三种新发现有机磷酸酯的鱼体代谢机制研究

申请人近期研究率先在环境介质中检出三种全新有机磷酸酯（NOPEs），其生态风险数据极度匮乏；全面评价NOPEs的生态风险，必先识别其生物代谢特征。细胞色素P450（CYP450）酶被认为是参与污染物代谢的主要酶系，而非CYP450酶对其代谢贡献尚未引起重视。本研究拟以三种NOPEs为目标物，基于鲫鱼体系研究其代谢特征，其核心思想是结合体内和体外代谢两种方式，兼顾CYP450酶及非CYP450酶介导作用，系统研究NOPEs的生物代谢机制。具体研究内容：开展NOPEs的动力学研究，基于建立的代谢图谱库和非靶向筛查方法，识别代谢产物，明确两类酶对NOPEs的代谢特征，揭示NOPEs的代谢规律；基于实验数据和理论模型，筛选两类酶中参与代谢的酶系，评估其对NOPEs代谢的贡献率，运用分子对接技术从分子水平上探究其对NOPEs作用机制。本研究可为准确评价和有效预测NOPEs的生态风险提供基础科学数据。

Three new identified organophosphate esters (NOPEs) were firstly detected in environment media in our recent study, and data on their ecological risks are extremely scarce. To comprehensively evaluate the ecological risks from NOPEs, it is priority and necessary to study metabolic features of NOPEs. Cytochrome P450 (CYP450) enzyme is recognized to be the major enzyme family that catalyzes biotransformation in pollutants, but the contribution of non-CYP450s to the metabolism of pollutants has not yet been paid much attention. The project, using the three NOPEs as target compounds and crucian carp as research system, will systematically study the metabolic features and mechanism of NOPEs mediated by CYP450s and non-CYP450s in vivo and in vitro. The detailed tasks are described following as: 1) study on the kinetics of NOPEs, and identification of the metabolites based on the established metabolic pathway database and non-targeted screening strategy, whereby the metabolic features of NOPEs mediated by CYP450s and non-CYP450s will be clarified and metabolic rules of NOPEs will be revealed; 2) screening of the enzymes participating in metabolism of NOPEs in both CYP450s and non-CYP450s, and evaluation of their contribution to NOPEs metabolism based on experiment data and theoretical models, and analysis of the interaction between NOPEs and the enzymes involved using molecular docking technology, whereby the metabolism mechanism of NOPEs at molecular level will be explored. The study will provide essential scientific data for the accurate evaluation and effective prediction of ecological risks of NOPEs.