title: Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity.
abstract: Individual differences in metabolism of the sulfonamides may predispose patients to idiosyncratic reactions. Sulfonamides are metabolized by N-acetylation (mediated by a genetically polymorphic enzyme) and oxidation to potentially toxic metabolites. We examined 6 patients who had severe reactions to sulfonamides and compared them with 20 controls. Acetylator phenotype was determined with caffeine, a safe in-vivo probe of enzyme activity. All 6 patients were slow acetylators (expected, 55%; p less than 0.05). Detoxification of oxidative metabolites was studied in vitro with a lymphocyte assay evaluating cell death from metabolites generated by a murine hepatic microsomal system. Cells from each patient showed increased toxicity from sulfonamide metabolites but not from the drugs themselves. Cells from parents of 3 patients had intermediate toxicity from sulfonamide metabolites, whereas cells from a sibling of 1 patient had a normal response. Susceptibility to sulfonamide reactions may be due to interaction of metabolic pathways, possibly under genetic control, regulating N-acetylation and specific detoxification of toxic metabolites of the drugs.
mesh_terms: D000107:Acetylation; D000328:Adult; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D010641:Phenotype; D013449:Sulfonamides / Q000009:adverse effects / Q000378:metabolism*
chemical_list: D013449:Sulfonamides