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Mechanistic Investigation of the Non-Cytochrome P450 Mediated Metabolism of Triadimefon and Implications for Toxicity
Citation:
KENNEKE, J. F., C. S. MAZUR, S. E. Ritger, AND T. SACK. Mechanistic Investigation of the Non-Cytochrome P450 Mediated Metabolism of Triadimefon and Implications for Toxicity. Presented at 4th Pan Pacific Conference on Pesticide Science, Honolulu, HI, June 01 - 05, 2008.
Impact/Purpose:
Our research objective is to develop and apply innovative techniques for elucidating the kinetics and mechanisms of xenobiotic metabolism, and apply these techniques to the understanding and modeling of chemical exposure for informing human health and ecological risk assessment.
Description:
Triazole containing compounds have been used for decades as agricultural and medicinal fungicides. Recently, emphasis has been placed on the potential adverse effects of these compounds within mammalian systems and an effort has been made to understand their toxic mode of action. Triadimefon is a triazole fungicide used on turf grasses, shrubs and agricultural products including pineapples. It is classified as a possible human carcinogen and the U.S. Environmental Protection Agency (EPA) has concluded that it does not share a common mechanism of toxicity with other triazole fungicides. We postulate that one reason for this difference is that while many triazole fungicides are metabolized via an oxidative cytochrome P450 (CYP)-mediated pathway, triadimefon is not. Results from specific enzyme inhibitor and pure enzyme studies indicated that the microsomal short-chain dehydrogenase/reductase, 11B-hydroxysteroid dehydrogenase type1 (11B-HSD1), mediated the stereoselective carbonyl reduction of triadimefon to yield triadimenol. Additionally, hexose-6-phosphate dehydrogenase (H6PDH) was found to be indirectly involved in triadimefon metabolism by acting as a source of NADPH for 11B-HSD1. These results ultimately associate xenobiotic metabolism with both steroidogenesis (i.e., the physiological role of 11B-HSD1 is glucocorticoid regulation) and carbohydrate metabolism (i.e., H6PDH is involved in the pentose phosphate pathway). Considering the impact of triadimefon on these biochemical pathways may help explain some of triadimefon’s unique toxicological effects relative to other triazole fungicides.