ArticleDrug metabolism and disposition: the biological fate of chemicals2025
Impact of sex and pregnancy on hepatic CYP3A4 expression and activity in a humanized mouse model.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 6 papers.
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Who cites it
6 citing papers in PubMed.
- Beyond pooled analysis: sex-specific cardiovascular adverse event reporting signals with antiarrhythmic drugs in FAERS.Naunyn-Schmiedeberg's archives of pharmacology · 2026Article
- Sex differences in the disposition of cannabidiol and its metabolites in mice.Journal of cannabis research · 2026Article
- Comparative analysis of sex-based, vendor-based, and species differences in cytochrome P450 metabolism.Scientific reports · 2026Article
- Sex differences in hepatic enzymes and transporters involved in pharmacokinetics.Liver research (Beijing, China) · 2025Review
- Mechanisms of altered hepatic drug disposition during pregnancy: small molecules.Expert opinion on drug metabolism & toxicology · 2025Review
- Estrogen associations with human pregnancy related increases in cytochrome P450 3A activity.Frontiers in pharmacology · 2025Article
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Authors and funding
7 authors.
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Abstract
Cytochrome P450 (CYP) 3A4 is an essential drug-metabolizing enzyme in humans, which shows substantial interindividual variation in response to various intrinsic and extrinsic factors such as sex and pregnancy. In humans, higher CYP3A4 metabolism has been observed in females compared with that in males and in pregnant compared with that in nonpregnant individuals, which has been linked to increased CYP3A4 expression in liver. However, sex differences and pregnancy-mediated changes in hepatic CYP3A4 expression and activity in vivo are not fully understood. In this study, we investigated the utility of a genetically engineered humanized mouse model that carries human CYP3A4/7, pregnane X receptor (PXR) and constitutive androstane receptor (CAR) (huPXR/CAR/CYP3A4/7) to recapitulate sex-associated and pregnancy-associated differences in the hepatic CYP3A4 expression and metabolism observed in humans. We found that female huPXR/CAR/CYP3A4/7 mice exhibited higher basal CYP3A4 mRNA levels and CYP3A4 absolute protein concentrations in liver, and higher 1-hydroxymidazolam formation in liver microsomes, compared with male humanized mice. In contrast, pregnant huPXR/CAR/CYP3A4/7 mice exhibited lower CYP3A4 mRNA levels, CYP3A4 absolute protein concentrations, and 1-hydroxymidazolam formation compared with nonpregnant and postpartum humanized mice. Expression of CAR and Cyp2b10 (a CAR responsive gene) were also higher in females and decreased during pregnancy and were positively correlated with hepatic CYP3A4 mRNA levels. Overall, the huPXR/CAR/CYP3A4/7 mouse model demonstrated utility to study higher basal hepatic CYP3A4 metabolism in females compared with that in males in vivo; however, this humanized mouse model did not demonstrate utility to study pregnancy-mediated increases in CYP3A4 drug substrate metabolism and clearance observed in humans. SIGNIFICANCE STATEMENT: This study assessed the impact of sex and pregnancy on hepatic CYP3A4 protein concentrations and metabolism in humanized PXR/CAR/CYP3A4 mice. Consistent with humans, female mice demonstrated higher hepatic CYP3A4 expression and activity than male mice. In contrast, pregnant mice showed decreased CYP3A4 expression and metabolism compared with nonpregnant mice. The humanized mouse model appeared useful to evaluate sex differences in basal hepatic CYP3A4 metabolism in vivo, but not to study the pregnancy-mediated increase in CYP3A4 metabolism observed during human pregnancy.
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