Drug Metabolism by Leukocytes and Its Role in Drug-Induced Lupus and Other Idiosyncratic Drug Reactions

Abstract

This review presents a unifying hypothesis that provides a connection between several types of hypersensitivity reactions associated with several types of drugs and explains some of the therapeutic effects (antiinflammatory activity and antithyroid effects) of these same drugs. This hypothesis centers on the oxidation of these drugs to chemically reactive metabolites by peroxidases. The drugs of interest have functional groups that are easily oxidized. The major peroxidase involved in this hypothesis is MPO because of its critical location in leukocytes which play a key role in the function of the immune system. However, thyroid peroxidase can probably also oxidize many of the same drugs to reactive metabolites, and this may be responsible for the thyroid autoimmunity observed in connection with some hypersensitivity reactions. Peroxidases have also been described in the skin²⁹⁴ and in platelets²⁹⁵, and their presence may be responsible for the high incidence of skin reactions in the hypersensitivity response and the occurrence of immune-mediated thrombocytopenia, respectively. Involvement of other peroxidases, such as prostaglandin peroxidase, may also be important for antiinflammatory effects of drugs. In addition, leukocytes contain prostaglandin synthetase, and the activation of leukocytes leads to the release of arachidonic acid and the production of prostaglandins. This process may also lead to the metabolism of drugs to reactive metabolites. In studies of the metabolism of procainamide and dapsone, aspirin and indomethacin did not inhibit the formation of the hydroxylamine by neutrophils and mononuclear leukocytes. This is evidence against the involvement of prostaglandin synthetase in these oxidation; however, preliminary studies with other drugs suggest that prostaglandin synthetase may contribute to the metabolism of some drugs by leukocytes. Furthermore, the metabolism of phenylbutazone, phenytoin, and tenoxicam, as well as our preliminary work with other drugs such as carbamazepine, suggests that the range of drugs that are metabolized to reactive metabolites by peroxidases may be broader than initially suspected. There are several other drugs that do not fit into the functional group classes covered in this review but have similar properties. A good example is alpha-methyldopa, which is associated with drug-induced lupus, immune-mediated hemolytic anemia, and other hypersensitivity reactions. Such drugs may also be metabolized to reactive metabolites by peroxidases.

Another aspect of the hypothesis is that an infection, or other inflammatory condition, may be an important risk factor for a hypersensitivity reaction because such a stimulus leads to activation of leukocytes which can lead to formation of reactive metabolites from certain drugs. This may explain why some types of hypersensitivity reactions are more common in patients with certain types of infection or inflammatory disease such as SLE. Other possible risk factors, such as binding of hap-tenized protein to class II MHC antigens, which will be different for each patient, are much more difficult to predict.

It should also be noted that this hypothesis is limited to the initial steps of hypersensitivity reactions, and even if correct, does not explain how antibodies lead to the observed pathology. In addition, it does not explain why reactive metabolites from different drugs lead to a different spectrum of hypersensitivity reactions. Procainamide and dapsone are similar arylamines, and yet, procainamide causes a high incidence of drug-induced lupus and agranulocytosis, but it seldom causes a generalized hypersensitivity reaction. In contrast, dapsone causes agranulocytosis and hypersensitivity reactions, but seldom, if ever, causes drug-induced lupus. In general, the data presented in this review were selected to emphasize common patterns, but it should be understood that such patterns belie the complexity of drug hypersensitivity reactions.