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Research ArticleArticle

RETRACTION: CYP2D6 Is Inducible by Endogenous and Exogenous Corticosteroids

Muhammad Farooq, Edward J. Kelly and Jashvant D. Unadkat
Drug Metabolism and Disposition May 2016, 44 (5) 750-757; DOI: https://doi.org/10.1124/dmd.115.069229
Muhammad Farooq
Department of Pharmaceutics, University of Washington, Seattle, Washington
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Edward J. Kelly
Department of Pharmaceutics, University of Washington, Seattle, Washington
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Jashvant D. Unadkat
Department of Pharmaceutics, University of Washington, Seattle, Washington
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This article has been retracted. Please see:

  • Notice of Retraction - September 01, 2018

Abstract

Although cytochrome P450 (CYP) 2D6 has been widely considered to be noninducible on the basis of human hepatocyte studies, in vivo data suggests that it is inducible by endo- and xenobiotics. Therefore, we investigated if the experimental conditions routinely used in human hepatocyte studies may be a confounding factor in the lack of in vitro induction of CYP2D6. Sandwich cultured human hepatocytes (SCHH) were preincubated with or without dexamethasone (100 nM) for 72 hours before incubation with 1 μM endogenous (cortisol or corticosterone) or exogenous (dexamethasone or prednisolone) corticosteroids. At 72 hours, CYP2D6 mRNA, protein, and activity were quantified by real-time quantitative polymerase chain reaction, quantitative proteomics, and formation of dextrorphan from dextromethorphan, respectively. In the absence of supplemental dexamethasone, CYP2D6 activity, mRNA, and protein were significantly and robustly (>10-fold) induced by all four corticosteroids. However, this CYP2D6 induction was abolished in cells preincubated with supplemental dexamethasone. These data show, for the first time, that CYP2D6 is inducible in vitro but the routine presence of 100 nM dexamethasone in the culture medium masks this induction. Our cortisol data are in agreement with the clinical observation that CYP2D6 is inducible during the third trimester of pregnancy when the plasma concentrations of cortisol increase to ∼1 μM. These findings, if confirmed in vivo, have implications for predicting CYP2D6-mediated drug-drug interactions and call for re-evaluation of regulatory guidelines on screening for CYP2D6 induction by xenobiotics. Our findings also suggest that cortisol may be a causative factor in the in vivo induction of CYP2D6 during pregnancy.

Footnotes

    • Received December 29, 2015.
    • Accepted March 9, 2016.
  • This work was supported by the National Institutes of Health National Institute on Drug Abuse [Grant P01DA032507].

  • dx.doi.org/10.1124/dmd.115.069229.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (5)
Drug Metabolism and Disposition
Vol. 44, Issue 5
1 May 2016
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Research ArticleArticle

CYP2D6 Is Inducible by Corticosteroids

Muhammad Farooq, Edward J. Kelly and Jashvant D. Unadkat
Drug Metabolism and Disposition May 1, 2016, 44 (5) 750-757; DOI: https://doi.org/10.1124/dmd.115.069229

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Research ArticleArticle

CYP2D6 Is Inducible by Corticosteroids

Muhammad Farooq, Edward J. Kelly and Jashvant D. Unadkat
Drug Metabolism and Disposition May 1, 2016, 44 (5) 750-757; DOI: https://doi.org/10.1124/dmd.115.069229
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