Differences in metabolism of sulfonamides predisposing to idiosyncratic toxicity
Abstract
Individual differences in metabolism of the sulfonamides may predispose patients to idiosyncratic reactions. Sulfonamides are metabolized by N-acetylation (mediated by a genetically polymorphic enzyme) and oxidation to potentially toxic metabolites. We examined 6 patients who had severe reactions to sulfonamides and compared them with 20 controls. Acetylator phenotype was determined with caffeine, a safe in-vivo probe of enzyme activity. All 6 patients were slow acetylators (expected, 55%; p less than 0.05). Detoxification of oxidative metabolites was studied in vitro with a lymphocyte assay evaluating cell death from metabolites generated by a murine hepatic microsomal system. Cells from each patient showed increased toxicity from sulfonamide metabolites but not from the drugs themselves. Cells from parents of 3 patients had intermediate toxicity from sulfonamide metabolites, whereas cells from a sibling of 1 patient had a normal response. Susceptibility to sulfonamide reactions may be due to interaction of metabolic pathways, possibly under genetic control, regulating N-acetylation and specific detoxification of toxic metabolites of the drugs.
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Hypersensitivity reactions to SMX have been primarily linked to the slow acetylator phenotype.
“This is critical as hypersensitivity reactions to SMX have been primarily linked to the slow acetylator phenotype.17,30”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [17]
SMX-HA can undergo further auto-oxidation to form the reactive metabolite SMX-NO, which has been linked to protein binding and hypersensitivity reactions.
“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 [17]
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- Authors
- SHEAR, N. H., SPIELBERG, S. P., GRANT, D. M., TANG, B. K., & KALOW, W.
- Affiliations
- Toronto, Ontario Canada
- Corresponding author
- SHEAR, NEIL H.
- ORCID
- SHEAR, NEIL H.
- Venue
- Annals of Internal Medicine
- Publisher
- American College of Physicians
- Published
- 1986-08-01
- Volume
- 105
- Issue
- 2
- Pages
- 179-184
- ISSN
- 0003-4819 (ISSN-L)
- 1539-3704
- OpenAlex
- W2058391540
- Cited by
- 373
- References
- 16
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 1 · 2023: 1 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 5 · 2018: 6 · 2017: 4 · 2016: 7 · 2015: 8 · 2014: 6 · 2013: 3 · 2012: 15
- FWCI
- 9.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Annals of Internal Medicine (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pharmacology › Drug-Induced Adverse Reactions
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- sulfonamides, idiosyncratic drug toxicity, N-acetylation, acetylator phenotype, slow acetylators, detoxification, genetic polymorphism, hepatic microsomal enzymes, lymphocyte cytotoxicity, familial predisposition
- MeSH terms
- Acetylation, Adult, Animals, Cell Survival, Child, Child, Preschool, Female, Humans, Infant, Lymphocytes, Male, Microsomes, Liver, Phenotype, Sulfonamides, Mice, In Vitro Techniques
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