Hepatic microsomal metabolism of sulfamethoxazole to the hydroxylamine
Abstract
Sulfonamides are oxidized to protein reactive cytotoxic metabolites by murine hepatic microsomes. Mononuclear leukocytes from patients with idiosyncratic reactions to sulfonamides were more susceptible to toxicity from these metabolites than were leukocytes from a control population, suggesting that these metabolites play a role in the pathogenesis of such reactions. Here we have shown that murine hepatic microsomes oxidize sulfamethoxazole at the N4-position to form the hydroxylamine. Formation of the hydroxylamine was dependent on the presence of microsomes, NADPH, and oxygen. The addition of SKF 525-A, cimetidine, or gassing with carbon monoxide inhibited formation. The enzymic activity was stable at 37 degrees C in the absence of NADPH. Ascorbic acid, N-acetylcysteine, and reduced glutathione significantly increased the yield of hydroxylamine, presumably by decreasing further oxidation and covalent binding. Microsomes prepared from mice treated with phenobarbital or beta-naphthoflavone catalyzed the formation of the hydroxylamine more readily than did microsomes from untreated mice. These results demonstrate that cytochrome P-450-mediated oxidation of sulfamethoxazole results in the formation of hydroxylamines, which can be further oxidized to more reactive intermediates. These metabolites are likely involved in the pathogenesis of idiosyncratic reactions.
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SMX is metabolized by cytochrome P450-mediated oxidation to form SMX-hydroxylamine (SMX-HA).
“SMX is metabolized by N-acetyltransferases (NAT1/NAT2) to form N4-acetyl sulfamethoxazole (NA-SMX), and by cytochrome P450-mediated oxidation to form SMX-hydroxylamine (SMX-HA).”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [14]
SMX can produce chemically reactive metabolites, which may contribute to toxicity mechanisms.
“SMX can produce chemically reactive metabolites, which may contribute to toxicity mechanisms.”
From N-Acetyltransferase (NAT) 1 and NAT2 Enzyme Activities Drive Interindividual Variability in Sulfamethoxazole N-Acetylation (2025) · cites this paper as [14]
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- Authors
- Cribb, A. E., & Spielberg, S. P.
- Affiliations
- Hospital for Sick Children (CA)
- ORCID
- Cribb, A E
- Venue
- Drug Metabolism and Disposition
- Publisher
- Elsevier BV
- Published
- 1990-09
- Volume
- 18
- Issue
- 5
- Pages
- 784-787
- ISSN
- 0090-9556 (ISSN-L)
- OpenAlex
- W2113235931
- Cited by
- 65
- References
- 0
- Citations by year
- 2025: 1 · 2023: 2 · 2021: 1 · 2020: 1 · 2014: 2 · 2012: 2
- FWCI
- 1.24
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Drug Metabolism and Disposition (publishedVersion)
- PubMed (publishedVersion)
- PubMed
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Health Sciences › Medicine › Pharmacology › Drug-Induced Adverse Reactions
- Keywords
- sulfamethoxazole, hydroxylamine, liver microsomes, cytochrome P450, sulfonamide metabolism, idiosyncratic drug reactions, NADPH-dependent oxidation, phenobarbital, beta-naphthoflavone, glutathione, cimetidine, SKF 525-A, carbon monoxide
- MeSH terms
- Animals, Benzoflavones, Chromatography, High Pressure Liquid, Cytochrome P-450 Enzyme System, Enzyme Induction, Hydroxylamines, Kinetics, Microsomes, Liver, Neutrophils, Oxidation-Reduction, Phenobarbital, Sulfamethoxazole, Time Factors, beta-Naphthoflavone, Mice, Cytochrome P-450 Enzyme Inhibitors, In Vitro Techniques
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