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 i nvolving mitochondrial injury. The effect of an acute dose of cocaine in rats on the mitochondrial level of reduced glutathione, nicotinamid e adenine dinucleotide (NADH) and nicotinamide adenine dinucleotide ph osphate (NADPH), important determinants in cellular defense against ox idative stress, was investigated. Under these conditions, the extent o f lipid peroxidation was assessed as thiobarbituric acid reactive subs tances formation and the energy transducing capability of the inner mi tochondrial membrane was evaluated by membrane potential measurements. Female Wistar albino rats were given an acute 50 mg/kg intraperitonea l dose of cocaine and, 6 hours later, hepatic and mitochondrial bioche mical analyses were made. Rats administered intraperitoneally, 7.5 hou rs 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 intoxi cation did not impair mitochondrial functions, although a significant increase of lipid peroxidation occurred. By contrast the combination o f L-buthionine-(S,R)-sulphoximine with cocaine induced a severe derang ement of mitochondrial functional efficiency, a large depletion of red uced glutathione, and a further enhancement of lipid peroxidation. The mitochondrial functional anomalies were largely restored by the use o f cyclosporin A, ethyleneglycotetraacetic acid (EGTA) and glutathione methylmonoester. A nonspecific calcium dependent inner membrane permea bility transition (pore opening) accounted for the partial loss of mit ochondrial 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 aga inst cocaine-induced oxidative stress.