The purpose of this study was to investigate possible mechanism of cocaine-induced hepatotoxicity and its potentiation by ethanol in mice. Ethanol (2 g/kg) and/or cocaine (25 mg/kg) injections were given as binge model (five injections in 3 days). Cocaine administration with or without ethanol caused an increase in lipid peroxidation in liver homogenate and its subcellular fractions. The greatest increases were observed in mitochondrial fraction following cocaine plus ethanol treatment. Also, glutathione (GSH) levels were increased in liver homogenate and its mitochondrial fractions after cocaine and cocaine plus ethanol treatment. Microsomal calcium sequestration was found to decrease in all treatments. These results suggest that increased lipid peroxidation and decreased microsomal calcium sequestration in the liver may play a possible role cocaine-induced hepatotoxicity and its potentiation by ethanol. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved.