Enantioselective Metabolism of Mefentrifluconazole by Human Liver Microsomes

A better understanding of the metabolic differences between chiral pesticide enantiomers in organisms is crucial for accurately assessing their risk. The enantioselective metabolism of mefentrifluconazole was investigated by the human liver microsome reaction system. The metabolic rate of <i>S</i>-mefentrifluconazole was found to be 4 times that of <i>R</i>-mefentrifluconazole. The chemical inhibitor method was used to further explore the cause of metabolic difference, and it was found that the inhibitors of CYP2C19 and CYP2C8 significantly reduced the metabolism of <i>S</i>-mefentrifluconazole (70.3-92.0%) and <i>R</i>-mefentrifluconazole (53.0-78.6%), respectively. CYP2C19 is a key metabolic enzyme of <i>S</i>-mefentrifluconazole. Molecular docking indicates that the internal energy of binding of <i>R</i>-mefentrifluconazole to CYP2C19 is too high, resulting in a positive docking fraction (0.1730 kJ/moL). Therefore, <i>R</i>-mefentrifluconazole cannot bind to CYP2C19 under natural conditions. CYP2C8 is the key metabolic enzyme of <i>R</i>-mefentrifluconazole. The lower docking energies (-37.80 kJ/moL for <i>R</i>-mefentrifluconazole and -35.64 kJ/moL for <i>S</i>-mefentrifluconazole) make CYP2C8 more capable of metabolizing <i>R</i>-mefentrifluconazole. This study provides essential data for exploring the toxicological assessment of mefentrifluconazole.