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Research ArticleSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Hepatic Cyp2d and Cyp26a1 mRNAs and Activities Are Increased During Mouse Pregnancy

Ariel R. Topletz, Huong N. Le, Nora Lee, John D. Chapman, Edward J. Kelly, Joanne Wang and Nina Isoherranen
Drug Metabolism and Disposition February 2013, 41 (2) 312-319; DOI: https://doi.org/10.1124/dmd.112.049379
Ariel R. Topletz
University of Washington School of Pharmacy, Department of Pharmaceutics (A.R.T., H.N.L. N.L., E.J.K., J.W., N.I.) and Medicinal Chemistry (J.D.C.), Seattle, Washington
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Huong N. Le
University of Washington School of Pharmacy, Department of Pharmaceutics (A.R.T., H.N.L. N.L., E.J.K., J.W., N.I.) and Medicinal Chemistry (J.D.C.), Seattle, Washington
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Nora Lee
University of Washington School of Pharmacy, Department of Pharmaceutics (A.R.T., H.N.L. N.L., E.J.K., J.W., N.I.) and Medicinal Chemistry (J.D.C.), Seattle, Washington
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John D. Chapman
University of Washington School of Pharmacy, Department of Pharmaceutics (A.R.T., H.N.L. N.L., E.J.K., J.W., N.I.) and Medicinal Chemistry (J.D.C.), Seattle, Washington
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Edward J. Kelly
University of Washington School of Pharmacy, Department of Pharmaceutics (A.R.T., H.N.L. N.L., E.J.K., J.W., N.I.) and Medicinal Chemistry (J.D.C.), Seattle, Washington
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Joanne Wang
University of Washington School of Pharmacy, Department of Pharmaceutics (A.R.T., H.N.L. N.L., E.J.K., J.W., N.I.) and Medicinal Chemistry (J.D.C.), Seattle, Washington
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Nina Isoherranen
University of Washington School of Pharmacy, Department of Pharmaceutics (A.R.T., H.N.L. N.L., E.J.K., J.W., N.I.) and Medicinal Chemistry (J.D.C.), Seattle, Washington
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Abstract

There is considerable evidence that drug disposition is altered during human pregnancy and based on probe drug studies, CYP2D6 activity increases during human pregnancy. The aim of this study was to determine whether the changes of CYP2D6 activity observed during human pregnancy could be replicated in the mouse, and explore possible mechanisms of increased CYP2D6 activity during pregnancy. Cyp2d11, Cyp2d22, Cyp2d26 and Cyp2d40 mRNA was increased (P < 0.05) on gestational days (GD) 15 and 19 compared with the non-pregnant controls. There was no change (P > 0.05) in Cyp2d9 and Cyp2d10 mRNA. In agreement with the increased Cyp2d mRNA, Cyp2d-mediated dextrorphan formation from dextromethorphan was increased 2.7-fold (P < 0.05) on GD19 (56.8±39.4 pmol/min/mg protein) when compared with the non-pregnant controls (20.8±11.2 pmol/min/mg protein). An increase in Cyp26a1 mRNA (10-fold) and retinoic acid receptor (Rar)β mRNA (2.8-fold) was also observed during pregnancy. The increase in Cyp26a1 and Rarβ mRNA during pregnancy indicates increased retinoic acid signaling in the liver during pregnancy. A putative retinoic acid response element was identified within the Cyp2d40 promoter and the mRNA of Cyp2d40 correlated (P < 0.05) with Cyp26a1 and Rarβ. These results show that Cyp2d mRNA is increased during mouse pregnancy the and mouse may provide a suitable model to investigate the mechanisms underlying the increased clearance of CYP2D6 probes observed during human pregnancy. Our findings also suggest that retinoic acid signaling in the liver is increased during pregnancy, which may have broader implications to energy homeostasis in the liver during pregnancy.

Footnotes

  • This work was supported in part by National Institutes of Health [Grant R01 GM081569]. Research reported in this publication was supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health through the Clinical and Translational Science Awards Program (CTSA) under Grants [Grants TL1TR000422 and UL1TR000423]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

  • dx.doi.org/dmd.112.049379.

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

  • Received October 2, 2012.
  • Accepted November 13, 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

Increased Cyp2d and Cyp26a1 During Mouse Pregnancy

Ariel R. Topletz, Huong N. Le, Nora Lee, John D. Chapman, Edward J. Kelly, Joanne Wang and Nina Isoherranen
Drug Metabolism and Disposition February 1, 2013, 41 (2) 312-319; DOI: https://doi.org/10.1124/dmd.112.049379

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Research ArticleSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Increased Cyp2d and Cyp26a1 During Mouse Pregnancy

Ariel R. Topletz, Huong N. Le, Nora Lee, John D. Chapman, Edward J. Kelly, Joanne Wang and Nina Isoherranen
Drug Metabolism and Disposition February 1, 2013, 41 (2) 312-319; DOI: https://doi.org/10.1124/dmd.112.049379
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