Enantioselective\nMetabolism of Mefentrifluconazole\nby Human Liver Microsomes

A better understanding of the metabolic differences between\nchiral\npesticide enantiomers in organisms is crucial for accurately assessing\ntheir risk. The enantioselective metabolism of mefentrifluconazole\nwas investigated by the human liver microsome reaction system. The\nmetabolic rate of <i>S</i>-mefentrifluconazole was found\nto be 4 times that of <i>R</i>-mefentrifluconazole. The\nchemical inhibitor method was used to further explore the cause of\nmetabolic difference, and it was found that the inhibitors of CYP2C19\nand CYP2C8 significantly reduced the metabolism of <i>S</i>-mefentrifluconazole (70.3–92.0%) and <i>R</i>-mefentrifluconazole\n(53.0–78.6%), respectively. CYP2C19 is a key metabolic enzyme\nof <i>S</i>-mefentrifluconazole. Molecular docking indicates\nthat the internal energy of binding of <i>R</i>-mefentrifluconazole\nto CYP2C19 is too high, resulting in a positive docking fraction (0.1730\nkJ/moL). Therefore, <i>R</i>-mefentrifluconazole cannot\nbind to CYP2C19 under natural conditions. CYP2C8 is the key metabolic\nenzyme of <i>R</i>-mefentrifluconazole. The lower docking\nenergies (−37.80 kJ/moL for <i>R</i>-mefentrifluconazole\nand −35.64 kJ/moL for <i>S</i>-mefentrifluconazole)\nmake CYP2C8 more capable of metabolizing <i>R</i>-mefentrifluconazole.\nThis study provides essential data for exploring the toxicological\nassessment of mefentrifluconazole.