基于有害结局路径的中药毒性进程动态机制研究思路

Research on dynamic mechanism of toxic processes of traditional Chinese medicines based on adverse outcome pathway

2017年,马兜铃酸致肝癌事件引起了国内外对中药毒性的重视。由于中药本身的特殊性,其毒性基础研究中尚存在进程效应指标及毒性始动因素不清楚两大问题。本文借助毒性监控的研究框架--有害结局路径(AOP),研究其三个基本组成模块(分子起始事件、关键事件和有害结局)并整合联系起来。以补骨脂为例,从整体动物出发确定毒性结局;随后采用组学等技术构建"核心靶标"群,发现并验证关键事件;再以运用已有的小分子靶标鉴定技术,如点击化学(click chemistry)",钓取"毒性成分的直接靶标,确定分子起始事件;从而建立补骨脂致肝毒性AOP框架。本文将为中药毒性进程动态机制研究提出一条新思路。

The aristolochic acid event raised worldwide concern in 2017.The two major problems facing the toxicity study of traditional Chinese medicines(TCM),are the lack of process effect indicators,and the mystery surrounding the initiating factors of toxicity.In order to resolve these problems,this project uses a new method called the adverse outcome pathway(AOP)framework,which has replayed for the regulatory toxicity.To construct the structure,three key elements of AOP-molecular initiating events,key events and adverse outcomes,and correlations between the elements-need to be investigated.Take Fructus Psoraleae as an example.The toxicity in the organism level is determined before metabolomics and quantitative proteomics are used to construct the"core targets"group.Then,the developed technologies for molecular target identification such as click chemistry are employed as a tool to"fish"the direct target of toxic components,before the molecular initiation events are verified by experiments,and such data is integrated to establish the AOP framework.The study will recommend a suitable modular method for the toxic mechanism study of TCM and promote TCM internationalization and modernization.