, 5.1-fold and 2.7-fold higher expression and activity compared with male T-carriers, but only 2.2-fold and 1.4-fold higher expression and activity compared with males of genotype CC. A regression analysis indicates that the impact of these single nucleotide polymorphisms in men goes beyond the previously reported sex effect. The rs4646437C undergoes positive selection in Caucasians, as evidenced by its relative extended haplotype homozygosity value located within the uppermost percentile of a genome-wide test set of haplotypes in the same 5% frequency bin.

CONCLUSIONS

Our findings reconcile the apparent contradiction between the evidence for the influence of the individual genetic makeup on CYP3A4 expression and activity suggested by clinical studies, and the failure to identify the responsible gene variants.