title: New therapeutic approach: diphenyl diselenide reduces mitochondrial dysfunction in acetaminophen-induced acute liver failure.
abstract: The acute liver failure (ALF) induced by acetaminophen (APAP) is closely related to oxidative damage and depletion of hepatic glutathione, consequently changes in cell energy metabolism and mitochondrial dysfunction have been observed after APAP overdose. Diphenyl diselenide [(PhSe)2], a simple organoselenium compound with antioxidant properties, previously demonstrated to confer hepatoprotection. However, little is known about the protective mechanism on mitochondria. The main objective of this study was to investigate the effects (PhSe)2 to reduce mitochondrial dysfunction and, secondly, compare in the liver homogenate the hepatoprotective effects of the (PhSe)2 to the N-acetylcysteine (NAC) during APAP-induced ALF to validate our model. Mice were injected intraperitoneal with APAP (600 mg/kg), (PhSe)2 (15.6 mg/kg), NAC (1200 mg/kg), APAP+(PhSe)2 or APAP+NAC, where the (PhSe)2 or NAC treatment were given 1 h following APAP. The liver was collected 4 h after overdose. The plasma alanine and aspartate aminotransferase activities increased after APAP administration. APAP caused a remarkable increase of oxidative stress markers (lipid peroxidation, reactive species and protein carbonylation) and decrease of the antioxidant defense in the liver homogenate and mitochondria. APAP caused a marked loss in the mitochondrial membrane potential, the mitochondrial ATPase activity, and the rate of mitochondrial oxygen consumption and increased the mitochondrial swelling. All these effects were significantly prevented by (PhSe)2. The effectiveness of (PhSe)2 was similar at a lower dose than NAC. In summary, (PhSe)2 provided a significant improvement to the mitochondrial redox homeostasis and the mitochondrial bioenergetics dysfunction caused by membrane permeability transition in the hepatotoxicity APAP-induced.
authors.affiliation: Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Campus UFSM, Santa Maria, Rio Grande do Sul, Brasil.
authors.forename: Nélson R
authors.initials: NR
authors.lastname: Carvalho
authors.affiliation: Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Campus UFSM, Santa Maria, Rio Grande do Sul, Brasil.
authors.forename: Edovando F
authors.initials: EF
authors.lastname: da Rosa
authors.affiliation: Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Campus UFSM, Santa Maria, Rio Grande do Sul, Brasil.
authors.forename: Michele H
authors.initials: MH
authors.lastname: da Silva
authors.affiliation: Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Campus UFSM, Santa Maria, Rio Grande do Sul, Brasil.
authors.forename: Cintia C
authors.initials: CC
authors.lastname: Tassi
authors.affiliation: Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Campus UFSM, Santa Maria, Rio Grande do Sul, Brasil.
authors.forename: Cristiane L
authors.initials: CL
authors.lastname: Dalla Corte
authors.affiliation: Institute of Biomedicine (IBIOMED) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of León, León, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Carbajo-Pescador
authors.affiliation: Institute of Biomedicine (IBIOMED) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of León, León, Spain.
authors.forename: Jose L
authors.initials: JL
authors.lastname: Mauriz
authors.affiliation: Institute of Biomedicine (IBIOMED) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), University of León, León, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: González-Gallego
authors.affiliation: Departamento de Química, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Campus UFSM, Santa Maria, Rio Grande do Sul, Brasil.
authors.forename: Félix A
authors.initials: FA
authors.lastname: Soares
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000111:Acetylcysteine / Q000494:pharmacology; D000410:Alanine Transaminase / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001555:Benzene Derivatives / Q000494:pharmacology*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015227:Lipid Peroxidation; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D016566:Organoselenium Compounds / Q000494:pharmacology*; D018384:Oxidative Stress; D050050:Protein Carbonylation; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000975:Antioxidants; D001555:Benzene Derivatives; D016566:Organoselenium Compounds; D017382:Reactive Oxygen Species; C061132:diphenyldiselenide; D000082:Acetaminophen; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000111:Acetylcysteine