Review article: drug-induced hepatotoxicity

The liver is central to the metabolic disposition of virtually all drugs and xenobiotics (foreign substances). For the most part, this process is accomplished without injury to the liver itself or to other organs. A few compounds such as acetaminophen, CCl4 and the toxin responsible for mushroom poisoning are toxic themselves or produce metabolites which cause liver injury in a uniform, dose-dependent fashion. However, most agents form a sufficiently toxic byproduct and cause liver injury only quite rarely, under special circumstances. Generation of a toxic metabolite within the hepatocyte may produce direct cell injury with disruption of intracellular function, or may cause indirect injury by immune-mediated membrane damage. Factors promoting the accumulation of toxins include genetic enzyme variants which allow greater formation of the harmful metabolite, induction of an isozyme species which produces more than the usual quantity of the toxin, interference with regular (non-toxic) metabolic pathways by substrate competition for enzyme, or depletion of required detoxifying substrates. The following review will provide clinical examples of some of these well-known metabolic reactions, discuss some new issues in drug-induced hepatotoxicity, such as use of combination agents and complex multiple drug regimens, alternative health strategies (vitamins and herbal remedies) as well as the widespread use of cocaine. The overall message is that, as new compounds are issued, new opportunities for drug-induced hepatotoxicity arise. Until extensive experience with any new compound has evolved, it is best to maintain a healthy paranoia concerning the newer drugs--there are very few totally safe agents.