Dermatitis herpetiformis: effects of sulfones and sulfonamides on neutrophil myeloperoxidase-mediated iodination and cytotoxicity.
The effects of sulfones and sulfonamides on neutrophil myeloperoxidase-mediated iodination and cytotoxicity were studied using in vitro assays to measure these parameters. Leukocyte iodination was documented using a quantitative assay to measure the iodination of protein by human neutrophils undergoing phagocytosis. Cytotoxicity for the tumor cell line LSTRA by human neutrophils activated by exposure to phorbol myristate acetate was measured by a 51Cr release assay. Dapsone, diasone, and sulfapyridine, at concentrations comparable to serum levels obtained by therapeutic doses of drug, effectively inhibited iodination and cytotoxicity mediated by human neutrophils. Other sulfonamides showed little inhibition of either iodination or cytotoxicity. The amount of inhibition was comparable to that seen with the inhibitors azide or cyanide and occurred in a dose dependent manner with all three drugs. A cell-free cytotoxic system using myeloperoxidase, iodide, a H2O2 generating system, and target cells also showed inhibition by dapsone, diasone and sulfapyridine in a similar fashion. The active drugs inhibited both the intra- and the extracellular myeloperoxidase-H2O2-halide cytotoxic systems. Serial iodination studies of four dermatitis herpetiformis patients, evaluated while taking dapsone or sulfapyridine, showed inhibition of iodination by either drug. Levels of IgA immune complexes, as measured by the Raji cell radioimmune assay adapted for IgA, did not change when medication was withheld. These studies demonstrate that dapsone, diasone, and sulfapyridine inhibit both neutrophil iodination and cytotoxicity for tumor cells, while other sulfonamides have no effect. This confirms previous studies showing inhibition by myeloperoxidase mediated iodination by dapsone. Furthermore, the effect on neutrophils is quickly reversible; in vivo administered drug has no effect on in vitro function. The active drugs inhibit both intra- and extracellular cytotoxic systems. This may represent an important mechanism by which these drugs produce their therapeutic effects when used to treat inflammatory skin diseases.
D000936:Antigen-Antibody Complex; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003622:Dapsone / Q000494:pharmacology; D003874:Dermatitis Herpetiformis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D066298:In Vitro Techniques; D007455:Iodine / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology; D009504:Neutrophils / Q000187:drug effects*; D009195:Peroxidase / Q000097:blood; D013449:Sulfonamides / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology*
D000936:Antigen-Antibody Complex; D013449:Sulfonamides; D013450:Sulfones; D003622:Dapsone; D007455:Iodine; D009195:Peroxidase