Cell‐based studies reveal differences in glutathione S‐transferase induction between oltipraz and tert‐butylhydroquinone

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Abstract
Selective induction of Phase II over Phase I drug‐metabolizing enzymes has been proposed as a mechanism for reduction of chemical carcinogenesis. Enzymes likely to play a role in this amelioration include the glutathione S‐transferases (GSTs) and among compounds that selectively induce key GSTs are tert‐butylhydroquinone (tBHQ) and oltipraz [4‐methyl‐5‐(2‐pyrazinyl)‐3H‐1,2‐dithiole‐3‐thione]. In vivo, and in hepatoma cells (H4IIE), these two agents induce rat GSTA2 mRNA to a similar extent. However, with a luciferase reporter construct containing 1651 bp of the proximal 5′ flanking region of the rGSTA2 gene in the same cell line and under similar conditions, luciferase activity was induced to a much greater extent by tBHQ than by oltipraz. A similar large intercompound differential was seen with reporter constructs containing either the rGSTA2 ARE enhancer and HNF1 site (−872 to −582) or XRE enhancer and HNF1 site (−1110 to −812). In H4IIE cells, the rGSTA2 mRNA response to each agent was completely inhibited by 1 μM actinomycin‐D cotreatment. With 1 μM cycloheximide cotreatment however, some induction by tBHQ remained, while induction by oltipraz was completely abolished. The induction response to tBHQ but not oltipraz was augmented by pretreatment with PD98059, a MEK1/2 specific inhibitor. Notwithstanding induction characteristics in common, oltipraz, and tBHQ have sufficient dissimilarities to indicate that rGSTA2 upregulation by the two agents is not identical. © 2002 Wiley Periodicals, Inc. J Biochem Mol Toxicol 16:154–161, 2002; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.10033