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Research ArticleSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Isoform-Specific Regulation of Cytochromes P450 Expression by Estradiol and Progesterone

Su-Young Choi, Kwi Hye Koh and Hyunyoung Jeong
Drug Metabolism and Disposition February 2013, 41 (2) 263-269; DOI: https://doi.org/10.1124/dmd.112.046276
Su-Young Choi
Departments of Pharmacy Practice (K.H.K., H.J.) and Biopharmaceutical Sciences (H.J.) and Center for Pharmaceutical Biotechnology (S.-Y.C.), College of Pharmacy, University of Illinois, Chicago, Illinois
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Kwi Hye Koh
Departments of Pharmacy Practice (K.H.K., H.J.) and Biopharmaceutical Sciences (H.J.) and Center for Pharmaceutical Biotechnology (S.-Y.C.), College of Pharmacy, University of Illinois, Chicago, Illinois
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Hyunyoung Jeong
Departments of Pharmacy Practice (K.H.K., H.J.) and Biopharmaceutical Sciences (H.J.) and Center for Pharmaceutical Biotechnology (S.-Y.C.), College of Pharmacy, University of Illinois, Chicago, Illinois
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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.

Footnotes

  • This work was supported by National Institutes of Health National Institute of Child Health and Human Development [Grant HD065532]. Human hepatocytes were obtained through the Liver Tissue Cell Distribution System [National Institutes of Health Contract N01-DK-7-0004/HHSN267200700004C].

  • dx.doi.org/10.1124/dmd.112.046276.

  • Received April 21, 2012.
  • Accepted July 26, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (2)
Drug Metabolism and Disposition
Vol. 41, Issue 2
1 Feb 2013
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Research ArticleSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

CYP Regulation by Female Hormones

Su-Young Choi, Kwi Hye Koh and Hyunyoung Jeong
Drug Metabolism and Disposition February 1, 2013, 41 (2) 263-269; DOI: https://doi.org/10.1124/dmd.112.046276

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Research ArticleSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

CYP Regulation by Female Hormones

Su-Young Choi, Kwi Hye Koh and Hyunyoung Jeong
Drug Metabolism and Disposition February 1, 2013, 41 (2) 263-269; DOI: https://doi.org/10.1124/dmd.112.046276
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