RGD Reference Report - Role of Glucocorticoid Receptor and Pregnane X Receptor in Dexamethasone Induction of Rat Hepatic Aryl Hydrocarbon Receptor Nuclear Translocator and NADPH-Cytochrome P450 Oxidoreductase. - Rat Genome Database

Send us a Message



Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   

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

Authors: Hunter, Sarah R  Vonk, Alex  Mullen Grey, Anne K  Riddick, David S 
Citation: Hunter SR, etal., Drug Metab Dispos. 2017 Feb;45(2):118-129. doi: 10.1124/dmd.116.073833. Epub 2016 Nov 16.
RGD ID: 127285625
Pubmed: (View Article at PubMed) PMID:27856527
DOI: Full-text: DOI:10.1124/dmd.116.073833

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.

Annotation

Gene Ontology Annotations    

Biological Process

Phenotype Annotations    

Mammalian Phenotype
Objects Annotated

Genes (Rattus norvegicus)
Arnt  (aryl hydrocarbon receptor nuclear translocator)
Cyp3a23-3a1  (cytochrome P450, family 3, subfamily a, polypeptide 23-polypeptide 1)
Nr1i2  (nuclear receptor subfamily 1, group I, member 2)
Nr1i2em1Sage  (nuclear receptor subfamily 1, group I, member 2; ZFN induced mutant1, Sage)
Por  (cytochrome p450 oxidoreductase)
Tat  (tyrosine aminotransferase)

Strains
F344/NCrl  (NA)
SD-Nr1i2em1Sage  (NA)

Objects referenced in this article
Gene Ahr aryl hydrocarbon receptor Rattus norvegicus
Gene Ahrem2Sage aryl hydrocarbon receptor; ZFN induced mutant2, Sage Rattus norvegicus
Strain SD-Ahrem2Sage null Rattus norvegicus

Additional Information