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Research ArticleSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Induction of Hepatic CYP3A Enzymes by Pregnancy-Related Hormones: Studies in Human Hepatocytes and Hepatic Cell Lines

Ioannis Papageorgiou, Susan Grepper and Jashvant D. Unadkat
Drug Metabolism and Disposition February 2013, 41 (2) 281-290; DOI: https://doi.org/10.1124/dmd.112.049015
Ioannis Papageorgiou
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (I.P., J.D.U.), and LifeTechnologies, Carlsbad, California (S.G.)
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Susan Grepper
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (I.P., J.D.U.), and LifeTechnologies, Carlsbad, California (S.G.)
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Jashvant D. Unadkat
Department of Pharmaceutics, School of Pharmacy, University of Washington, Seattle, Washington (I.P., J.D.U.), and LifeTechnologies, Carlsbad, California (S.G.)
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Abstract

CYP3A activity is induced by approximately 2-fold during the third trimester of human pregnancy. Placental growth hormone (PGH), estrogens (primarily 17β-estradiol), cortisol, and progesterone have the potential to modulate CYP3A activity. Therefore, we determined whether the elevated plasma concentrations of these hormones during pregnancy induce hepatic CYP3A expression. We incubated sandwich-cultured human hepatocytes (SCHH) from premenopausal female donors (n = 2) with the physiologic (unbound, 1× total) and the 10× total third trimester hormone plasma concentrations (individually and in combination) and determined their effect on CYP3A activity and the transcripts of CYP3A4, CYP3A5, and the respective hormone receptors (growth hormone receptor, glucocorticoid receptor, and estrogen receptor alpha). Of all the hormones, cortisol was the most potent inducer of CYP3A activity and CYP3A4, CYP3A5 mRNA expression. The combination of PGH/growth hormone and cortisol induced CYP3A activity and expression significantly more than did cortisol alone. When incubated with the unbound or total plasma concentration of all the hormones, CYP3A activity in SCHH was induced to an extent comparable to that observed in vivo during the third trimester. These hormones had only a modest effect on the mRNA expression of the hormone receptors. The pattern of induction observed in SCHH was reproduced in HepaRG cells but not in HuH7/HepG2 cells. SCHH or HepaRG cells could be used to determine the mechanistic basis of CYP3A induction during pregnancy and to predict the magnitude of induction likely to be observed during the first and second trimesters, when phenotyping studies to measure in vivo CYP3A activity are logistically difficult to perform.

Footnotes

  • This work was supported, in part, by the Drug Metabolism, Transport and Pharmacogenomic Research (DMTPR) program of the School of Pharmacy, University of Washington.

  • dx.doi.org/10.1124/dmd.112.049015.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Received September 10, 2012.
  • Accepted December 6, 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

Effect of Pregnancy-Related Hormones on Hepatic CYP3A Induction

Ioannis Papageorgiou, Susan Grepper and Jashvant D. Unadkat
Drug Metabolism and Disposition February 1, 2013, 41 (2) 281-290; DOI: https://doi.org/10.1124/dmd.112.049015

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Research ArticleSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Effect of Pregnancy-Related Hormones on Hepatic CYP3A Induction

Ioannis Papageorgiou, Susan Grepper and Jashvant D. Unadkat
Drug Metabolism and Disposition February 1, 2013, 41 (2) 281-290; DOI: https://doi.org/10.1124/dmd.112.049015
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