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A Reflection on the Fate of Chiral 1,2,4-Triazole Fungicides in Biological Systems
Citation:
Kenneke, J. A Reflection on the Fate of Chiral 1,2,4-Triazole Fungicides in Biological Systems. Presented at 34th Annual SETAC North America, Nashville, TN, November 17 - 21, 2013.
Impact/Purpose:
Presentation given at SETAC North America 34th in Nashville, TN (Nov 17-21, 2013)
Description:
In biological systems, stereoisomers of chiral compounds can exhibit significantly different pharmacokinetics (absorption, distribution, metabolism, and elimination) and pharmacodynamics (physiological effects). Pharmacokinetic processes (i.e., what the body does to the chemical) can have a profound impact on the internal dose of a chemical. In the context of risk assessment, internal dose provides a critical linkage between exposure and effects. Approximately 30% of pesticides are chiral and used as mixtures of two or more stereoisomers; however, these mixtures are often treated as a single compound in human health and ecological risk assessment. To that end, we utilized a variety of in vitro approaches to evaluate the stereospecific differences of select pharmacokinetic properties for more than 25, chiral 1,2,4-triazole fungicides and their individual stereoisomers. We studied the metabolic stability (intrinsic clearance) of these fungicides and their individual stereoisomers in hepatic microsomes, hepatocytes, and purified cytochrome P450s (P450). Stereoisomers of the same compound exhibited significantly different clearance rates. From this data we developed quantitative structure activity relationship (QSAR) clearance models. We found that the prochiral carbonyl of triadimefon undergoes stereoselective carbonyl reduction to produce four stereoisomers of triadimenol; the relative formation of triadimenol stereoisomers varied among 16 vertebrate species. We observed that the Individual triadimenol stereoisomers exhibited different toxicities in cell-based assays and different degrees of P450 inhibition. In vitro and in vivo metabolomic studies were conducted with the individual stereoisomers of triadimefon and triadimenol, and differences in metabolomic responses were observed in all cases. Triadimefon was found to undergo abiotic racemization (the irreversible transformation of one enantiomer into the racemic mixture), which could be a significant, but overlooked transformation route for chiral compounds. Collectively, these results illustrate that the stereoisomers of chiral compounds can have significantly different pharmacokinetic and pharmacodynamic properties, which should be considered when conducting risk assessment.
