Sex Differences of Drug-metabolizing Enzyme: Female Predominant Expression of Human and Mouse Cytochrome P450 3A Isoforms

Sex differences have been found in the pharmacokinetics of many drugs, and sex differences of drug-metabolizing enzymes have been considered one of the major factors of this issue. Cytochrome P450, a Phase I drug-metabolizing enzyme, consists of many isoforms having divergent substrate specificities. Some isoforms in rodents show sex-specific expression, and some in humans also show moderate differences, e.g., the activity of CYP2E1 and CYP1A2 is slightly higher in men than women. CYP3A4, the most clinically relevant isoform in humans, appears to have greater expression in women, as determined by mRNA and protein levels as well as the activities for more than ten clinically employed drugs, and the difference is increased by induction of the gene expression during pregnancy, implying the need to adjust the dose of a variety of drugs ingested by pregnant women. Regarding the mechanism of the sexually dimorphic expression of CYP3A genes, at least two hypotheses have been suggested. The first is that pregnane X receptor (PXR), activated by a higher concentration of female sex hormones, enhances the expression of PXR-target genes, including CYP3A. The second is that the different secretion patterns of growth hormone between men and women activate divergent sets of the signal transduction cascade discriminately, resulting in the sexually dimorphic expression of subsets of genes. In this review, we mainly introduce studies of female-specific CYP3A genes due to the recent progress of analysis.