Abstract
The pathogenesis of idiosyncratic “hypersensitivity” reactions to the sulphonamides is thought to be mediated by reactive intermediates. We have previously demonstrated dose-related toxicity of reactive intermediates of sulphonamides generated by murine microsomes using an in vitro lymphocyte assay. We have previously described the production of sulphonamide hydroxylamine by murine microsomes, and have synthesized pure hydroxylamine sulfadiazine and sulfamethoxazole. The toxicity of the hydroxylamine derivative of sulfamethoxazole was tested in ymphocytes of 11 normal volunteers, 3 patients who had sustained idiosyncratic reactions to the sulphonamides and a patient with GSH-S deficiency Cells from the patients had been tested with our microsomal lymphocyte assay and found to be sensitive to sulphonamides in the presence of a metabolic activating system. Hydroxylamine toxicity was assesed by the ability of the cells to convert MTT (tetrazolium) to a purple formazan using an automated microtitre plate assay. Toxicity of the hydroxylamine was greater in cells from patients who had hypersensitivity reactions to the sulphonamides. At 25 μg/ml, the control cells had 47.9% cell death (95% confidence limit 39.7 - 56.2), compared to the patients toxicity of 65.3 cell death (58.9 - 71.7). Similarly, at 50 μg/ml the control toxicity was 58.6% cell death (47.1 - 70.1) compared to the patients toxicity ol 82.6% cell death (78 - 87.3). GSH-S deficient cells displayed a marked increase in dose-related toxicity throughout the concentration range. These results support the theory that idiosyncratic reactions to the sulphonamides are the result of abnormal detoxification of hydroxylamine metabolites, perhaps by glutathione-mediated pathways.
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Rieder, M., Cannon, M., Uetrecht, J. et al. SULFAMETHOXAZOLE HYPERSENSITIVITY REACTIONS ARE MEDIATED BY A HYDROXYLAMINE METABOLITE. Pediatr Res 21 (Suppl 4), 241 (1987). https://doi.org/10.1203/00006450-198704010-00442
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DOI: https://doi.org/10.1203/00006450-198704010-00442