Idiosyncratic drug reactions: possible role of reactive metabolites generated by leukocytes

Idiosyncratic drug reactions represent a poorly understood problem with serious medical implications. Many idiosyncratic drug reactions appear to be hypersensitivity reactions that involve an immune mechanism. The initiating step appears to involve the formation of a chemically reactive metabolite which can act as a hapten. Although the major site of drug metabolism is the liver, we have found that leukocytes, which contain myeloperoxidase and can generate hydrogen peroxide when stimulated, can also generate reactive metabolites. This has obvious implications for such idiosyncratic reactions as agranulocytosis. Furthermore, because of the importance of monocytes in the processing of antigen and the presentation of antigen to T lymphocytes in the initiation of an immunological reaction, formation of reactive metabolites by monocytes may also have implications for other idiosyncratic reactions such as drug-induced lupus and generalized idiosyncratic reactions.