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

Drug Metab Dispos. 2017 Feb;45(2):118-129. doi: 10.1124/dmd.116.073833. Epub 2016 Nov 16.

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.

MeSH terms

  • Animals
  • Aryl Hydrocarbon Receptor Nuclear Translocator / biosynthesis*
  • Dexamethasone / pharmacology*
  • Dose-Response Relationship, Drug
  • Enzyme Induction
  • Gene Knockout Techniques
  • Male
  • Microsomes, Liver / drug effects*
  • Microsomes, Liver / metabolism
  • NADPH-Ferrihemoprotein Reductase / biosynthesis*
  • Pregnane X Receptor
  • Rats, Inbred F344
  • Rats, Sprague-Dawley
  • Receptors, Glucocorticoid / genetics
  • Receptors, Glucocorticoid / physiology*
  • Receptors, Steroid / genetics
  • Receptors, Steroid / physiology*

Substances

  • Pregnane X Receptor
  • Receptors, Glucocorticoid
  • Receptors, Steroid
  • Aryl Hydrocarbon Receptor Nuclear Translocator
  • Dexamethasone
  • NADPH-Ferrihemoprotein Reductase