Shi Yuan, Pan Xinglu, Wu Xiaohu, Xu Jun, Xiang Wensheng, Li Zhiyuan, Zheng Yongquan, Wang Xiangjing, Dong Fengshou
State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China; Key laboratory of microbiology, Northeast Agricultural University, Harbin 150030, China.
State Key Laboratory for Biology of Plant Diseases and Insect Pests, Institute of Plant Protection, Chinese Academy of Agricultural Sciences, Beijing 100193, China.
Sci Total Environ. 2024 Dec 1;954:176408. doi: 10.1016/j.scitotenv.2024.176408. Epub 2024 Sep 19.
Guvermectin is a new chemical isolated from the microbial metabolites and is registered as a novel plant growth regulator. However, the biotransformation behavior and toxicity of guvermectin to mammals remain unclear and have unknown implications for consumers or occupationally exposed persons. Therefore, we investigated the biotransformation of guvermectin in vivo and in vitro, its effects on CYP450s activities, and its oral toxicity in rats. The results showed that guvermectin could be rapidly absorbed when administered orally and eliminated rapidly in the serum, with a half-life of 6.3 h. Four phase І metabolism products of guvermectin in the serum were screened and identified using UPLC-QTOF/MS. Two products, adenine and psicofuramine, were confirmed using reference standards. Hydrolysis and oxidation reactions were the main transformation pathways. Oral toxicity tests in rats showed that guvermectin exhibited light toxicity to rats (LC > 5000 mg/kg b.w.). However, an in vitro probe drug experiment revealed that guvermectin could induce CYP2D6 activity, and a lower concentration of guvermectin exhibited a stronger effect on CYP2D6 than higher concentration (1.38-fold). Molecular docking studies implied that guvermectin was an antagonist of CYP1A2, CYP2C9, and CYP3A4. These findings provided a better understanding of the environmental and human health risks associated with guvermectin and promote its rational use. However, the potential risk of endocrine disruption can not be ignored due to the presence of nucleoside-like metabolites.
古维菌素是一种从微生物代谢产物中分离出的新型化学物质，已注册为新型植物生长调节剂。然而，古维菌素对哺乳动物的生物转化行为和毒性仍不清楚，对消费者或职业接触者具有未知影响。因此，我们研究了古维菌素在体内和体外的生物转化、其对细胞色素P450酶（CYP450s）活性的影响及其对大鼠的口服毒性。结果表明，口服给药时古维菌素可迅速吸收并在血清中迅速消除，半衰期为6.3小时。使用超高效液相色谱-四极杆飞行时间质谱（UPLC-QTOF/MS）筛选并鉴定了血清中古维菌素的四种Ⅰ相代谢产物。使用参考标准品确认了其中两种产物腺嘌呤和拟茎点霉胺。水解和氧化反应是主要的转化途径。大鼠口服毒性试验表明，古维菌素对大鼠表现出轻度毒性（半数致死浓度>5000 mg/kg体重）。然而，体外探针药物实验表明，古维菌素可诱导CYP2D6活性，较低浓度的古维菌素对CYP2D6的作用比较高浓度更强（1.38倍）。分子对接研究表明，古维菌素是CYP1A2、CYP2C9和CYP3A4的拮抗剂。这些发现有助于更好地了解与古维菌素相关的环境和人类健康风险，并促进其合理使用。然而，由于存在核苷样代谢产物，内分泌干扰的潜在风险不容忽视。
