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Vol. 30, Issue 5, 570-575, May 2002

Induction of CYP3A Expression by Dehydroepiandrosterone: Involvement of the Pregnane X Receptor

Sharon L. Ripp, Jennifer L. Fitzpatrick,1 Jeffrey M. Peters, and Russell A. Prough

Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky (S.L.R., J.L.F., R.A.P.); and Department of Veterinary Science and Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania (J.M.P.)

Dehydroepiandrosterone (DHEA) is a steroid produced by the human adrenal gland. Administration of pharmacological doses of DHEA to rats changes expression of many genes, including the cytochrome P450 family members CYP4A1 and CYP3A23. It is known that induction of CYP4A expression by DHEA requires the peroxisome proliferator-activated receptor alpha  (PPARalpha ). In the current study, PPARalpha -null mice were used to examine the role of PPARalpha in expression of CYP3A. In wild-type mice, 150 mg/kg DHEA-sulfate induced Cyp4a and Cyp3a11 mRNAs by 5- and 2-fold, respectively. Induction of Cyp4a expression by DHEA-sulfate was not observed in PPARalpha -null mice, whereas induction of Cyp3a11 expression by DHEA-sulfate was similar between genotypes. This suggests that PPARalpha is not involved in induction of Cyp3a11 expression by DHEA. Because expression of CYP3A family members can be induced by activation of another member of the nuclear receptor superfamily, the pregnane X receptor (PXR), we examined the ability of DHEA to activate PXR. In transient transfection assays, DHEA and its metabolites androst-5-ene-3beta ,17beta -diol (ADIOL), androst-5-ene-3,17-dione, and androst-4-ene-3,17-dione were activators of PXR. Maximal induction of a PXR-responsive reporter gene of approximately 3-fold was observed at concentrations of 50 to 100 µM, indicating that these steroids are relatively weak activators of PXR. Human and murine PXR exhibited different specificities for DHEA and its metabolites. ADIOL activated reporter gene expression in the presence of murine but not human PXR. Results of these studies suggest that the induction of rodent CYP3A expression upon treatment with high doses of DHEA occurs through activation of PXR.

1 Present address: Department of Pharmacology, University of Washington School of Medicine, 1959 NE Pacific St., Box 356560, Seattle, WA 98195.

Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics


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