Abstract：
Hexaconazole (Hex) has been widely used in agricultural products, and its residues may pose a potential risk to human health. However, the metabolic behavior of Hex enantiomers in mammal organisms is still unknown, which is important for evaluating the differences in their toxicity. In this study, the distribution of S-(+)- and R-(-)-Hex in mice was detected by an ultra-high performance liquid chromatography coupled with tandem mass spectrometry (UPLC-MS/MS), and the mechanism differences in the toxicokinetic behavior were analyzed by molecular docking. Good linearities, accuracies, and precisions were achieved for S-(+)- and R-(-)-Hex, with recoveries of 88.7~104.2% and RSDs less than 9.45% in nine tissues of mice. This established method was then used to detect the toxicokinetic of Hex enantiomers in mice after oral administration within 96 h. The results showed that the half-lives of S-(+)- and R-(-)-Hex were 3.07 and 3.71 h in plasma. Hex was mainly accumulated in the liver, followed by the kidneys, brain, lungs, spleen, and heart. The enantiomeric fraction (EF) values of Hex enantiomers in most of the samples were below 1, indicating that S-(+)-Hex decreased faster than its antipode. The molecular docking showed that the binding of S-(+)-Hex with P450arom was much more stable than R-(-)-Hex, which verified the fact that S-(+)-Hex was prefer to decrease in most of the tissues. The results of this study could be helpful for further evaluating the potential toxic risk of Hex enantiomers and for the development and usage of its pure monomer.
摘要：
己唑醇(Hex)已广泛应用于农产品中,其残留物可能对人类健康构成潜在风险。然而,Hex对映体在哺乳动物体内的代谢行为尚不清楚，这对于评估它们的毒性差异很重要。在这项研究中,采用超高效液相色谱-串联质谱(UPLC-MS/MS)检测小鼠体内S-(+)-和R-(-)-Hex的分布,并通过分子对接分析毒物动力学行为的机制差异。良好的线性度，准确性,并实现了S-(+)-和R-(-)-十六进制的精度，在9个小鼠组织中，回收率为88.7〜104.2%，RSD小于9.45%。然后用所建立的方法在96h内检测Hex对映体在小鼠体内的毒代动力学。结果表明，S-（）-和R-（-）-Hex在血浆中的半衰期分别为3.07和3.71h。十六进制主要积累在肝脏中，其次是肾脏，大脑,肺,脾,脾和心脏。大多数样品中Hex对映体的对映体分数（EF）值低于1，表明S-（）-Hex的下降速度快于其对映体。分子对接表明S-(+)-Hex与P450arom的结合比R-(-)-Hex稳定得多,这验证了S-（）-Hex在大多数组织中更喜欢减少的事实。本研究结果有助于进一步评估Hex对映体的潜在毒性风险及其纯单体的开发和使用。
