title: Oxidized metabolites of oltipraz exert cytoprotective effects against arachidonic acid through AMP-activated protein kinase-dependent cellular antioxidant effect and mitochondrial protection.
abstract: Oltipraz protects cells from chemical-induced carcinogenesis partly because of phase 2 enzyme induction. Certain oltipraz metabolites also induce phase 2 enzymes. This study investigated the cytoprotective effects of the oxidized metabolites of oltipraz against arachidonic acid (AA), a proinflammatory fatty acid that causes cellular reactive oxygen species (ROS) production and mitochondrial impairment, and the mechanistic basis of their action in HepG2 cells. Treatment with 4-methyl-5-(pyrazin-2-yl)-3H-1,2-dithiol-3-one (M1) or 7-methyl-6,8-bis(methylthio)H-pyrrolo[1,2-a]-pyrazine (M2), but not 7-methyl-8-(methylsulfinyl)-6-(methylthio)H-pyrrolo[1,2-a]pyrazine (M3) or 7-methyl-6,8-bis(methylsulfinyl)H-pyrrolo[1,2-a]pyrazine (M4), enabled cells to protect against AA-induced apoptosis. M1 and M2 treatment protected cells from ROS produced by AA and inhibited AA-induced glutathione depletion. Moreover, both M1 and M2 effectively inhibited mitochondrial dysfunction induced by AA, although M2 alone slightly elicited it at a relatively high concentration. M1 and M2 activated AMP-activated protein kinase (AMPK), but M3 and M4 failed to do so. AMPK activation by M1 and M2 contributed to cell survival against AA through a decrease in cellular ROS production and prevention of mitochondrial dysfunction, as shown by the reversal of the metabolites' restoration of mitochondrial membrane potential by compound C treatment or overexpression of a dominant-negative mutant AMPK. Consistently, 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranoside, an AMPK activator, also had a cytoprotective and antioxidant effect against AA. Our results demonstrate that, of the major metabolites of oltipraz, M1 and M2 are capable of protecting cells from AA-induced ROS production and mitochondrial dysfunction, which may be associated with AMPK activation.
authors.affiliation: Innovative Drug Research Center for Metabolic and Inflammatory Disease, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, South Korea.
authors.forename: Young Nam
authors.initials: YN
authors.lastname: Kwon
authors.forename: Sang Mi
authors.initials: SM
authors.lastname: Shin
authors.forename: Il Je
authors.initials: IJ
authors.lastname: Cho
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D016718:Arachidonic Acid / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D019610:Cytoprotection; D004336:Drug Antagonism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D011719:Pyrazines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013871:Thiones; D013876:Thiophenes; D014407:Tumor Cells, Cultured
chemical_list: D000975:Antioxidants; D011719:Pyrazines; D017382:Reactive Oxygen Species; D013871:Thiones; D013876:Thiophenes; D016718:Arachidonic Acid; C026209:oltipraz; D055372:AMP-Activated Protein Kinases