中药肝毒性的物质基础与作用机制研究进展

近年来,中药引起的肝损伤报道时有发生,已成为临床上药物性肝损伤的重要病因之一。大多数中药的成分复杂,其产生疗效/毒性的物质基础与对应的临床症状和毒性作用及其机制不明确。目前中药肝毒性的研究策略简单地遵循传统毒理学的基本原则,导致中药毒性被夸大或错误的解释。对中药肝毒性物质基础分类及可能的毒性机制进行综述,旨在整理中药致肝损伤危险因素的分类、机制和靶点,以进一步指导中药的安全应用。根据中药所含成分的化学结构,中药中潜在的毒性成分可分为生物碱类、糖苷类、萜类和内酯类、蒽醌类。根据中药诱导肝损伤过程中药物代谢是否被激活或肝细胞是否受到直接攻击,高危物质可分为代谢激活型、非代谢激活型和混合型。此外,从脂肪代谢,细胞色素P450(CYP450)、线粒体功能、氧化损伤、细胞凋亡、内质网应激和特异质反应等角度总结了中药诱导肝毒性的潜在机制,并提出了毒性成分所涉及的靶点,主要包括代谢酶、核受体、转运体和信号通路。通过对中药诱导肝损伤(traditional Chinese medicine-induced liver injury,TILI)危险信号的回顾和总结,讨论了中药肝毒性研究中存在的问题,以期为中药肝毒性的研究提供新的视角,有助于对中药致肝毒性的多成分、多靶点、多效应特点进行综合分析,为肝脏毒性中药的毒性研究及临床合理应用提供重要的理论支持和科学建议。

Material basis for liver toxicity of traditional Chinese medicine and research progress on its mechanism

In recent years, the adverse effects on the liver system or TCM-induced hepatotoxicity have been reported frequently, TCM has become an important clinical cause of drug-induced liver injury (DILI). Generally, the ingredients of TCM with typical therapeutic or toxic effects are complex and unclear, resulting in the uncertainty of specific material basis for efficacy/toxicity, specific clinical symptoms and toxic mechanisms. However, the strategies adopted for TCM-induced hepatotoxicity research mainly refer to the basic principles of conventional toxicology, causing exaggerative or incorrect interpretations in the toxicity of TCM. This review highlights the basic classification of hepatotoxic substances in TCM and the possible toxicity mechanism, aiming to summarize the classification, mechanisms and targets of the risk components in TCM-induced liver injury (TILI) with view to guiding clinical rational use. According to the different chemical structures, the risk ingredients mainly include alkaloids, glycosides, terpenoids and lactones, and anthraquinones. According to whether the drug metabolism is activated or whether the liver cells are directly attacked in the process of TCM-induced liver injury, the potential poisonous components can be classified into metabolic activation, non-metabolic activation, and mixed types. In addition, this review summarizes the potential mechanism of TCM-induced hepatotoxicity from the aspects of fat metabolism, cytochrome P450 (CYP450), mitochondrial function, oxidative damage, apoptosis, endoplasmic reticulum stress and idiosyncratic reaction, and put forward the targets involved in the TILI, including metabolic enzymes, nuclear receptors, transporter and signaling pathways. Our periodic review and summary on the risk signals of TCM-induced liver injury must be beneficial to the integrated analysis on the multi-component, multi-target, and multi-effect characteristics of TCM-induced hepatotoxicity. In this review, we also present the existing problems in toxicity studies for TCM and provide new perspectives for research on the potential TILI. We hope that this study can offer important theoretical support and scientific advice for the toxicity study and clinical rational use of TCM with hepatotoxicity.