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DIFFERENTIAL EFFECTS OF THE OXIDIZED METABOLITES OF OLTIPRAZ ON THE ACTIVATION OF CCAAT/ENHANCER BINDING PROTEIN-ß AND NF-E2-RELATED FACTOR-2 FOR GSTA2 GENE INDUCTION

National Research Laboratory, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea (M.S.K., S.J.L., S.G.K.); and CJ Pharmaceutical Research Institute, CJ Corp., Kyonggi-Do, Korea (J.W.K., J.W.L.)

Comprehensive mechanistic studies suggest that oltipraz exerts cancer chemopreventive effects through the induction of glutathione S-transferase (GST). Previously, we have shown that the activation of CCAAT/enhancer binding protein-ß (C/EBPß), promoted by oltipraz, contributes to the transcriptional induction of the GSTA2 gene. Studies also indicated that exposure of animals to oltipraz triggers nuclear accumulation of NF-E2-related factor-2 (Nrf2) with an increase in Nrf2's antioxidant response element (ARE) binding activity. Given the previous reports that C/EBPß activation contributes to oltipraz's induction of the GSTA2 gene and that Nrf2 activation by oltipraz was variable depending on the concentrations, this study investigated whether the major oxidized metabolites of oltipraz induce GSTA2 through the activation of C/EBPß and/or Nrf2. Immunoblot analysis revealed that M1 [4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one] and M2 (7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]pyrazine), but not M3 (7-methyl-8-(methylsulfinyl)-6-(methylthio)H-pyrrolo[1,2-a]pyrazine) and M4 (7-methyl-6,8-bis(methylsulfinyl)H-pyrrolo[1,2-a]pyrazine), induced GSTA2 in H4IIE cells. M1 and M2 also increased the luciferase activity from pGL-1651, which contained the luciferase structural gene downstream of the –1.65-kilobase GSTA2 promoter region. Nuclear C/EBPß levels were enhanced by the metabolites but not by M3 or M4. Among the oxidized metabolites examined, only M2, which elicited cell death at a relatively high concentration, activated Nrf2, as indicated by nuclear accumulation of Nrf2 and its ARE binding activity. The present study provides evidence that M1 and M2, but not M3 and M4, induce GSTA2 and that M1 induces GSTA2 only via C/EBPß activation, whereas M2 does so by activating Nrf2 as well as C/EBPß. These results substantiate the differential effects of oltipraz's metabolites on C/EBPß- and/or Nrf2-mediated GSTA2 induction.