Hepatic microsomal metabolism of sulfamethoxazole to the hydroxylamine.
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.
Cribb
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AE
Division of Clinical Pharmacology and Toxicology, Hospital for Sick Children, Toronto, Ontario, Canada.
Spielberg
S P
SP
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D006898:Hydroxylamines / Q000378:metabolism* / Q000633:toxicity; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology; D013420:Sulfamethoxazole / Q000378:metabolism* / Q000633:toxicity; D013997:Time Factors; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D065607:Cytochrome P-450 Enzyme Inhibitors; D006898:Hydroxylamines; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D013420:Sulfamethoxazole; D010634:Phenobarbital