Zhou Jie, Peng Fu, Cao Xiaoyu, Xie Xiaofang, Chen Dayi, Yang Lian, Rao Chaolong, Peng Cheng, Pan Xiaoqi
State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
School of Pharmacy and School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Front Pharmacol. 2021 Mar 30;12:578796. doi: 10.3389/fphar.2021.578796. eCollection 2021.
Chinese materia medica (CMM) has been applied for the prevention and treatment of diseases for thousands of years. However, arrhythmia, myocardial ischemia, heart failure, and other cardiac adverse reactions during CMM application were gradually reported. CMM-induced cardiotoxicity has aroused widespread attention. Our review aimed to summarize the risk compounds, preclinical toxicity evaluation, and potential mechanisms of CMM-induced cardiotoxicity. All relevant articles published on the PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases for the latest twenty years were searched and manually extracted. The risk substances of CMM-induced cardiotoxicity are relatively complex. A single CMM usually contains various risk compounds, and the same risk substance may exist in various CMM. The active and risk substances in CMM may be transformed into each other under different conditions, such as drug dosage, medication methods, and body status. Generally, the risk compounds of CMM-induced cardiotoxicity can be classified into alkaloids, terpenoids, steroids, heavy metals, organic acids, toxic proteins, and peptides. Traditional evaluation methods of chemical drug-induced cardiotoxicity primarily include cardiac function monitoring, endomyocardial biopsy, myocardial zymogram, and biomarker determination. In the preclinical stage, CMM-induced cardiotoxicity should be systematically evaluated at the overall, tissue, cellular, and molecular levels, including cardiac function, histopathology, cytology, myocardial zymogram, and biomarkers. Thanks to the development of systematic biology, the higher specificity and sensitivity of biomarkers, such as genes, proteins, and metabolic small molecules, are gradually applied for evaluating CMM-induced cardiotoxicity. Previous studies on the mechanisms of CMM-induced cardiotoxicity focused on a single drug, monomer or components of CMM. The interaction among ion homeostasis (sodium, potassium, and calcium ions), oxidative damage, mitochondrial injury, apoptosis and autophagy, and metabolic disturbance is involved in CMM-induced cardiotoxicity. Clarification on the risk compounds, preclinical toxicity evaluation, and potential mechanisms of CMM-induced cardiotoxicity must be beneficial to guide new CMM development and post-marketed CMM reevaluation.
中药已应用于疾病的防治数千年。然而，中药应用过程中出现的心律失常、心肌缺血、心力衰竭等心脏不良反应逐渐被报道。中药引起的心脏毒性已引起广泛关注。我们的综述旨在总结中药引起心脏毒性的风险化合物、临床前毒性评估及潜在机制。检索了过去二十年在PubMed、Embase和中国知网（CNKI）数据库上发表的所有相关文章并进行人工提取。中药引起心脏毒性的风险物质相对复杂。单一中药通常含有多种风险化合物，且同一风险物质可能存在于多种中药中。中药中的活性物质和风险物质在不同条件下（如药物剂量、用药方法和身体状况）可能相互转化。一般来说，中药引起心脏毒性的风险化合物可分为生物碱、萜类、甾体、重金属、有机酸、有毒蛋白质和肽类。化学药物引起心脏毒性的传统评估方法主要包括心功能监测、心内膜活检、心肌酶谱和生物标志物测定。在临床前阶段，应从整体、组织、细胞和分子水平对中药引起的心脏毒性进行系统评估，包括心功能、组织病理学、细胞学、心肌酶谱和生物标志物。得益于系统生物学的发展，基因、蛋白质和代谢小分子等生物标志物的更高特异性和敏感性正逐渐应用于评估中药引起的心脏毒性。以往关于中药引起心脏毒性机制的研究主要集中在单一药物、单体或中药成分上。离子稳态（钠、钾和钙离子）、氧化损伤、线粒体损伤、凋亡和自噬以及代谢紊乱之间的相互作用参与了中药引起的心脏毒性。阐明中药引起心脏毒性的风险化合物、临床前毒性评估及潜在机制必定有助于指导新型中药的研发及上市后中药的再评价。
