Cell-based studies reveal differences in glutathione S-transferase induction between oltipraz and tert-butylhydroquinone.
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 microM actinomycin-D cotreatment. With 1 microM 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.
Lamb
John G
JG
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, Utah 84112, USA.
Franklin
Michael R
MR
D000818:Animals; D015152:Blotting, Northern; D004790:Enzyme Induction; D005982:Glutathione Transferase / Q000096:biosynthesis* / Q000235:genetics; D006873:Hydroquinones / Q000494:pharmacology*; D008156:Luciferases / Q000235:genetics; D010957:Plasmids; D011401:Promoter Regions, Genetic; D011719:Pyrazines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D013871:Thiones; D013876:Thiophenes; D014407:Tumor Cells, Cultured
D006873:Hydroquinones; D011719:Pyrazines; D012333:RNA, Messenger; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; C018855:2-tert-butylhydroquinone; D008156:Luciferases; D005982:Glutathione Transferase