title: Vitamin E succinate protects hepatocytes against the toxic effect of reactive oxygen species generated at mitochondrial complexes I and III by alkylating agents.
abstract: The mechanism of alpha-tocopheryl succinate (TS) cytoprotection against mitochondria-derived oxidative stress was investigated. Incubation of isolated rat hepatocytes with ethyl methanesulfonate (EMS), a mitochondrial alkylating toxicant caused mitochondrial dysfunction and necrotic cell death that was dependent on the production of reactive oxygen species (ROS) and lipid peroxidation. Mitochondria isolated from these cells showed a 3-fold increase in lipid hydroperoxides and a selective depletion of alpha-tocopherol (T), which preceded cell death. The pretreatment of hepatocytes with TS dramatically enriched cells and mitochondria with alpha-tocopherol and provided these membranes with complete protection against EMS-induced oxidative damage. TS pretreatment suppressed EMS-induced cellular ROS production, generated from mitochondrial complex I and III sites. In addition, the treatment with either rotenone (ROT, a complex I inhibitor) or antimycin A (AA, a complex III inhibitor) potentiated EMS-induced lipid peroxidation and necrotic cell death which were again completely prevented by TS treatment. Surprisingly, TS did not protect hepatocytes against thenoyltrifluoroacetone (TTFA), a complex II inhibitor-induced enhancement of EMS-induced toxic oxidative damage. We conclude that the inhibition of mitochondrial ROS production and lipid peroxidation by T released from TS, are the critical events responsible for TS-mediated cytoprotection against toxic oxidative stress derived from both mitochondrial complexes I and III. Our findings suggest that TS treatment may prove useful in combating diseases associated with mitochondrial-derived oxidative stress.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Pullman, WA 99164-6534, USA.
authors.forename: J G
authors.initials: JG
authors.lastname: Zhang
authors.forename: F A
authors.initials: FA
authors.lastname: Nicholls-Grzemski
authors.forename: M A
authors.initials: MA
authors.lastname: Tirmenstein
authors.forename: M W
authors.initials: MW
authors.lastname: Fariss
mesh_terms: D000818:Animals; D000968:Antimycin A / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004336:Drug Antagonism; D004579:Electron Transport / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005020:Ethyl Methanesulfonate / Q000633:toxicity*; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation; D008297:Male; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009336:Necrosis; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D012402:Rotenone / Q000494:pharmacology; D013804:Thenoyltrifluoroacetone / Q000494:pharmacology; D024505:Tocopherols / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000975:Antioxidants; D004791:Enzyme Inhibitors; D017382:Reactive Oxygen Species; D012402:Rotenone; D014810:Vitamin E; D013804:Thenoyltrifluoroacetone; D000968:Antimycin A; D005020:Ethyl Methanesulfonate; D024505:Tocopherols