Abstract
Results from clinical studies suggest that pregnancy alters hepatic drug metabolism in a cytochrome P450 (CYP) isoform-specific manner, and rising concentrations of female hormones are potentially responsible for the changes. The objective of this study was to comprehensively characterize the effects of estrogen and progesterone on the expression and activity of major drug-metabolizing CYPs. To this end, primary human hepatocytes were treated with estradiol and progesterone, and mRNA expression and activity levels of 10 different CYP isoforms were determined. The results showed that estradiol enhances CYP2A6, CYP2B6, and CYP3A4 expression, whereas progesterone induces CYP2A6, CYP2B6, CYP2C8, CYP3A4, and CYP3A5 expression. The induction was mainly observed when the average hormone concentrations were at the levels reached during pregnancy, suggesting that these effects are likely pregnancy-specific. Estradiol also increased enzyme activities of CYP2C9 and CYP2E1 without affecting the mRNA expression levels by unknown mechanisms. Taken together, our results show differential effects of estrogen and progesterone on CYP expression, suggesting involvement of different regulatory mechanisms in female hormone-mediated CYP regulation. Our findings potentially provide a basis in mechanistic understanding for altered drug metabolism during pregnancy.
- Received April 23, 2012.
- Accepted July 26, 2012.
- The American Society for Pharmacology and Experimental Therapeutics