Cocaine-induced peroxidative stress in rat liver: antioxidant enzymes and mitochondria.
This study investigated how the cocaine-induced lipid peroxidation affected liver antioxidant enzymes and mitochondria. Acute cocaine (40 mg/kg) injection produced a significant, time-dependent increase in manganese-superoxide dismutase (Mn/SOD) activity and cellular thiobarbuturic acid reactive substances (TBARS), but activities of glutathione peroxidase and catalase were reduced significantly. These changes coincided with increased production of reactive oxygen species by mitochondria 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 reduction of glutathione was seen in mitochondria. Activities and mRNA of Mn/SOD and copper-zinc-superoxide dismutase were significantly elevated, but mRNA and activities of glutathione peroxidase and catalase were 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-diphenylvalerate, inhibitor of cocaine bioactivation, curtailed in part the generation of reactive oxygen species by mitochondrial fraction. Dimethylaminoethyl-2,2-diphenylvalerate also prevented the increase of TBARS and Mn/SOD. The results suggest that elevated levels of Mn/SOD and copper-zinc-superoxide dismutase, without a concomitant increase in glutathione peroxidase, catalase and glutathione s-transferase, may have contributed to cocaine-induced cellular and mitochondrial peroxidative stress. Reactive metabolites of cocaine N-oxidative metabolism may be responsible for the cocaine-induced oxidative stress and liver necrosis.
Devi
B G
BG
Research Institute on Addictions, Office of the Alcohol and Substance Aubse Service, Buffalo, New York, USA.
Chan
A W
AW
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002374:Catalase / Q000378:metabolism; D003042:Cocaine / Q000633:toxicity*; D005979:Glutathione Peroxidase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley
D000975:Antioxidants; D002374:Catalase; D005979:Glutathione Peroxidase; D005982:Glutathione Transferase; D003042:Cocaine