Mechanisms of NADPH - cytochrome P450 oxidoreductase induction by dexamethasone in the H4IIE rat hepatoma cell line.

Abstract

Expression of NADPH - cytochrome P450 oxidoreductase (POR), electron donor for microsomal P450s, is induced in rat liver by dexamethasone (DEX), an activator of the glucocorticoid receptor (GR) and the pregnane X receptor (PXR). DEX induction of POR in rat liver is primarily PXR-mediated, although GR may contribute to mRNA effects. We examined the role of GR and PXR in the DEX induction of POR mRNA and protein in the H4IIE rat hepatoma cell line. The DEX EC50 for a PXR target, CYP3A23, exceeded that for the GR targets tyrosine aminotransferase and PXR as well as POR itself. POR protein levels were induced 3- and 4-fold, respectively, by DEX concentrations activating GR selectively (100 nM) or both GR and PXR (10 μM). POR was induced by triamcinolone acetonide, a selective GR agonist, but not pregnenolone-16α-carbonitrile, a selective PXR agonist. POR induction was blocked by the GR antagonist RU486 but minimally influenced by the PXR antagonist FLB-12. The half-life for POR mRNA was prolonged by DEX at both 100 nM and 10 μM. GR is more important in DEX-induced POR expression in H4IIE cells compared to rat liver in vivo, calling into question the suitability of this cell model for mechanistic studies.