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Pharmacokinetics, Pharmacodynamics, and Stereoselective Metabolism of the 1,2,4-Triazole Fungicide, Triadimefon, in Vertebrate Species
Citation:
Kenneke, J. AND S. Marchitti. Pharmacokinetics, Pharmacodynamics, and Stereoselective Metabolism of the 1,2,4-Triazole Fungicide, Triadimefon, in Vertebrate Species. Presented at 20th International Symposium on Microsomes and Drug Oxidations, Stuttgart, GERMANY, May 18 - 22, 2014.
Impact/Purpose:
Poster presented at the 20th International Symposium on Microsomes and Drug Oxidations in Stuttgart, Germany
Description:
Questions Agricultural and pharmaceutical 1,2,4-triazole fungicides are potent cytochrome P450 modulators that can disrupt mammalian steroid biosynthesis. Triadimefon [(RS)-1-(4-chlorophenoxy)-3,3-dimethyl-1-(1H-1,2,4-triazol-1-yl)butan-2-one] 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 1,2,4-triazole fungicides. Methods To gain insight into the pharmacokinetics of triadimefon and its impact on toxicity, we conducted a variety of in vitro studies with hepatic microsomes, hepatocytes, and purified enzymes. Results Enzyme inhibitor and pure enzyme studies indicated that the microsomal short-chain dehydrogenase/reductase, 11B-hydroxysteroid dehydrogenase type1 (11B-HSD1), mediated carbonyl reduction of triadimefon to yield triadimenol [(1RS,2RS;1RS,2SR)-1-(4-chlorophenoxy)-3,3-dimethyl-1 (1H-1,2,4-triazol-1-yl)butan-2-ol)]. 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). We used a battery of kinetic and mechanistic-based in vitro assays for 16 species to examine the role of 11B-HSD1 and H6PDH in the metabolism of triadimefon. In all species tested, 11B-HSD1 appeared to be involved in the metabolism of triamefon. Carbonyl reduction of the prochiral carbon occurred stereoselectively with S-(+) triadimefon being metabolized more quickly than R(-)-triadimefon. Significant differences in the formation of the four triadimenol stereoisomers was observed across species, but not genders; phylogenetically related species tended to exhibit greater similarity in the relative formation of the four amino acid sequence (i.e., 11B-HSD1) among species. We measured significant differences in cytotoxicity for the four triadimenol stereoisomers in mouse embryonic 3T3 cells. The four triadimenol stereoisomers also yielded different relative degrees of inhibition for ten different cytochrome P450s (P450) that we tested. The impact of triadimefon exposure on the metabolic clearance of 20 other 1,2,4-triazole fungicides was investigated to gain insight into co-exposure scenarios (chemical-chemical interactions). Conclusions Kinetic parameters and mechanistic information were integrated to develop physiologically-based pharmacokinetic (PBPK) models, which were then validated in vivo.
