Cited by 65Pharmacogenetics and Drug MetabolismDrug-Induced Hepatotoxicity and ProtectionDrug-Induced Adverse Reactions

Hepatic microsomal metabolism of sulfamethoxazole to the hydroxylamine

Cribb, A E, Spielberg, S P·1990·Drug Metabolism and Disposition

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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Crossref · 10.1016/s0090-9556(25)08652-0

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Authors
Cribb, A. E., & Spielberg, S. P.
Affiliations
Hospital for Sick Children (CA)
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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