RT Journal Article SR Electronic T1 Regulation of the CYP3A4 Gene by Hydrocortisone and Xenobiotics: Role of the Glucocorticoid and Pregnane X Receptors JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 493 OP 496 VO 28 IS 5 A1 Wafaa El-Sankary A1 Nick J. Plant A1 G. Gordon Gibson A1 David J. Moore YR 2000 UL http://dmd.aspetjournals.org/content/28/5/493.abstract AB The molecular mechanisms of regulation of theCYP3A4 gene have been examined in an in vitro reporter gene system, containing −1 kb of the CYP3A4 promoter, in a HepG2 cell line. This system allows for the separate and combined transfection of expression plasmids encoding the human glucocorticoid receptor (hGR) and the human pregnane X receptor (hPXR), and, therefore, the opportunity to assess the role of these receptors in the induction process. Hydrocortisone produces a dose-dependent increase in CYP3A4 activation, a response that is increased in the presence of either receptor. Moreover, transfection of the hPXR decreased the EC50 for hydrocortisone-dependent induction by a factor of 3.3, a response that was not changed by simultaneous cotransfection of the hGR. In addition, the hydrocortisone dose-response curve falls within the physiological blood level concentration of this steroid, implicating a regulatory role for hydrocortisone in the basal level of CYP3A4 expression. Although the responses to dexamethasone and rifampicin were both increased by both receptors, dexamethasone activation of CYP3A4 was similar for both the hGR and the hPXR, whereas rifampicin-dependent activation favored the hPXR. We conclude that regulation of the CYP3A4 gene is receptor-dependent and that hydrocortisone may function as a regulator of basal expression via the hPXR and the hGR. The implications of this latter conclusion for possible regulatory interactions between hydrocortisone and xenobiotic inducers remain to be clarified. The American Society for Pharmacology and Experimental Therapeutics