Metabolism of drugs by activated leukocytes: implications for drug-induced lupus and other drug hypersensitivity reactions

Abstract

Despite their importance, little is known about the mechanism of idiosyncratic reactions, many such reactions have characteristics that suggest an immune-mediated mechanism. This is particularly true of drug-induced lupus which is an autoimmune syndrome. Certain functional groups are associated with a high incidence of idiosyncratic reactions, probably reflecting the ease with which they are metabolized to reactive metabolites. Although the liver is the principal organ of drug metabolism, most reactive metabolites generated in the liver would not reach other organs in significant concentrations. Because of the function of leukocytes, especially monocytes, in the induction of an immune response, the generation of reactive metabolites by monocytes would seem likely to lead to an immune-mediated adverse reaction. We have found that drugs that are associated with drug-induced lupus are oxidized to reactive metabolites by the myeloperoxidase system of monocytes. The initial step in drug-induced lupus could be haptenization of a protein on the surface of monocytes by these reactive metabolites. Other types of idiosyncratic drug reactions may involve a similar mechanism and the same drugs that induce lupus are usually associated with a high incidence of other types of idiosyncratic reactions. for example, procainamide, which causes the highest incidence of drug-induced lupus, also causes a relatively high incidence of agranulocytosis. Even some of the therapeutic effects of drugs may involve the production of reactive metabolites by myeloperoxidase or thyroid peroxidase.