Role of glucocorticoid receptor and pregnane X receptor in dexamethasone induction of rat hepatic aryl hydrocarbon receptor nuclear translocator and NADPH‐cytochrome P450 oxidoreductase (LB597)

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 important players in the adaptive and toxic responses to polycyclic and halogenated 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 study the role of GR in ARNT and POR regulation, we treated male rats with a low DEX dose (0.5 mg/kg), shown to activate GR selectively, and a high DEX dose (50 mg/kg), shown to activate both GR and PXR, in the absence and presence of the GR antagonist RU486 (50 mg/kg). The role of PXR was assessed by comparing the responses to similar low (1 mg/kg) and high (50 mg/kg) DEX doses in wild‐type and PXR‐knockout rats. In both studies, rats were euthanized at 6 and 24 h after DEX dosing. The induction of ARNT mRNA levels by low‐dose DEX and the increase in ARNT protein levels by high‐dose DEX were prevented by RU486, whereas the induced levels of ARNT mRNA and protein did not differ between wild‐type and PXR‐knockout rats. RU486 did not inhibit the induction by DEX of POR expression at the mRNA, protein, and catalytic activity levels. The induction of POR mRNA levels by low‐ and high‐dose DEX was significantly attenuated in PXR‐knockout rats and the increase in POR protein levels and catalytic activity by high‐dose DEX was completely absent in PXR‐knockout rats. These results are consistent with important roles for GR in the DEX induction of rat hepatic ARNT and PXR in the DEX induction of rat hepatic POR.Grant Funding Source: Supported by the Canadian Institutes of Health Research