COCAINE-INDUCED PEROXIDATIVE STRESS IN RAT-LIVER - ANTIOXIDANT ENZYMES AND MITOCHONDRIA

This study investigated how the cocaine-induced lipid peroxidation aff ected liver antioxidant enzymes and mitochondria. Acute cocaine (40 mg /kg) injection produced a significant, time-dependent increase in mang anese-superoxide dismutase (Mn/SOD) activity and cellular thiobarbutur ic acid reactive substances (TBARS), but activities of glutathione per oxidase and catalase were reduced significantly. These changes coincid ed with increased production of reactive oxygen species by mitochondri a and decreased cellular ATP and glutathione. Binge cocaine (25 mg/kg; 5 injections in 3 days) significantly increased TBARS and conjugated dienes, but decreased ATP and glutathione. Accumulation of TBARS and r eduction of glutathione was seen in mitochondria. Activities and mRNA of Mn/SOD and copper-zinc-superoxide dismutase were significantly elev ated, but mRNA and activities of glutathione peroxidase and catalase w ere decreased in cocaine-treated rats. Cocaine (binge model) produced scattered liver necrosis (20%) and compromised cell integrity. This is the first report demonstrating cocaine-induced liver necrosis in rats . Pretreatment (acute model) with dimethylaminoethyl-2,2-diphenylvaler ate, inhibitor of cocaine bioactivation, curtailed in part the generat ion of reactive oxygen species by mitochondrial fraction. Dimethylamin oethyl-2,2-diphenylvalerate also prevented the increase of TBARS and M n/SOD. The results suggest that elevated levels of Mn/SOD and copper-z inc-superoxide dismutase, without a concomitant increase in glutathion e peroxidase, catalase and glutathione s-transferase, may have contrib uted to cocaine-induced cellular and mitochondrial peroxidative stress . Reactive metabolites of cocaine N-oxidative metabolism may be respon sible for the cocaine-induced oxidative stress and liver necrosis.