Membrane potential of hepatic mitochondria after acute cocaine administration in rats--the role of mitochondrial reduced glutathione.
Cocaine hepatotoxicity may be mediated by oxidative damage, possibly involving mitochondrial injury. The effect of an acute dose of cocaine in rats on the mitochondrial level of reduced glutathione, nicotinamide adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide phosphate (NADPH), important determinants in cellular defense against oxidative stress, was investigated. Under these conditions, the extent of lipid peroxidation was assessed as thiobarbituric acid reactive substances formation and the energy transducing capability of the inner mitochondrial membrane was evaluated by membrane potential measurements. Female Wistar albino rats were given an acute 50 mg/kg intraperitoneal dose of cocaine and, 6 hours later, hepatic and mitochondrial biochemical analyses were made. Rats administered intraperitoneally, 7.5 hours before the sacrifice, a specific inhibitor of glutathione synthesis, L-buthionine-(S,R)-sulphoximine, either alone or in combination with cocaine, underwent in parallel the same determinations. Cocaine intoxication did not impair mitochondrial functions, although a significant increase of lipid peroxidation occurred. By contrast the combination of L-buthionine-(S,R)-sulphoximine with cocaine induced a severe derangement of mitochondrial functional efficiency, a large depletion of reduced glutathione, and a further enhancement of lipid peroxidation. The mitochondrial functional anomalies were largely restored by the use of cyclosporin A, ethyleneglycotetraacetic acid (EGTA) and glutathione methylmonoester. A nonspecific calcium dependent inner membrane permeabilty transition (pore opening) accounted for the partial loss of mitochondrial coupled functions at a period of cocaine intoxication when no cell damage occurred. The level of mitochondrial glutathione played a critical role in protecting inner membrane functional integrity against cocaine-induced oxidative stress.
Masini
A
A
Dipartmento di Scienze Biodemiche, Sezione di Patologia Generale, Università di Modena, Italy.
Gallesi
D
D
Giovannini
F
F
Trenti
T
T
Ceccarelli
D
D
D000244:Adenosine Diphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003042:Cocaine / Q000494:pharmacology*; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D008564:Membrane Potentials / Q000187:drug effects; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology; D009294:Narcotics / Q000494:pharmacology*; D010084:Oxidation-Reduction; D051381:Rats; D017208:Rats, Wistar
D009294:Narcotics; C042415:buthionine; D000244:Adenosine Diphosphate; D008715:Methionine; D005978:Glutathione; D003042:Cocaine; D002118:Calcium