Phagocyte-mediated oxidation in idiosyncratic adverse drug reactions

The drug-metabolizing capacity of the liver is well known but cannot accoun t for most idiosyncratic adverse drug reactions. Of the extrahepatic source s of reactive drug metabolites, the neutrophil has received the most attent ion because of its vast numbers and robust oxidizing machinery. Many drugs associated with autoimmunity are susceptible to oxidative transformation by the enzymatic action of myeloperoxidase, a protein released into the extra cellular environment when neutrophils are activated. Production of the resu lting drug metabolites within lymphoid organs maximizes their immune-pertur bing effects. Mechanisms proposed for the initiation of drug-induced blood dyscrasias, hypersensitivity reactions, or lupus-like symptoms center aroun d three views: (1) presentation of the implicated compound in the major his tocompatibility complex of antigen-presenting cells via direct binding or a fter processing as a hapten bound to self-macromolecules, (2) direct cytoto xicity, or (3) interference in the development of T-cell tolerance in the t hymus. How participation of reactive drug metabolites in these processes mi ght lead to symptomatic disease is discussed. (C) 2001 Lippincott Williams & Wilkins, Inc.