Phagocyte-mediated oxidation in idiosyncratic adverse drug reactions.
The drug-metabolizing capacity of the liver is well known but cannot account for most idiosyncratic adverse drug reactions. Of the extrahepatic sources of reactive drug metabolites, the neutrophil has received the most attention 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 extracellular environment when neutrophils are activated. Production of the resulting drug metabolites within lymphoid organs maximizes their immune-perturbing effects. Mechanisms proposed for the initiation of drug-induced blood dyscrasias, hypersensitivity reactions, or lupus-like symptoms center around three views: (1) presentation of the implicated compound in the major histocompatibility complex of antigen-presenting cells via direct binding or after processing as a hapten bound to self-macromolecules, (2) direct cytotoxicity, or (3) interference in the development of T-cell tolerance in the thymus. How participation of reactive drug metabolites in these processes might lead to symptomatic disease is discussed.
Rubin
R L
RL
Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA. rrubin@scripps.edu
Kretz-Rommel
A
A
D017951:Antigen Presentation; D016923:Cell Death; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D010586:Phagocytes / Q000276:immunology / Q000378:metabolism*