Cocaine-induced hepatotoxicity

Cocaine treatment caused a dose-related decrease in the microsomal monooxygenase and conjugative activities at one day following administration, with progressive recovery of the activities over five days. Liver pathology showed midzonal necrosis with subsequent hepatocyte regeneration and resolution of necrotic areas. Serum glutamate-pyruvate transaminase activities were dramatically elevated in the early stages of toxicity. Norcocaine, an oxidative metabolite of cocaine, but not benzoyl-ecgonine, a hydrolytic metabolite, produced a pattern of hepa-totoxicity similar to cocaine. Both SKF 525-A and cobaltous chloride pretreatment decreased the hepatotoxic changes caused by cocaine and norcocaine. Phenobarbital pretreatment decreased the depression of monooxygenase activity with no effect on the increase in SGPT activity. Norcocaine-induced liver necrosis shifted from midzonal to periportal areas after phenobarbital-pretreatment of the animals. Pretreatment with 3-methylcholan-threne did not alter the midzonal necrosis caused by cocaine and norcocaine nor did it affect the changes in monooxygenase, conjugative, and SGPT activities. Both cocaine and norcocaine treatment produced a dose-dependent decrease in hepatic glutathione concentration. Diethyl maleate pretreatment potentiated the cocaine- and norcocaine-induced changes in enzyme parameters, while cysteine pretreatment decreased the changes. It was concluded that both cocaine and norcocaine are oxidatively metabolized to a reactive metabolite, and glutathione conjugation may be an important pathway in detoxifying the metabolite. The possible relationship between cocaine metabolism and cocaine- and norcocaine-induced hepatotoxicity was investigated in rats and mice. The microsomal enzyme systems from both untreated rats and mice were capable of metabolizing cocaine to oxidative and hydrolytic products. The pattern of in vitro me-tabolism of the two species showed quantitative rather than qualitative differences. Benzoylecgonine, a hydrolytic metabolite, was formed in greater amounts in rats than in mice, while norcocaine, an oxidative metabolite, was produced in approximately equal quantities. The total percent of cocaine metabolized was only slightly greater in rats than mice because the latterpro-duced greater quantities of unidentified metabolites. Rats pre-treated with diethyl maleate developed cocaine- and norcocaine-induced hepatotoxicity based on liver pathology and changes in the microsomal monooxygenase, conjugative, and serum glutamate-pyruvate transaminase activities. It was concluded that even though both rats and mice can oxidatively metabolize cocaine and norcocaine to a hepatotoxic reactive intermediate, rats do not normally demonstrate toxicity because of a more favorable ratio of glutathione related detoxication relative to activation.