Mechanistic Investigation of the Noncytochrome P450-Mediated Metabolism of Triadimefon to Triadimenol in Hepatic Microsomes

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• 作者：John F. Kenneke ; Christopher S. Mazur ; Susan E. Ritger ; Thomas J. Sack
• 刊名：Chemical Research in Toxicology
• 出版年：2008
• 出版时间：October 20, 2008
• 年：2008
• 卷：21
• 期：10
• 页码：1997-2004
• 全文大小：213K
• 年卷期：v.21,no.10(October 20, 2008)
• ISSN：1520-5010

文摘

Recently, much emphasis has been placed on understanding the toxic mode of action of the 1,2,4-triazole fungicides (i.e., conazoles) in an effort to improve and harmonize risk assessment. Relative to other conazoles, triadimefon is unique with respect to tumorigenesis in rodents, and it has been proposed that triadimefon does not share a common mechanism of toxicity with other conazoles. We postulate that one reason for this difference is that while many conazoles are metabolized via an oxidative P450-mediated pathway, triadimefon is not. In studies conducted with rat hepatic microsomes, triadimenol was identified as the major metabolite (∼80%) of triadimefon metabolism, and reduction of the carbonyl group in triadimefon occurred stereoselectively with preferential formation of the less toxic triadimenol B diastereomer. Using chemical inhibitors of P450s (i.e., clotrimazole and 1-aminobenzotriazole) and carbonyl reducing enzymes (i.e., glycyrrhetinic acid, quercitrin, and cortisone), both triadimefon depletion and triadimenol formation were found to be mediated by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Studies examining NADPH production and inhibitor studies for glucose-6-phosphate translocation across the endoplasmic reticulum (ER) membrane implicated hexose-6-phosphate dehydrogenase (H6PDH) in the metabolism of triadimefon as well. These results ultimately associate triadimefon metabolism not only with steroidogenesis (i.e., 11β-HSD1) but carbohydrate metabolism (i.e., H6PDH) as well. Considering the impact of triadimefon on these biochemical pathways may help explain some of triadimefon’s unique toxicological effects relative to other conazole fungicides.