TRANSFORMATION OF LUPUS-INDUCING DRUGS TO CYTOTOXIC PRODUCTS BY ACTIVATED NEUTROPHILS

Drug-induced lupus is a serious side effect of certain medications, bu t the chemical features that confer this property and the underlying p athogenesis are puzzling. Prototypes of all six therapeutic classes of lupus-inducing drugs were highly cytotoxic only in the presence of ac tivated neutrophils. Removal of extracellular hydrogen peroxide before , but not after, exposure of the drug to activated neutrophils prevent ed cytotoxicity. Neutrophil-dependent cytotoxicity required the enzyma tic action of myeloperoxidase, resulting in the chemical transformatio n of the drug to a reactive product. The capacity of drugs to serve as myeloperoxidase substrates in vitro was associated with the ability t o induce lupus in vivo.