TY - JOUR T1 - Oxidized Metabolites of Oltipraz Exert Cytoprotective Effects against Arachidonic Acid through AMP-Activated Protein Kinase-Dependent Cellular Antioxidant Effect and Mitochondrial Protection JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 1187 LP - 1197 DO - 10.1124/dmd.108.025908 VL - 37 IS - 6 AU - Young Nam Kwon AU - Sang Mi Shin AU - Il Je Cho AU - Sang Geon Kim Y1 - 2009/06/01 UR - http://dmd.aspetjournals.org/content/37/6/1187.abstract N2 - 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-β-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. The American Society for Pharmacology and Experimental Therapeutics ER -