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Reactions of the nitroso and hydroxylamine metabolites of sulfamethoxazole with reduced glutathione. Implications for idiosyncratic toxicity
Abstract
N4-oxidation of sulfonamides has been implicated in the pathogenesis of idiosyncratic reactions to these antimicrobials. In vitro toxicity assays employing mononuclear leukocytes as target cells have shown that the toxicity of sulfamethoxazole hydroxylamine (SMX-HA) is inhibited by exogenous glutathione, suggesting that conjugation with glutathione is an important detoxification pathway. However, in these experiments, significant depletion of cellular glutathione only occurred at concentrations of SMX-HA greater than or equal to 300 microM. At concentrations of SMX-HA which produce 50% toxicity in mononuclear leukocytes (approximately 100 microM), there was not a significant loss of glutathione. SMX-HA also caused a small but significant increase in oxidized glutathione concentrations. In cell-free experiments, reduced glutathione (GSH) prevented the autooxidation of SMX-HA to nitrososulfamethoxazole (nitroso-SMX). During this process, oxidized glutathione was formed. GSH rapidly reacted with nitroso-SMX to form a labile semimercaptal conjugate. Physiologically relevant concentrations of GSH (i.e. 1 mM) favored thiolytic cleavage of the semimercaptal to form SMX-HA. Isomerization of the semimercaptal to the more stable sulfinamide occurred at low GSH concentrations. Purified glutathione transferases had no effect on the reaction of SMX-HA with GSH. Therefore, glutathione is important in protecting cells from the toxicity of SMX-HA largely by preventing its further oxidation to nitroso-SMX. Stable glutathione conjugates are likely to be formed only in small quantities under physiological conditions. Conjugation with glutathione would not be expected to be a major pathway for clearance of the hydroxylamine and nitroso metabolites of sulfonamides.
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“SMX-HA can then undergo further auto-oxidation to form the reactive metabolite, sulfamethoxazole-nitroso (SMX-NO), which has been linked to protein binding and hypersensitivity reactions.15–17”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [15]
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Stepan, A. F., Walker, D. P., Bauman, J. N., Price, D. A., Baillie, T. A., Kalgutkar, A. S. S., & Aleo, M. D. (2011) · Chemical Research in Toxicology · doi:10.1021/tx200168d · Cited by 725
Svensson, C. K., Cowen, E. W., & Gaspari, A. A. (2001) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01501-1 · Cited by 274
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Pirmohamed, M., Naisbitt, D. J., Gordon, F., & Park, B. K. (2002) · Toxicology · doi:10.1016/s0300-483x(02)00255-x · Cited by 169
Metadata
- Authors
- Cribb, A. E., Miller, M., Leeder, J. S., Hill, J., & Spielberg, S. P.
- Affiliations
- University of Toronto (CA)
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 1991-09
- Volume
- 19
- Issue
- 5
- Pages
- 900-906
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W1790339004
- Cited by
- 155
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 2 · 2023: 1 · 2022: 2 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 7 · 2017: 5 · 2016: 1 · 2015: 2 · 2014: 7 · 2013: 5 · 2012: 7
- FWCI
- 2.94
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Topics
- Health Sciences › Medicine › Pharmacology (medical) › Drug-Induced Adverse Reactions
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Glutathione Transferases and Polymorphisms
- Keywords
- sulfamethoxazole, reduced glutathione, glutathione conjugation, idiosyncratic drug toxicity, mononuclear leukocytes, glutathione depletion, glutathione disulfide, glutathione S-transferase, drug detoxification
- MeSH terms
- Cell-Free System, Glutathione, Glutathione Reductase, Humans, Leukocytes, Mononuclear, Inactivation, Metabolic, Oxidation-Reduction, Sulfamethoxazole, In Vitro Techniques
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