The results from previous animal studies indicate that while cocaine alone is not a potent hepatotoxin, its administration in conjunction with other drugs may result in substantial hepatic injury. These results are supported by clinical observations, including reports of significant hepatic injury among users of cocaine with other substances of abuse. While there is a mechanistic basis of predict that variety of substances of abuse may potentiate cocaine hepatotoxicity, there has been no systematic examination of this phenomenon, nor has a basis been established for the extrapolation of studies of cocaine hepatoxicity in animals to man. The hepatic bioactivation pathway shown to result in liver toxicity in mice in previous studies will be examined in human hepatic microsomes. Rates of formation of metabolites and identification of responsible enzymes will be used in conjunction with a measurement of in vitro toxicity to define similarities and differences in inherent mechanisms leading to cocaine-induced liver damage. Further experiments will utilize the mouse model to identify mixed substance abuse scenarios in which cocaine use carries the highest risk of hepatic injury. Co- exposure to morphine, butorphanol, alcohol, amphetamine and pentobarbital will be studied, as each of these agents represents a group of drugs upon which there is a mechanistic basis to predict potentiation of cocaine-induced hepatotoxicity. Dose-response and temporal relationships will be established, as well as the influence of opiate or barbiturate tolerance. When exposure regimens which result in potentiation (or inhibition) of cocaine hepatotoxicity are identified, the mechanism for the interaction will be studied through a series of experiments in which effects on toxic metabolite formation and hepatocellular glutathione status are monitored. These experiments will collectively provide information essential to our understanding of the types of substance abuse circumstances which may lead to significant health consequences from the use of cocaine.
