近日，中国农业大学理学院王鹏课题组肖守淳老师，使用IPHASE品牌产品：ICR/CD-1小鼠肝微粒体、CYP450代谢表型研究试剂盒在《Journal of Hazardous Materials》权威期刊上发表文章《Systematic health risks assessment of chiral fungicide famoxadone:Stereoselectivities in ferroptosis-mediated cytotoxicity and metabolic behavior》，影响因子12.2！
噁唑菌酮是一种手性杀菌剂，常见于环境和农产品中。然而，噁唑菌酮对映体的健康风险尚不清楚。本研究调查了噁唑菌酮对映体在哺乳动物中的立体选择性细胞毒性和代谢行为。结果表明，R-噁唑菌酮对HepG2细胞的毒性是S-噁唑菌酮的1.5倍。与S-噁唑菌酮相比，R-噁唑菌酮诱导的铁死亡更为明显。它导致与铁转运和脂质过氧化相关的基因上调幅度更大，与过氧化物清除相关的基因下调幅度更大。进一步实验表明，R-噁唑菌酮通过激活ACSL4和抑制GPX4诱导更严重的脂质过氧化和活性氧(ROS)积累。此外，R-噁唑菌酮在小鼠中的生物利用度是S-噁唑菌酮的六倍。肝微粒体试验、细胞色素P450抑制试验、人重组CYP450试验和分子对接表明，CYP2C8、CYP2C19和CYP2E1对R-噁唑菌酮的结合亲和力较低，导致其优先积累。总体而言，R-噁唑菌酮比S-噁唑菌酮具有更高的风险，因为它具有更大的细胞毒性和持久性。本研究首次提供了铁死亡诱导立体选择性毒性的证据，为全面评估手性噁唑菌酮的健康风险提供了启示，并为高效、低风险农药对映体的应用提供了有价值的参考。
摘要
Famoxadone is a chiral fungicide frequently found in the environment and agricultural products. However, the health risks of famoxadone enantiomers are not well understood. This study investigated the stereoselective cytotoxicity and metabolic behavior of famoxadone enantiomers in mammals. Results showed that R-famoxadone was 1.5 times more toxic to HepG2 cells than S-famoxadone. R-famoxadone induced more pronounced ferroptosis compared to S-famoxadone. It caused greater upregulation of genes related to iron transport and lipid peroxidation, and greater downregulation of genes related to peroxide clearance. Furthermore, R-famoxadone induced more severe lipid peroxidation and reactive oxygen species (ROS) accumulation through ACSL4 activation and GPX4 inhibition. Additionally, the bioavailability of R-famoxadone in mice was six times higher than that of S-famoxadone. Liver microsome assays, cytochrome P450 (CYP450) inhibition assays, human recombinant CYP450 assays, and molecular docking suggested that the lower binding affinities of CYP2C8, CYP2C19,and CYP2E1 for R-famoxadone caused its preferential accumulation.
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