Ethanol enhancement of cocaine-induced hepatotoxicity

Abstract

Ethanol administration (4.3% ethanol in a liquid diet for 5 days) to adult male mice produced a peak blood ethanol concentration of 180 mg/100 ml and resulted in a significant increase in hepatic cytochrome P-450 levels. Ethanol treatment significantly reduced cocaine-induced acute lethality from 67 to 23 per cent. However, ethanol treatment resulted in a potentiation of a latent (1–7 day) cocaine-induced toxicity characterized by hepatic dysfunction, as monitored by serum glutamate-pyruvate transaminase (SGPT) activity, and a profound centrilobular necrosis. The minimum dose of cocaine that caused elevations of SGPT activity was 20 mg/kg, i.p.; maximum elevations of SGPT activity were produced by a dose of 40 mg/kg, i.p. The peak elevations of SGPT activity were seen between 24 and 30 hr following adminstration of cocaine. Frank hepatic necrosis was seen following administration of 30 mg/kg of cocaine. Ethanol potentiation of cocaine-induced hepatoxicity was dependent on induction of the hepatic cytochrome P-450 mixed function oxidase enzyme system. The intralobular location of the cocaine-induced hepatic necrosis was also dependent upon the inducing agent used. Ethanol potentiated the cocaine-induced delayed toxicity presumably by enhancing its biotransformation to a chemically reactive intermediate metabolite that produced the hepatic centrilobular necrosis.