title: Isoform-specific regulation of cytochromes P450 expression by estradiol and progesterone.
abstract: Results from clinical studies suggest that pregnancy alters hepatic drug metabolism in a cytochrome P450 (P450) 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 P450s. To this end, primary human hepatocytes were treated with estradiol and progesterone, and mRNA expression and activity levels of 10 different P450 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 P450 expression, suggesting involvement of different regulatory mechanisms in female hormone-mediated P450 regulation. Our findings potentially provide a basis in mechanistic understanding for altered drug metabolism during pregnancy.
authors: Department of Pharmacy Practice (MC 886), College of Pharmacy, University of Illinois at Chicago, Chicago, IL 60612, USA. yjeong@uic.edu
authors: Su-Young
authors: SY
authors: Choi
authors: Kwi Hye
authors: KH
authors: Koh
authors: Hyunyoung
authors: H
authors: Jeong
mesh_terms: D000328:Adult; D000368:Aged; D001711:Biotransformation; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004958:Estradiol / Q000378:metabolism / Q000494:pharmacology*; D005260:Female; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007527:Isoenzymes; D008875:Middle Aged; D011247:Pregnancy; D061251:Primary Cell Culture; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D013379:Substrate Specificity; D013997:Time Factors
chemical_list: D007527:Isoenzymes; D012333:RNA, Messenger; D011374:Progesterone; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System