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Vol. 30, Issue 5, 570-575, May 2002
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 
(PPAR). In the
current study, PPAR-null mice were used to examine the role of
PPAR 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 PPAR-null mice, whereas induction of Cyp3a11 expression by DHEA-sulfate was similar
between genotypes. This suggests that PPAR 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-3
,17-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.
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