Induction ofCYP3AExpression by Dehydroepiandrosterone: Involvement of the Pregnane X Receptor

Abstract

ABSTRACT: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 Administration of dehydroepiandrosterone (DHEA 2 ) to rodents results in several beneficial biological responses. DHEA acts as a chemopreventive agent in rodent cancer models (Schwartz, 1979;Schwartz and Tannen, 1981;Nyce et al., 1984;Pashko et al., 1984). Rodents with a predisposition toward obesity demonstrate decreased rates of weight gain without appetite suppression upon treatment with DHEA (Yen et al., 1977). Administration of DHEA ameliorated symptoms of diabetes and systemic lupus erythematosis in the appropriate rodent models (Coleman et al., 1982;Lucas et al., 1985). DHEA may act as a neurosteroid, and is thought to enhance memory function (Robel and Baulieu, 1995), as well as immune function (Morfin and Courchay, 1994).DHEA is the most abundant circulating steroid in humans. It is secreted by the adrenal gland as the 3␤-sulfate conjugate. DHEAsulfate (DHEA-S) is taken up by target tissues (e.g., testis and ovary), and hydrolyzed by sulfatases back to DHEA (Kroboth et al., 1999). DHEA can then be further metabolized to active androgens and estrogens in steroidogenic tissues, as well as to several hydroxylated metabolites in liver (Fitzpatrick et al., 2001).In rodents, DHEA is not produced by the adrenal, but limited amounts of DHEA are produced from progesterone in steroidogenic tissues (Pelletier et al., 1992;van Weerden et al., 1992). Although treatment of rodents with exogenous DHEA can produce the beneficial effects described above, high doses of DHEA induce peroxisome proliferation (Wu et al., 1989;Prough et al., 1994). Peroxisome proliferators, including DHEA, modulate expression of genes involved in fatty acid metabolism, including fatty acyl CoA oxidase, cytochrome P450 4A (CYP4A), and malic enzyme (Webb et al., 1996).3 DHEA and other peroxisome proliferators require the perox- drost-5-en-17-one); DHEA-S, dehydroepiandrosterone 3␤-sulfate; PPAR␣, peroxisome proliferator-activated receptor ␣; PXR, pregnane X receptor; ADIOL, androst-5-ene-3␤,17␤-diol; ADIONE, androst-4-ene-3,17-dione; 11␤-hydroxy-DHEA, 3␤,11␤-dihydroxy-androst-5-en-17-one; 16␣-hydroxy-DHEA, 3␤,16␣-dihydroxy-androst-5-en-17-one; 7-oxo-DHEA, 3␤-hydroxy-androst-5-ene-7,17-dione; 7␣-hydroxy-DHEA, 3␤,7␣-dihydroxy-androst-5-en-17-one; DMSO, dimethyl s...

Modulation of the peroxisomal gene expression pattern by dehydroepiandrosterone and vitamin D: therapeutic implications

“…Bruder et al (1997) suggested that DHEA might stimulate the oestrogen response element. Very recently, it was proposed that DHEA might activate the pregnane X receptor (Singleton et al 1999, Ripp et al 2002. A recent clinical study on the treatment of X-ALD patients with DHEA showed a lowering of long chain FAs but not of C24 FAs ( J Assies, E B Haverkort, R Lieverse & P Vreken, unpublished observations).…”

Novel mechanisms for DHEA action

“…We observed the induction of P4503A23 in the livers of rats fed DHEA and, because DHEA is a pregnane derivative, it was likely that DHEA and its metabolites may act as a ligand of PXR (Ripp et al 2002). Using Pparα-null mice fed DHEA, we were unable to detect the induction of Cyp4a1, but there was a two-fold increase in the enzymatic activity and mRNA specific for Cyp3a11 in both wild-type and PPARα-null mice (Ripp et al 2002). In Pxr-null mice, we did not observe P4503A11 induction upon DHEA feeding (S J Webb and R A Prough, unpublished observations).…”

“…In Pxr-null mice, we did not observe P4503A11 induction upon DHEA feeding (S J Webb and R A Prough, unpublished observations). Other experiments demonstrated that DHEA, Adiol, and Adione activate PXR in luciferase assays in HepG2 cells, using a vector containing two copies of the PXR responsive element (PXRE) from the rat Cyp3a23 gene (Ripp et al 2002). However, other oxidized metabolites of DHEA have no effect in stimulating PXRE-luciferase activity at low micromolar concentrations (Ripp et al 2002).…”

“…Other experiments demonstrated that DHEA, Adiol, and Adione activate PXR in luciferase assays in HepG2 cells, using a vector containing two copies of the PXR responsive element (PXRE) from the rat Cyp3a23 gene (Ripp et al 2002). However, other oxidized metabolites of DHEA have no effect in stimulating PXRE-luciferase activity at low micromolar concentrations (Ripp et al 2002). Human and murine PXRs have been shown to have differences, in which the ligand activates each receptor; the human receptor is activated by rifampicin but not the murine receptor.…”

“…DHEA binds steroid hormone receptors (class I NRs) and selects class II NRs (Table 1) (reviewed in Webb et al 2006, Traish et al 2011 with the following reported affinities: pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR, NR1I2), K d ~ 50-100 µM (Webb et al 2006); estrogen receptors α and β (ERα (ESR1) and ERβ (ESR2)), K d ~ 1.2 and 0.5 µM, respectively; androgen receptor (AR), K d ~ 1.1 µM (Chen et al 2005); peroxisome proliferator-activated receptors (PPAR), K m ~7 µM (Webb et al 2006); and PXR, Kd ~10-50 µM (Ripp et al 2002). Although higher and lower binding affinities have been reported, the binding affinities for the DHEA-NR interactions are much lower compared with cognate ligands for the receptors (Table 1).…”