PIII‐46

BACKGROUND/AIMS Reactive sulfonamide intermediates appear to be key elements in the pathogenesis of sulfonamide hypersensitivity reactions. The molecular mechanism(s) driving this remains unclear. Reactive stress may be involved in undesired effects of reactive compounds; thus we studied the generation of reactive oxygen species by sulfonamide reactive intermediates. METHODS Design _ An in vitro study using Jurkat cells incubated with increasing concentrations of the hydroxylamine metabolite of sulfamethoxazole over increasing incubation times. Toxicity was evaluated by MTT assay and FACS analysis. Reactive oxygen stress was determined with a colorometric assay with DCFH‐DA as an indicator. Setting _ Lab. Targets _Jurkat E6‐1 cells. Intervention _ Incubation of cells with a reactive intermediate of sulfamethoxazole from 0 to 800 micromolar. The metabolite was synthesized using our previously described method. RESULTS Concentration and time dependent increases in reactive oxygen stress were demonstrated when cells were incubated with the hydroxylamine of sulfamethoxazole but not with the parent drug or vehicle control. The increase was statistically significant for all concentrations above 100 micromolar (p<0.05). At the 800 micromolar concentration, the increase was 700‐fold (p<0.01). CONCLUSIONS Reactive oxygen stress may be an important molecular determinant of sulfonamide hypersensitivity and thus interventions to reduce or reverse this may be therapeutic options. Clinical Pharmacology & Therapeutics (2005) 79 , P70–P70; doi: 10.1016/j.clpt.2005.12.254