Mechanism-Based Inhibitors from Phytomedicine: Risks of Hepatotoxicity and their Potential Hepatotoxic Substructures

Background: The adverse drug reactions and poisoning events associated with the use of herbal medicines, especially the potential damaging effects of them on the liver organs, have increasingly been reported worldwide. Some herbal ingredients in medicinal plants carry the risk of herb-induced liver injury with a severe or potentially lethal clinical course, but the hepatotoxicity mechanisms and risk factors of them are not well characterized until now. Xenobiotics are converted by cytochrome P450 enzymes into highly reactive metabolites that covalently bind to the catalytic site of the enzyme itself, subsequently causing mechanism-based inhibition (MBI). Compared to reversible inhibition, MBI more frequently results in unfavorable acute and/or immune system-mediated idiosyncratic toxicities and drug/herb-drug interactions (DDI/HDIs). Methods: We searched PubMed databases (1980-2015) for articles published in the English language to identify publications on mechanism-based inhibitors from phytomedicine and herbal ingredients hepatotoxicity. Results: 43 mechanism-based inhibitors from phytomedicine were summarized. Twelve of these inhibitors could cause hepatotoxicity, whereas the rest have no related reports. Among them, six hepatotoxic mechanism-based inhibitors are proven to induce hepatotoxicity via their reactive metabolites (RMs). The possible mechanism for this hepatotoxicity is that RMs react with cellular components such as proteins, DNA, and membranes, resulting in ROS overproduction, respiratory chain dysfunction, and cell stress. Moreover, the amine and furan heterocycle groups might be the most potential substructures in mechanism-based inhibitors which can cause hepatotoxicity. Conclusion: These results suggest that when mechanism-based inhibitors from phytomedicine containing amine or furan heterocycle substructures are used alone or with other drugs, in vivo hepatotoxicity screening or its clinical implications for herb-drug interactions are needed to attention.