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.