Enantioselective metabolism of four chiral triazole fungicides in rat liver microsomes

Triazole fungicides with one or two chiral centers are widely used worldwide. The liver microsomes plays a major role in the metabolism and systemic elimination of chiral pesticides after exposure. In this present work, enantioselective metabolism of four representative chiral triazole fungicides (prothioconazole, flutriafol, triticonazole, and epoxiconazole) in rat liver microsomes (RLM) was investigated using LC-MS/MS. Baseline separation of the four chiral fungicides and prothioconazole-desthio was achieved on Lux-cellulose-1. The results demonstrated that the R-enantiomers of flutriafol and triticonazole were preferentially metabolized with half-life ranged from 17.33 min to 99.00 min. The R,S-epoxiconazole accumulated with a half-life of 173.25 min. There was no stereoselectivity for prothioconazole. However, remarkable stereoselective metabolism was observed for prothioconazole-desthio. The results of enzyme kinetic revealed different affinities between the enantiomers and metabolic enzymes. In addition, homologous modeling and molecular docking results indicated that enantioselectivity were partially to enantiospecific binding affinities with CYP enzymes. This study highlights a new quantitative approach for stereoselective metabolism of chiral agrochemicals and provides more accurate data on risk assessment of triazole fungicides. (C) 2019 Elsevier Ltd. All rights reserved.