Antigenicity and immunogenicity of sulphamethoxazole: demonstration of metabolism‐dependent haptenation and T‐cell proliferation in vivo
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Sulphamethoxazole has been associated with the occurrence of hypersensitivity reactions. There is controversy as to whether the immune response is metabolism-dependent or -independent. We have therefore investigated the site of antigen formation and the nature of the drug signal presented to the immune system in vivo. Male Wistar rats were dosed with sulphamethoxazole, sulphamethoxazole hydroxylamine or nitroso sulphamethoxazole. Antigen formation on cell surfaces was determined by flow cytometry using a specific anti-sulphamethoxazole antibody. Immunogenicity was determined by assessment of ex vivo T-cell proliferation. Administration of nitroso sulphamethoxazole, but not sulphamethoxazole or sulphamethoxazole hydroxylamine, resulted in antigen formation on the surface of lymphocytes, splenocytes and epidermal keratinocytes, and a strong proliferative response of splenocytes on re-stimulation with nitroso sulphamethoxazole. Rats dosed with sulphamethoxazole or sulphamethoxazole hydroxylamine did not respond to any of the test compounds. CD4+ or CD8+ depleted cells responded equally to nitroso sulphamethoxazole. The proliferative response to nitroso sulphamethoxazole was seen even after pulsing for only 5 min, and was not inhibited by glutathione. Responding cells produced IFN-gamma, but not IL-4. Haptenation of cells by sulphamethoxazole hydroxylamine was seen after depletion of glutathione by pre-treating the rats with diethyl maleate. Splenocytes from the glutathione-depleted sulphamethoxazole hydroxylamine-treated rats responded weakly to nitroso sulphamethoxazole, but not to sulphamethoxazole or sulphamethoxazole hydroxylamine. Dosing of rats with sulphamethoxazole produced a cellular response to nitroso sulphamethoxazole (but not to sulphamethoxazole or its hydroxylamine) when the animals were primed with complete Freund's adjuvant. These studies demonstrate the antigenicity of nitroso sulphamethoxazole in vivo and provide evidence for the role of drug metabolism and cell surface haptenation in the induction of a cellular immune response in the rat.
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Sulfamethoxazole acts as a prohapten because it is transformed to sulfamethoxazole-hydroxylamine and further oxidized to sulfamethoxazole-nitroso.
“Sulfamethoxazole is a typical example of a drug that acts as prohapten, because it is transformed to sulfamethoxazole–hydroxylamine and further oxidized to sulfamethoxazole–nitroso [107–109].”
From The diagnosis of acute interstitial nephritis caused by infection versus antibiotic-induced interstitial nephritis: a narrative review (2024) · cites this paper as [108]
Cites
Sulfamethoxazole is metabolized to the hydroxylamine in humans
Cribb, A. E., & Spielberg, S. P. (1992) · Clinical Pharmacology and Therapeutics · doi:10.1038/clpt.1992.57 · Cited by 175 · see citing works
Cribb, A. E., Spielberg, S. P., & Griffin, G. P. (1995) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(25)06552-3 · Cited by 169 · see citing works
Self-citationCribb, A. E., Miller, M., Leeder, J. S., Hill, J., & Spielberg, S. P. (1991) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(25)08967-6 · Cited by 155 · see citing works
Hepatic microsomal metabolism of sulfamethoxazole to the hydroxylamine
Cribb, A. E., & Spielberg, S. P. (1990) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(25)08652-0 · Cited by 65 · see citing works
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Naisbitt, D. J., Farrell, J., Gordon, S. F., Maggs, J. L., Burkhart, C., Pichler, W. J., Pirmohamed, M., & Park, B. K. (2002) · Molecular Pharmacology · doi:10.1124/mol.62.3.628 · Cited by 141 · see citing works
Self-citationCallan, H. E., Jenkins, R. E., Maggs, J. L., Lavergne, S. N., Clarke, S. E., Naisbitt, D. J., & Park, B. K. (2009) · Chemical Research in Toxicology · doi:10.1021/tx900034r · Cited by 84 · see citing works
Self-citationMuhammad, A., Zhang, Y., Huang, L., Yuan, Q., Wang, W., Pu, J., Lin, W., Tang, R., & Xiao, X. (2024) · Clinical Kidney Journal · doi:10.1093/ckj/sfae054 · Cited by 13 · see citing works
Sanderson, J. P., Hollis, F. J., Maggs, J. L., Clarke, S. E., Naisbitt, D. J., & Park, B. K. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.108.021246 · Cited by 8 · see citing works
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- Authors
- Naisbitt, D. J., Gordon, S. F., Pirmohamed, M., Burkhart, C., Cribb, A. E., Pichler, W. J., & Park, B. K.
- Affiliations
- University of Liverpool (GB)
- University of Bern (CH)
- University of Prince Edward Island (CA)
- Corresponding author
- Park, B Kevin
- ORCID
- Venue
- British Journal of Pharmacology
- Publisher
- Wiley
- Published
- 2001-05
- Volume
- 133
- Issue
- 2
- Pages
- 295-305
- ISSN
- 0007-1188 (ISSN-L)
- 1476-5381
- PMC
- PMC1572782
- OpenAlex
- W1998970549
- Cited by
- 133
- References
- 4
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 3 · 2021: 1 · 2020: 3 · 2018: 1 · 2017: 9 · 2016: 4 · 2015: 7 · 2014: 4 · 2013: 8 · 2012: 8
- FWCI
- 5.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- British Journal of Pharmacology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Drug-Induced Adverse Reactions
- Health Sciences › Medicine › Dermatology › Contact Dermatitis and Allergies
- Life Sciences › Immunology and Microbiology › Immunology › Immunotoxicology and immune responses
- Keywords
- sulfamethoxazole, drug hypersensitivity, haptenation, drug metabolism, T cell proliferation, glutathione depletion, diethyl maleate, interferon-gamma, CD4 and CD8 T cells, cell-mediated immunity, drug-induced skin reaction
- MeSH terms
- Adjuvants, Immunologic, Animals, Antigens, Surface, Cell Division, Drug Hypersensitivity, Haptens, Immunoglobulin G, Interferon-gamma, Male, Phenotype, Spleen, Sulfamethoxazole, T-Lymphocytes, Interleukin-4, Cytokines, Rats, Wistar, Antigen Presentation, Rats
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