Cocaine-induced hepatic necrosis in mice—The role of cocaine metabolism

Abstract

Liver damage following cocaine injection in mice is due to the action of a metabolite of cocaine rather than of cocaine itself. The bioactivation of cocaine to a toxic metabolite appears to be a multi-step process, and is carried out by the cytochrome P-450 microsomal mixed function oxidase system. Inhibitors and inducers of this system blocked or potentiated liver damage respectively. Norcocaine was found to be more potent than cocaine, but also required further metabolism for hepatotoxicity. Inhibition of esterase activity increased damage from both cocaine and norcocainee. Most metabolites and analogues of cocaine were not hepatotoxic, indicating fairly strict structure requirements for activation. N-Hydroxynorcocaine, a possible metabolite of norcocaine, was also hepatotoxic. However, it too required further metabolism in order to produce liver damage. Glutathione in the liver was depleted after cocaine or norcocaine by 25–30 per cent at 1 hr after injection. Cysteine pretreatment offered protection from cocaine. These results suggest that an active metabolite of N-hydroxynorcocaine may be responsible for the liver damage observed after injection of cocaine into mice.