Classification, hepatotoxic mechanisms, and targets of the risk ingredients in traditional Chinese medicine-induced liver injury

Traditional Chinese medicine (TCM) has become a crucial cause of drug-induced liver injury (DILI). Differ from chemical medicines, TCM feature more complex and mostly indefinite components. This review aimed to clarify the classification, underlying mechanisms and targets of the risk components in TCM-induced liver injury to further guide the secure application of TCM. Relevant studies or articles published on the PubMed database from January 2008 to December 2019 were searched. Based on the different chemical structures of the risk ingredients in TCM, they are divided into alkaloids, glycosides, toxic proteins, terpenoids and lactones, anthraquinones, and heavy metals. According to whether drug metabolism is activated or hepatocytes are directly attacked during TCM-induced liver injury, the high-risk substances can be classified into metabolic activation, non-metabolic activation, and mixed types. Mechanisms of the hepatotoxic ingredients in TCM-induced hepatotoxicity, including cytochrome P450 (CYP450) induction, mitochondrial dysfunction, oxidative damage, apoptosis, and idiosyncratic reaction, were also summarized. The targets involved in the risk ingredient-induced hepatocellular injury mainly include metabolic enzymes, nuclear receptors, transporters, 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.