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Research ArticleArticle

Role of Glucocorticoid Receptor and Pregnane X Receptor in Dexamethasone Induction of Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator and NADPH-Cytochrome P450 Oxidoreductase

Sarah R. Hunter, Alex Vonk, Anne K. Mullen Grey and David S. Riddick
Drug Metabolism and Disposition February 2017, 45 (2) 118-129; DOI: https://doi.org/10.1124/dmd.116.073833
Sarah R. Hunter
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada
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Alex Vonk
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada
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Anne K. Mullen Grey
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada
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David S. Riddick
Department of Pharmacology and Toxicology, Medical Sciences Building, University of Toronto, Toronto, Ontario, Canada
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Abstract

The aryl hydrocarbon receptor (AHR) nuclear translocator (ARNT), as the AHR’s heterodimerization partner, and NADPH-cytochrome P450 oxidoreductase (POR), as the key electron donor for all microsomal P450s, are independent and indispensable components in the adaptive and toxic responses to polycyclic aromatic hydrocarbons. Expression of both ARNT and POR in rat liver is induced by dexamethasone (DEX), a synthetic glucocorticoid known to activate both the glucocorticoid receptor (GR) and the pregnane X receptor (PXR). To better understand the role of GR and PXR in the in vivo DEX induction of rat hepatic ARNT and POR at the mRNA and protein levels, we studied the following: 1) the effects of DEX doses that activate GR (≥0.1 mg/kg) or PXR (≥10 mg/kg); 2) responses produced by GR- and PXR-selective agonists; 3) the impact of GR antagonism on DEX’s inducing effects; and 4) whether biologic responses to DEX are altered in PXR-knockout rats. Our findings are consistent with a role for GR as a key mediator of the induction of rat hepatic ARNT expression by glucocorticoids; a role for PXR in the modulation of ARNT protein levels could not be excluded. Although GR activation may contribute to POR mRNA induction, regulation of POR expression and function by DEX is primarily PXR-mediated. This work suggests that the hepatic expression and function of ARNT and POR may be modulated by exposure to exogenous PXR activators and/or conditions that alter glucocorticoid levels such as stress, steroidal therapies, and diseases of excess or deficiency.

Footnotes

    • Received October 5, 2016.
    • Accepted November 10, 2016.
  • ↵1 S.R.H. and A.V. contributed equally to this work.

  • This work was supported by the Canadian Institutes of Health Research [Grant MOP-142442 to D.S.R.].

  • dx.doi.org/10.1124/dmd.116.073833.

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

  • Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 45 (2)
Drug Metabolism and Disposition
Vol. 45, Issue 2
1 Feb 2017
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Research ArticleArticle

Role of GR and PXR in ARNT and POR Regulation

Sarah R. Hunter, Alex Vonk, Anne K. Mullen Grey and David S. Riddick
Drug Metabolism and Disposition February 1, 2017, 45 (2) 118-129; DOI: https://doi.org/10.1124/dmd.116.073833

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Research ArticleArticle

Role of GR and PXR in ARNT and POR Regulation

Sarah R. Hunter, Alex Vonk, Anne K. Mullen Grey and David S. Riddick
Drug Metabolism and Disposition February 1, 2017, 45 (2) 118-129; DOI: https://doi.org/10.1124/dmd.116.073833
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