Stereoselective <i>In Vitro</i> Metabolism, Hepatotoxicity, and Cytotoxic Effects of Four Enantiomers of the Fungicide Propiconazole

Propiconazole (PRO) is a chiral triazole fungicide that has been widely used for several years. However, its metabolic characteristics and hepatotoxicity in the chiral level environment remain unclear. In this study, the stereoselective behavior of PRO was investigated by using liver microsome incubation, cell viability assay, inhalation exposure, and molecular docking. Our results demonstrated that the isomers <i>trans</i> (-)-2<i>R</i>,4<i>R</i>-PRO and <i>cis</i> (+)-2<i>R</i>,4<i>S</i>-PRO exhibited slower metabolic rates in rat liver microsomes. The cytochrome P450 family 1 subfamily A polypeptide 2 enzyme was found to play a key role in the metabolism of PRO, contributing to its stereoselective behavior. Histopathological and cell viability results showed that exposure to <i>rac</i>-PRO could induce severe hepatotoxicity in mice. This effect might be related to the accumulation of <i>cis</i> (+)-2<i>R</i>,4<i>S</i>-PRO in the liver, which has a slow metabolism and is highly toxic. Our findings indicate that avoiding the application of <i>cis</i> (+)-2<i>R</i>,4<i>S</i>-PRO in agriculture can significantly reduce adverse effects on nontarget organisms.