CYPs介导的噻嗪酮体内代谢及其毒性机制研究

噻嗪酮是在当前农业生产中广泛使用的一种噻二嗪类昆虫生长调节剂，已发现在水稻、茶叶、土壤和湖水中均有残留。文献报道，噻嗪酮可抑制水中鱼卵的发育和孵化，并对哺乳动物细胞也表现出一定的遗传毒性。为了进一步揭示噻嗪酮在非靶标生物体内的代谢途径和致毒机理，本课题利用整体动物实验，考察噻嗪酮在肝、脑、肾等组织分布的差异，检测尿液、胆汁和粪便中噻嗪酮和最终代谢产物的形态及含量；运用体外酶反应学手段揭示哺乳动物体内参与噻嗪酮生物转化的关键CYP代谢酶、重要代谢产物及代谢特征，解析噻嗪酮体内代谢途径；采用原代培养大鼠细胞和人正常肝细胞L02模型，通过对CYP酶系特异性抑制和诱导，明确噻嗪酮代谢产物与毒效应的相关关系，探索噻嗪酮致毒的关键代谢产物。本项目的研究，旨在阐明噻嗪酮在生物体内的代谢与毒性作用机制，为指导噻嗪酮的合理用药，减小环境污染和对非靶标生物的影响提供基础数据。

Buprofezin, one of the current agricultural insecticides, has been extensively used and founded residual content in plants (rice, tea, etc.), soil and water environment. The previous works have displayed the inhibition on development and hatching of embryos, and the genotoxicity on mammalian cells. However, it is not explicit about its metabolic pathways and toxic mechanism in non-target organisms. To explain that, we design the whole animal experiments, analyzing the distribution in different tissues and the metabolites in different excreta; we plan to carry out the in-vitro enzymatic reactions in mice liver microsomes, revealing the key CYP enzymes, main metabolites and metabolic characteristics in mammals; we prepare to use the rat primary hepatocytes and L02 cell models, studying the variation of metabolites and toxicities when inhibitors and inducers were adopted. Finally, the correlation between buprofezin metabolism and toxicity variation was taken into discussion. And all the above investigation of chemical analysis, metabolic pathways and toxic mechanism, were combined to guide the rational use of buprofezin, reduce the risk of environmental pollution, and protect the non-target organisms from abuse of insecticides.