Divergent Modes of Induction of Rat Hepatic and Pulmonary CYP3A1 by Dexamethasone and Pregnenolone 16.ALPHA.-Carbonitrile

Abstract

Both the glucocorticoid receptor (GR) agonist dexamethasone (DEX) and GR antagonist pregnenolone 16α-carbonitrile (PCN) enhanced the transcription of CYP3A1 in rats though in a different fashion. Seven-week old male Wister rats were intraperitoneally administered one to three times with corn oil (vehicle) or DEX and/or PCN (80 mg/kg each) at 24-hr intervals according to various schedules. The animals were sacrificed twenty-four hours after the last treatment, and the dissected livers and lungs were examined for mRNA contents of CYP3A1 and pregnane X receptor (PXR) by real time PCR. DEX appeared to act mainly as an inducer of PXR, that in turn transactivated the CYP3A1 gene, by activating the GR, while PCN was deduced to have a direct effect on the expression of the CYP3A1 gene via activation of PXR from the rapid increase in CYP3A1 mRNA in comparison with DEX. Sequential treatment with DEX and PCN in this order induced CYP3A1 mRNA expression more effectively than treatment in the opposite order. When DEX and PCN were administered simultaneously, the induction of PXR by DEX was reversed by PCN, resulting from their competitive effects on the GR. In the lung, an increase in the CYP3A1 mRNA level was observed in the presence of DEX but not PCN, independently of the GR-activation.