Transformation of lupus-inducing drugs to cytotoxic products by activated neutrophils.
Drug-induced lupus is a serious side effect of certain medications, but the chemical features that confer this property and the underlying pathogenesis are puzzling. Prototypes of all six therapeutic classes of lupus-inducing drugs were highly cytotoxic only in the presence of activated neutrophils. Removal of extracellular hydrogen peroxide before, but not after, exposure of the drug to activated neutrophils prevented cytotoxicity. Neutrophil-dependent cytotoxicity required the enzymatic action of myeloperoxidase, resulting in the chemical transformation of the drug to a reactive product. The capacity of drugs to serve as myeloperoxidase substrates in vitro was associated with the ability to induce lupus in vivo.
Jiang
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W. M. Keck Autoimmune Disease Center, Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA 92037.
Khursigara
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Rubin
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D000818:Animals; D001681:Biological Assay; D001711:Biotransformation; D016923:Cell Death / Q000187:drug effects*; D002746:Chlorpromazine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D006830:Hydralazine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D006861:Hydrogen Peroxide / Q000378:metabolism; D007538:Isoniazid / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D008180:Lupus Erythematosus, Systemic / Q000139:chemically induced*; D051379:Mice; D018375:Neutrophil Activation; D009504:Neutrophils / Q000201:enzymology / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism*; D011342:Procainamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D011441:Propylthiouracil / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D011802:Quinidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D014407:Tumor Cells, Cultured
D006830:Hydralazine; D011441:Propylthiouracil; D006861:Hydrogen Peroxide; D009195:Peroxidase; D011802:Quinidine; D011342:Procainamide; D002746:Chlorpromazine; D007538:Isoniazid