Regulation of the CYP3A4 Gene by Hydrocortisone and Xenobiotics: Role of the Glucocorticoid and Pregnane X Receptors

• Published in: Drug metabolism and disposition Vol. 28; no. 5; pp. 493 - 496
• Main Authors: EL-SANKARY, W, PLANT, N. J, GIBSON, G. G, MOORE, D. J
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01-05-2000
• Subjects: Alkaline Phosphatase - metabolism; Anti-Inflammatory Agents - pharmacology; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Cell Line; Cells, Cultured; CYP3A4 gene; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System - genetics; cytochrome P4503A4; Gene Expression Regulation, Enzymologic - drug effects; Genes, Reporter - genetics; glucocorticoid receptors; Hormones. Endocrine system; Humans; hydrocortisone; Hydrocortisone - pharmacology; Liver - cytology; Liver - drug effects; Liver - enzymology; Medical sciences; Mixed Function Oxygenases - genetics; Pharmacology. Drug treatments; Plasmids - genetics; Pregnane X Receptor; pregnane X receptors; Receptors, Cytoplasmic and Nuclear - drug effects; Receptors, Glucocorticoid - drug effects; Receptors, Steroid - drug effects; Transfection - genetics; Xenobiotics - pharmacology; Corticosteroid; Unspecific monooxygenase; Enzyme; Isozyme; Cytochrome P450; Antiinflammatory agent; Molecular interaction; Gene expression; Hydrocortisone; Glucocorticoid; In vitro; Mechanism; Food drug interaction; Plasmid; Pregnane; Regulation(control); Transfection; Enzymatic activity; Gene; Drug-metabolizing enzyme; Drug interaction; Oxidoreductases; Xenobiotic; Hormonal receptor
• ISSN: 0090-9556; 1521-009X

The molecular mechanisms of regulation of the CYP3A4 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 EC 50 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.