Sulfonamide-induced cutaneous drug reactions: role of bioactivation, oxidative stress and folate deficiency

Sulfonamide- and sulfone-induced hypersensitivity reactions are thought to be mediated through bioactivation of parent drug molecule(s) to their respective reactive metabolite(s). In order to explain the cutaneous drug reactions caused by sulfonamides and sulfone, a mechanism can be proposed by which the bioactivation of these drugs in keratinocytes of the skin forms reactive hydroxylamine metabolites that can covalently bind to cellular proteins, which in turn act as antigens leading to the cascade of immune reactions resulting in a cutaneous drug reaction. In order to probe the proposed mechanism, we determined the enzymes responsible for the bioactivation of these parent drugs to their hydroxylamine metabolites in cultured human keratinocytes. It was found that flavin containing monooxygenases and peroxidases play an important role in the bioactivation of these drugs in keratinocytes. We also confirmed the presence of these enzymes in keratinocytes. Interestingly, though cytochrome P450s are important in the oxidation of parent arylamine xenobiotics to their hydroxylamine metabolites in the liver, they do not appear to play a significant role in the bioactivation of these drugs in keratinocytes. The hydroxylamine metabolites of sulfamethoxazole and dapsone can undergo autooxidation, generating reactive free radicals. Our studies showed that both of these metabolites elevate oxidative stress in keratinocytes by forming reactive oxygen species. Though the cytotoxicity induced by these metabolites is not correlated with the extent of oxidative stress, the generation of reactive oxygen species may be important finding as these species can act as danger signals that activate antigen presenting cells in the skin. As a possible explanation for the idiosyncratic nature of these reactions, folate deficiency was studied as a potential risk factor. However, the results of these studies suggested that deficiency of folic acid in keratinocytes does not predispose such cells to the toxicity associated with the parent drugs or their metabolites. Unexplored is the potential role of such deficiency on the immune response itself.