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Vol. 27, Issue 2, 193-200, February 1999
Department of Biochemistry and Molecular Biology, University of
Louisville, School of Medicine, Louisville, Kentucky
Dehydroepiandrosterone (DHEA) is the only known naturally occurring
compound that promotes peroxisome proliferation in rodent liver, and
stimulates transcriptional induction of genes involved in lipid
metabolism and peroxisomal 
-oxidation. Therefore, we examined mRNA
for several such genes in rat liver, specifically acyl-CoA oxidase and
the cytochromes P-450 (CYP4A1, CYP4A3, and CYP3A23), after 5 to 6 day
treatments with either DHEA, or nafenopin, a known peroxisome
proliferator. Acyl-CoA oxidase and CYP4A1 were induced nearly
identically by DHEA and nafenopin, with induction being more pronounced
in female rats. However, CYP3A23 was induced only by DHEA, suggesting
an induction mechanism independent of the peroxisome proliferator
activated receptor. Previously, we observed triiodothyronine
(T3) suppression of peroxisome proliferator induced CYP4As
and we sought to determine whether CYP3A23 might be regulated in a
different manner. T3 was found to also suppress DHEA-dependent induction of CYP3A23. CYP4A2 expression in kidney was
also negatively regulated by T3. To characterize a putative negative thyroid hormone response element (nTRE) in the 5' flanking region of this gene, a luciferase reporter gene containing a rat CYP4A2
flanking sequence extending to 
1865 bp was transfected into HepG2
cells along with human thryroid hormone receptor expression vector.
Expression of luciferase activity was unaffected by T3, suggesting the absence of a functional nTRE within this portion of
CYP4A2. These data demonstrate gene regulatory activity by DHEA
different from that of nafenopin, and a suppressive effect of
T3, consistent with indirect regulatory mechanisms not
involving an nTRE.
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S. L. Ripp, J. L. Fitzpatrick, J. M. Peters, and R. A. Prough Induction of CYP3A Expression by Dehydroepiandrosterone: Involvement of the Pregnane X Receptor Drug Metab. Dispos., May 1, 2002; 30(5): 570 - 575. [Abstract] [Full Text] [PDF]
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