基于“三因致毒”假说的中药免疫特异质肝损伤成因机制解析

Analyzing the Mechanism of Traditional Chinese Medicines-induced Immune Idiosyncratic Liver Injury Using the"Three Factors Causing Toxicity"Hypothesis

特异质药物性肝损伤(Idiosyncratic Drug-induced Liver Injury, IDILI)具有不可预测性和发病率低等特点,一直是新药撤市遇到的瓶颈问题。IDILI发生与机体、环境和药物密切相关,而机体免疫是IDILI发生的主要诱因,故免疫IDILI备受关注。囿于中草药组成和临床用药的复杂性,中药相关特异质肝损伤物质基础和机制的阐释成为研究的难点和热点。课题组前期针对何首乌肝损伤特点,提出了“三因致毒”机制假说,为中药免疫特异质肝损伤的评价和机制研究提供新的思路和方法。因此,本文基于“三因致毒”假说科学内涵,以仙灵骨葆为例,通过文献报道、临床回顾性分析及实验室研究,明确免疫应激可能是其特异质肝损伤的重要诱因;借助免疫应激模型,明确了其肝损伤的物质基础,并区分了成分类型;利用代谢组学技术初步探讨了其机制。结果表明,该假说能够解析其免疫特异质肝损伤的成因机制,具有一定的普适性,可为科学评价中药免疫特异质肝损伤风险防控提供研究思路和科学依据。

Idiosyncratic drug-induced liver injury(IDILI)poses a significant challenge in the withdrawal of new drugs due to its unpredictable nature and low incidence rate.IDILI results from a synergistic effect involving individual predisposition,environmental factors,and drug characteristics.Immune response is a key factor in IDILI,attracting considerable attention.The study of traditional Chinese medicines(TCM)-induced idiosyncratic liver injury has emerged as a prominent research area due to the complexity of TCM composition and application.Based on the liver injury characteristics of Polygonum Multiflorum,we propose the“Three Factors Causing Toxicity”hypothesis,offering new insights and methods for evaluating and researching the mechanism of TCM-induced immune idiosyncratic liver injury.Therefore,based on the scientific connotation of the“Three Factors Causing Toxicity”hypothesis and using Xianling Gubao(XLGB)as an example,this paper clarifies that immune stress may be an important causative factor of its IDILI through literature reports,clinical retrospective analysis and laboratory studies;with the help of immune stress model,the material basis of its liver injury is clarified and its component types are distinguished;and its mechanism is preliminarily explored by metabolomics technology.The results showed that this hypothesis can analyse the causative mechanism of immune idiosyncratic liver injury,and it has a certain degree of universality,which can provide research ideas and scientific basis for the scientific evaluation of the prevention and control of the risk of immune idiosyncratic liver injury in TCM.