Impairment of mitochondrial respiration and electron transport chain enzymes during cocaine-induced hepatic injury.
Morphological and biochemical changes in mitochondrial have been reported early in the course of cocaine-induced hepatotoxicity. This study was designed to examine the effects of repeated cocaine exposure in vivo on mitochondrial respiration, activities of respiratory chain enzymes, and lipid peroxide measures in liver. Male Sprague-Dawley rats were exposed to cocaine (5 i.p. injections of 25 mg/kg; 3-day period). Blood and liver samples were taken, and hepatic mitochondria were isolated by differential centrifugation. The cocaine-treated rats developed oxidative stress in hepatic mitochondria as evidenced by a significant increase in malonaldialdehyde (MDA; 52%; p < 0.0001) and a decreased glutathione (GSH; 22%; p < 0.0003). Blood aspartate aminotransferase (AST) and glutathione s-transferase (GST) levels in cocaine groups were significantly elevated (2.6 and 3.2 fold, respectively; p < 0.0001 for both). Cocaine caused a decrease in state-3 respiration and respiratory control ratio (RCR) ratio when exposed to site I and II substrates; these changes were parallelled by a decrease in complex I (22%; p < 0.003), succinate cytochrome c reductase (27%; p < 0.004), and complex IV (24%; p < 0.003). In conclusion, functional abnormalities of hepatic mitochondria accompany lipid peroxidation caused by cocaine, supporting the hypothesis that the mitochondria is one of the major intracellular targets of cocaine hepatotoxicity.
Devi
B G
BG
Research Institute on Addictions, New York State Office of Alcoholism and Substance Abuse Services, Buffalo 14203-1016, USA.
Chan
A W
AW
D000818:Animals; D056486:Chemical and Drug Induced Liver Injury; D003042:Cocaine / Q000633:toxicity*; D004579:Electron Transport / Q000187:drug effects; D004734:Energy Metabolism; D008054:Lipid Peroxides / Q000378:metabolism; D008107:Liver Diseases / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000187:drug effects* / Q000378:metabolism; D009294:Narcotics / Q000633:toxicity*; D018384:Oxidative Stress / Q000502:physiology; D010101:Oxygen Consumption / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species; D013997:Time Factors
D008054:Lipid Peroxides; D009294:Narcotics; D017382:Reactive Oxygen Species; D016660:NAD(P)H Dehydrogenase (Quinone); D003042:Cocaine