Recent case reports have indicated that cocaine is capable of producing severe, even fatal liver injury. While the incidence of cocaine-induced liver injury is unknown, there are reasons to suspect that it is probably underreported. The basic objective of this proposal is to gain a better understanding of the risk of liver injury posed by cocaine abuse, and of the influence of combined use of other substances of abuse on this risk. To accomplish this objective, a balance of observational studies in humans and mechanistic studies in animals will be conducted. A large series of medical examiner cases (greater than 1,200) involving cocaine use will be examined for relationships between liver pathology and the presence or absence of other drugs, as well as other relevant variables. The effect of combined use with alcohol (ethanol) will be of particular interest, since this combination appears prominently in emergency room visits and medical examiner cases. The influence of other factors such as type of cocaine (crack cocaine versus hydrochloride), route of administration, concentration of cocaine at autopsy, etc. will also be evaluated. This large scale study will provide badly needed information regarding the incidence of necrosis from cocaine use and apparent risk factors in humans. Studies in mice have suggested that combined use of other drugs with cocaine may be a critical factor influencing susceptibility to cocaine hepatotoxicity. One interaction of particular interest is the ability of both acute and repeated doses of alcohol (ethanol) to greatly increase cocaine hepatotoxicity in mice. Three potential mechanisms for this interaction will be tested. One involves a novel metabolite of cocaine and ethanol (cocaethylene), which occurs in humans and has been found in preliminary studies in mice to have hepatotoxic potency similar to cocaine. The other two mechanisms, also supported by preliminary studies, involve increased conversion of cocaine to its hepatotoxic metabolite: 1) through increased activity of bioactivation enzymes; and 2) through inhibition of esteratic metabolism. Relative contributions of each of these mechanisms to ethanol effects on cocaine hepatotoxicity will be assessed, as well as their human relevance. Another series of experiments will examine the unusual shifting pattern of necrosis from cocaine that has been observed following pretreatment with certain drugs. Possible roles of changes in intralobular distribution bioactivation enzymes or cocaine itself in this phenomenon will be tested in mice, and experiments using human tissue will determine whether the phenomenon occurs in humans as well. These studies should advance considerably our understanding of the mechanism of cocaine-induced liver damage, its risk in humans, and the importance of use of other drugs (particularly ethanol) in influencing this risk.
