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Production of tumour necrosis factor by cells exposed to sulphonamide reactive metabolites
1Department of Paediatrics, University of Western Ontario, London, Canada.
Abstract:
Hypersensitivity reactions are the most common adverse events associated with therapy with the sulphonamide antibiotics. These reactions have been shown to occur among individuals with pharmacogenetically determined differences in the capacity of their cells to detoxify reactive products of oxidative metabolism of the sulphonamides. These reactions appear to be propagated by an inflammatory response by the immune system. To investigate the role of the cytokine tumour necrosis factor (TNF-alpha) in these reactions, we studied the production of TNF-alpha by peripheral blood mononuclear cells (PBMCs) that had been incubated with sulfamethoxazole and murine microsomes in the presence and absence of a microsomal-activating system and TNF-alpha production by PBMCs in the presence and absence of the hydroxylamine derivative of sulfamethoxazole. The PBMCs showed a time-related increase in the production of TNF-alpha. There was no increase in TNF-alpha production seen during incubation with sulphonamide reactive metabolites; rather, there was a decrease in TNF-alpha elaboration that was most marked when PBMCs were incubated with the hydroxylamine of sulfamethoxazole. There is no evidence from these in vitro studies that TNF-alpha is involved as a mediator of the inflammatory response in sulphonamide hypersensitivity adverse drug reactions.
Insights
Sulphonamide antibiotics can cause hypersensitivity reactions. This study found that tumour necrosis factor-alpha (TNF-alpha) production by immune cells decreased when exposed to sulfamethoxazole metabolites, suggesting TNF-alpha does not mediate these reactions.
Area of Science:
- Pharmacology
- Immunology
- Toxicology
Background:
- Hypersensitivity reactions are common adverse events linked to sulphonamide antibiotics.
- Individual differences in metabolizing sulphonamides influence reaction susceptibility.
- Inflammatory responses, potentially involving cytokines, are implicated in these reactions.
Purpose of the Study:
- To investigate the role of tumour necrosis factor-alpha (TNF-alpha) in sulphonamide-induced hypersensitivity.
- To determine if TNF-alpha mediates the inflammatory response to sulphonamide antibiotics.
Main Methods:
- Incubation of peripheral blood mononuclear cells (PBMCs) with sulfamethoxazole and murine microsomes.
- Assessment of TNF-alpha production in the presence and absence of a microsomal-activating system.
- Evaluation of TNF-alpha production with a sulfamethoxazole hydroxylamine derivative.
Main Results:
- PBMCs demonstrated a time-related increase in TNF-alpha production.
- Incubation with sulphonamide reactive metabolites did not increase TNF-alpha production.
- A marked decrease in TNF-alpha elaboration was observed when PBMCs were incubated with the hydroxylamine of sulfamethoxazole.
Conclusions:
- These in vitro findings do not support TNF-alpha as a mediator of inflammation in sulphonamide hypersensitivity adverse drug reactions.
- The study suggests a potential inhibitory role of sulfamethoxazole metabolites on TNF-alpha production.