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Vol. 60, Issue 3, 611-619, September 2001
Department of Biochemistry and Molecular Biology, University of
Louisville School of Medicine, Louisville, Kentucky
Glucocorticoids regulate the rat glutathione
S-transferase A2 (GSTA2) gene in a
biphasic manner in cultured hepatocytes that repress gene expression at
low concentration (10-100 nM) but induce gene expression at high
concentration (>1 µM). High concentrations of the glucocorticoid
receptor (GR) antagonist RU38486 (5-10 µM) also induced the
expression of GSTA2. These effects were reproduced in
HepG2 cells transfected with a luciferase reporter containing 1.6 kilobase pairs of 5'-flanking sequence of GSTA2 and
expression plasmids for either GR, pregnane X receptor (PXR) or a
combination of both. Dexamethasone t-butylacetate (1 µM t-Bu-DEX) repressed gene expression between 60 to
75% when only GR was expressed. When PXR was expressed, both basal and
t-Bu-DEX-dependent gene expression was increased over
2-fold, respectively. Biphasic regulation of gene expression was
observed over a broad range of t-Bu-DEX concentrations
when expression plasmids for both receptors were cotransfected. Other
steroids of the pregnane class induced GSTA2 expression
as expected for a PXR-dependent process. Because no canonical
responsive element for the PXR-RXR
heterodimer was observed in the
5'-flanking region of the construct, deletion analysis was used to
identify a pregnane responsive region between base pairs 
700 and
683; this 20-bp region contains the antioxidant response element
(ARE). When the ARE sequence was mutated, basal, t-butylhydroquinone- and
17-hydroxypregnenolone-inducible expression were all lost. These
results suggest that PXR interacts with factors binding to the ARE to
elicit the pregnane inductive response for GSTA2.
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