Hepatic microsomal metabolism of sulfamethoxazole to ...

Description

Citation

Title Hepatic microsomal metabolism of sulfamethoxazole to the hydroxylamine
Author(s) Alastair E. Cribb, S. P. Spielberg
Journal Drug Metabolism and Disposition: The Biological Fate of Chemicals
Date 1990
Volume 18
Issue 5
Start page 784
End page 787
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.

Using APA 6th Edition citation style.

[Page generation failure. The bibliography processor requires a browser with Javascript enabled.]

Times viewed: 204

Adding this citation to "My List" will allow you to export this citation in other styles.