IDIOSYNCRATIC LIVER TOXICITY OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS -MOLECULAR MECHANISMS AND PATHOLOGY

This review explores the clinical hepatic pathology associated with th e use of nonsteroidal antiinflammatory drugs (NSAIDs), possible cellul ar and molecular mechanisms of injury, and future challenges. NSAIDs c omprise a group of widely used compounds that have been associated wit h rare adverse reactions in the liver, including fulminant hepatitis a nd cholestasis. These reactions are idiosyncratic, mostly independent of the dose administered, and host-dependent. The mechanisms responsib le for the initiation and perpetuation of NSAID-induced hepatotoxicity remain poorly understood and have been largely inferred from clinical manifestation. A mounting body of evidence, however, indicates that m any acidic NSAIDs are metabolized to reactive acyl glucuronides that c an form covalent adducts with plasma proteins and hepatocellular prote ins. In hepatocytes co-cultured with lymphocytes, these NSAID-altered proteins can become antigenic. Thus, long-lived, drug-altered proteins may act as immunogens and produce cytotoxic T-cell-mediated or antibo dy-dependent, cell-mediated toxicity in susceptible patients. Alternat ively, individual abnormalities in metabolism or disposition of some N SAIDs may lead to the formation or accumulation of toxic metabolites. Additional work with transgenic animal models is needed to permit bett er understanding of the general and specific risk factors involved in the pathogenesis of the idiosyncratic liver injuries related to NSAIDs and other drugs.