The aim of this research is to establish the roles of cocaine metabolism and of pharmacological responses to cocaine in producing liver damage in mice. The metabolism of active and inactive cocaine analogs by liver microsomes will be examined using high performance liquid chromatography. Modifying factors to be examined include sex and strain differences, adrenal hormones, and inducers of mixed function oxidases. Labeled metabolites of cocaine will be used to study the covalent binding of reactive intermediates to liver proteins. The effect of adrenergic agonists and antagonists on fat mobilization will be correlated with their ability to modify the hepatotoxicity of cocaine. The nature of the central narcotic receptors responsible for narcotic-induced fatty liver damage in mice will be examined. In order to determine whether respiratory depression plays a role in this damage, mice will be injected with narcotics and exposed to different concentrations of oxygen. Modifying factors to be studied include the role of sex hormones, age, strain differences, adrenal hormones, and the mobilization of triglycerides. The results of these experiments should cast light on the possible contribution of drug receptors to the liver damage which is encountered in some human addicts.
