@article {Falkner611, author = {K. C. Falkner and J. A. Pinaire and G.-H. Xiao and T. E. Geoghegan and R. A. Prough}, title = {Regulation of the Rat Glutathione S-Transferase A2 Gene by Glucocorticoids: Involvement of Both the Glucocorticoid and Pregnane X Receptors}, volume = {60}, number = {3}, pages = {611--619}, year = {2001}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {Glucocorticoids regulate the rat glutathioneS-transferase A2 (GSTA2) gene in a biphasic manner in cultured hepatocytes that repress gene expression at low concentration (10{\textendash}100 nM) but induce gene expression at high concentration (\>1 μM). High concentrations of the glucocorticoid receptor (GR) antagonist RU38486 (5{\textendash}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 andt-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-RXRα 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 17α-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. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/60/3/611}, eprint = {https://molpharm.aspetjournals.org/content/60/3/611.full.pdf}, journal = {Molecular Pharmacology} }