2. Academic Validation
  3. Enantioselective metabolic mechanism and metabolism pathway of tetraconazole in human liver microsomes: In vitro and in silico study

Enantioselective metabolic mechanism and metabolism pathway of tetraconazole in human liver microsomes: In vitro and in silico study

  • Environ Pollut. 2026 May 1:396:127849. doi: 10.1016/j.envpol.2026.127849.
Shiling Liu 1,  Junqi Zhu 1,  Yu Wang 1,  Wenyu Dai 1,  Ya Zhou 1,  Tengfei Zhang 1,  Xianzhang Yang 1,  Jingjing Wu 1,  Yanmei Liu 1,  Jie Luo 1,  Huihua Tan 1,  Feng Zhao 2
Affiliations

Affiliations

  • 1 Guangxi Key Laboratory of Agro-Environment and Agric-Products Safety, National Demonstration Center for Experimental Plant Science Education, College of Agriculture, Guangxi University, Nanning, Guangxi, 530004, China.
  • 2 Guangxi Key Laboratory of Agro-Environment and Agric-Products Safety, National Demonstration Center for Experimental Plant Science Education, College of Agriculture, Guangxi University, Nanning, Guangxi, 530004, China. Electronic address: [email protected].
PMID: 41720237 DOI: 10.1016/j.envpol.2026.127849
Abstract

A comprehensive understanding of the enantioselective metabolic behaviors of tetraconazole within organisms is crucial for accurately evaluating their potential risks. Herein, human liver microsome assays showed that S-tetraconazole had a half-life of 14.98 min while R-tetraconazole had a half-life of 41.18 min. By specific CYP inhibitors, the key metabolizing enzyme for S-tetraconazole was identified as CYP3A4. Molecular docking revealed that R-tetraconazole (-8.39 kcal mol-1) had lower binding energies with CYP3A4 than S-tetraconazole (-8.05 kcal mol-1). Further, in vitro heterologous expression of CYP3A4 and mutation of the key amino acid arginine212 showed that wild-type CYP3A4 could rapidly and enantioselectivity metabolize S-tetraconazole, whereas the mutant not. Finally, nine tetraconazole metabolites were identified in liver microsomes, and M365, M369, and M285 were predicted more toxic than parent compounds. Overall, this study offers crucial reference for accurate risk assessment of tetraconazole from chiral level for protecting human health.

Keywords

Chiral; Human liver microsomes; Metabolite; Silico study; Tetraconazole.

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