title: Lipid hydroperoxide induced mitochondrial dysfunction following acute ethanol intoxication in rats. The critical role for mitochondrial reduced glutathione.
abstract: It has been found that acute ethanol (EtOH) intoxication of rats caused depletion of mitochondrial reduced glutathione (GSH) of approximately 40%. A GSH reduction of similar extent was also observed after the administration to rats of buthionine sulphoximine (BSO), a specific inhibitor of GSH synthesis. Combined treatment with BSO plus EtOH further decreased mitochondrial GSH up to 70% in comparison to control. Normal functional efficiency was encountered in BSO-treated mitochondria, as evaluated by membrane potential measurements during a complete cycle of phosphorylation. In contrast a partial loss of coupled functions occurred in mitochondria from EtOH- and BSO plus EtOH-treated rats. The presence in the incubation system of either GSH methyl monoester (GSH-EE), which normalizes GSH levels, or of EGTA, which chelates the available Ca2+, partially restores the mitochondrial phosphorylative efficiency. Following EtOH and BSO plus EtOH intoxication, the presence of fatty-acid-conjugated diene hydroperoxides, such as octadecadienoic acid hydroperoxide (HPODE), was detected in the mitochondrial membrane. Exogenous HPODE, when added to BSO-treated mitochondria, induced, in a concentration-dependent system, membrane potential derangement. The presence of either GSH-EE or EGTA fully prevented a drop in membrane potential. The results obtained suggest that fatty acid hydroperoxides, endogenously formed during EtOH metabolism, brought about non-specific permeability changes in the mitochondrial inner membrane whose extent was strictly dependent on the level of mitochondrial GSH.
authors.affiliation: Istituti di Patologia Generale, Università di Modena, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Masini
authors.forename: D
authors.initials: D
authors.lastname: Ceccarelli
authors.forename: D
authors.initials: D
authors.lastname: Gallesi
authors.forename: F
authors.initials: F
authors.lastname: Giovannini
authors.forename: T
authors.initials: T
authors.lastname: Trenti
mesh_terms: D000435:Alcoholic Intoxication / Q000378:metabolism*; D000818:Animals; D019328:Buthionine Sulfoximine; D005260:Female; D005978:Glutathione / Q000032:analysis*; D007425:Intracellular Membranes / Q000187:drug effects; D008041:Linoleic Acids / Q000494:pharmacology; D008054:Lipid Peroxides / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D008041:Linoleic Acids; D008054:Lipid Peroxides; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; C049606:9-hydroperoxy-11,12-octadecadienoic acid; D005978:Glutathione