The role of leukocyte-generated reactive metabolites in the pathogenesis of idiosyncratic drug reactions

摘要: Evidence strongly suggests that many adverse drug reactions, including idiosyncratic involve reactive metabolites. Furthermore, certain functional groups, which are readily oxidized to metabolites, associated with a high incidence of reactions. Most drugs can probably form but simple comparison covalent binding in vitro is unlikely provide an accurate indication the relative risk causing reaction because it does not how efficiently metabolite detoxified vivo. In addition, and nature reactions given determined large measure by location formation, as well chemical reactivity metabolite. Such factors will determine macromolecules metabolites bind to, known some proteins, such those leukocyte membrane, much more likely lead immune-mediated or other type toxicity. Some acyl glucuronides, circulate freely could almost any organ; however, most have short biological half-life, although small amounts may escape organ where they formed, these reach sufficient concentrations cause toxicity organs. Many leukocytes, especially agranulocytosis drug-induced lupus. We others demonstrated be metabolized activated neutrophils monocytes The major appears leukocyte-generated hypochlorous acid. Hypochlorous acid quite reactive, therefore found leukocytes. neutrophil precursors contain myeloperoxidase NADPH oxidase system, cells also oxidize drugs. Therefore, there no direct evidence, reasonable speculate generated bone marrow, responsible for aplastic anemia. This reaction. These mechanisms mutually exclusive, both contribute toxicity, even same patient. case lupus, prevalent hypothesis lupus involves modification class II MHC antigens.(ABSTRACT TRUNCATED AT 400 WORDS)