Differential effects of the oxidized metabolites of oltipraz on the activation of CCAAT/enhancer binding protein-beta and NF-E2-related factor-2 for GSTA2 gene induction.

2.50
Hdl Handle:
http://hdl.handle.net/10146/57814
Title:
Differential effects of the oxidized metabolites of oltipraz on the activation of CCAAT/enhancer binding protein-beta and NF-E2-related factor-2 for GSTA2 gene induction.
Authors:
Ko, Myong Suk; Lee, Seung Jin; Kim, Jin Wan; Lim, Jee Woong; Kim, Sang Geon
Abstract:
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-beta (C/EBPbeta), 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/EBPbeta 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/EBPbeta 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/EBPbeta 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/EBPbeta activation, whereas M2 does so by activating Nrf2 as well as C/EBPbeta. These results substantiate the differential effects of oltipraz's metabolites on C/EBPbeta- and/or Nrf2-mediated GSTA2 induction.
Citation:
Drug Metab. Dispos. 2006, 34 (8):1353-1360
Journal:
Drug Metabolism and Disposition: the biological fate of chemicals
Issue Date:
Aug-2006
URI:
http://hdl.handle.net/10146/57814
DOI:
10.1124/dmd.106.009514
PubMed ID:
16714377
Additional Links:
http://dmd.aspetjournals.org/cgi/content/full/34/8/1353
Type:
Article
Language:
en
Description:
Lifestyle element evaluated: oxidized metabolites of oltipraz {M1 [4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one]; M2 (7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]pyrazine); M3 (7-methyl-8-(methylsulfinyl)-6-(methylthio)H-pyrrolo[1,2-a]pyrazine); M4 (7-methyl-6,8-bis(methylsulfinyl)H-pyrrolo[1,2-a]pyrazine)}Outcome studied: induction of glutathione S-transferase (GST) gene through the activation of C/EBPbeta and/or Nrf2. Method of biomarker analysis: immunoblot analysis using an antibody directed against GSTA2. Study type: the rat hepatocyte-derived cell line H4IIE.Impact on outcome: 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/EBPbeta 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. KEYWORDS - CLASIFFICATION: analysis;Animals;Anticarcinogenic Agents;biosynthesis;CCAAT-Enhancer-Binding Protein-beta;Cell Line;drug effects;Enzyme Induction;Gene Expression;genetics;Glutathione;Glutathione Transferase;humans;Isoenzymes;Korea;lifestyle modulation of cancer & cancer biomarkers;mechanisms of carcinogenesis;metabolism;NF-E2-Related Factor 2;pharmacology;Pyrazines;Rats;Research;
ISSN:
0090-9556
Appears in Collections:
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Full metadata record

DC FieldValue Language
dc.contributor.authorKo, Myong Suk-
dc.contributor.authorLee, Seung Jin-
dc.contributor.authorKim, Jin Wan-
dc.contributor.authorLim, Jee Woong-
dc.contributor.authorKim, Sang Geon-
dc.date.accessioned2009-03-30T09:39:32Z-
dc.date.available2009-03-30T09:39:32Z-
dc.date.issued2006-08-
dc.identifier.citationDrug Metab. Dispos. 2006, 34 (8):1353-1360en
dc.identifier.issn0090-9556-
dc.identifier.pmid16714377-
dc.identifier.doi10.1124/dmd.106.009514-
dc.identifier.urihttp://hdl.handle.net/10146/57814-
dc.descriptionLifestyle element evaluated: oxidized metabolites of oltipraz {M1 [4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one]; M2 (7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]pyrazine); M3 (7-methyl-8-(methylsulfinyl)-6-(methylthio)H-pyrrolo[1,2-a]pyrazine); M4 (7-methyl-6,8-bis(methylsulfinyl)H-pyrrolo[1,2-a]pyrazine)}Outcome studied: induction of glutathione S-transferase (GST) gene through the activation of C/EBPbeta and/or Nrf2. Method of biomarker analysis: immunoblot analysis using an antibody directed against GSTA2. Study type: the rat hepatocyte-derived cell line H4IIE.Impact on outcome: 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/EBPbeta 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. KEYWORDS - CLASIFFICATION: analysis;Animals;Anticarcinogenic Agents;biosynthesis;CCAAT-Enhancer-Binding Protein-beta;Cell Line;drug effects;Enzyme Induction;Gene Expression;genetics;Glutathione;Glutathione Transferase;humans;Isoenzymes;Korea;lifestyle modulation of cancer & cancer biomarkers;mechanisms of carcinogenesis;metabolism;NF-E2-Related Factor 2;pharmacology;Pyrazines;Rats;Research;en
dc.description.abstractComprehensive 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-beta (C/EBPbeta), 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/EBPbeta 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/EBPbeta 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/EBPbeta 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/EBPbeta activation, whereas M2 does so by activating Nrf2 as well as C/EBPbeta. These results substantiate the differential effects of oltipraz's metabolites on C/EBPbeta- and/or Nrf2-mediated GSTA2 induction.en
dc.language.isoenen
dc.relation.urlhttp://dmd.aspetjournals.org/cgi/content/full/34/8/1353en
dc.subject.meshAnimals-
dc.subject.meshAnticarcinogenic Agents-
dc.subject.meshCCAAT-Enhancer-Binding Protein-beta-
dc.subject.meshCell Line-
dc.subject.meshEnzyme Induction-
dc.subject.meshGene Expression-
dc.subject.meshGlutathione Transferase-
dc.subject.meshIsoenzymes-
dc.subject.meshNF-E2-Related Factor 2-
dc.subject.meshPyrazines-
dc.subject.meshRats-
dc.titleDifferential effects of the oxidized metabolites of oltipraz on the activation of CCAAT/enhancer binding protein-beta and NF-E2-related factor-2 for GSTA2 gene induction.en
dc.typeArticleen
dc.identifier.journalDrug Metabolism and Disposition: the biological fate of chemicalsen
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