Risk Compounds, Preclinical Toxicity Evaluation, and Potential Mechanisms of Chinese Materia Medica-Induced Cardiotoxicity.

Jie Zhou,Lian Yang,Dayi Chen,Xiaoqi Pan,Xiaoyu Cao,Chaolong Rao,Fu Peng,Xiaofang Xie,Cheng Peng

doi:10.3389/fphar.2021.578796

Abstract

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.

Highlights

Chinese materia medica (CMM) as an alternative therapy for disease treatment has become increasingly popular all over the world
Natriuretic peptides and troponins are recommended for assessing myocardial injuries with the advantages of higher specificity and sensitivity than myocardial enzymes, they are still less used for studying CMM-induced cardiotoxicity in clinical application
In response to the problem of adverse cardiac reactions induced by CMM, research teams have carried out a large number of studies on the performances and characteristics, toxic substance basis, and mechanisms of cardiotoxicity induced by CMM, their extracts, or single compounds

Summary

INTRODUCTION

Chinese materia medica (CMM) as an alternative therapy for disease treatment has become increasingly popular all over the world. Drug-induced cardiotoxicity refers to the toxicity or negative effects of chemical drugs or CMM on the heart, including arrhythmia, myocardial ischemia, heart failure, and other cardiac adverse reactions (Li et al, 2015). The study indicated that ephedrine isolated from Ephedra sinica Stapf could trigger a range of cardiovascular toxicities, including myocarditis, arrhythmias, myocardial infarction, cardiac arrest, heart failure, and sudden death (Samenuk et al, 2002; Adamson et al, 2004; Naik and Freudenberger, 2004; Nyska et al, 2005). Another study suggested that colchicine could directly damage cardiac endothelial cells to induce cardiotoxicity (Mikaelian et al, 2010) Terpenoids, such as triptolide, celastrol, and rhodojaponin, are other important compounds of CMM-induced cardiotoxicity. A study on the toxicological effects of rhodojaponins demonstrated that myocardial injury was elicited by Rhododendron molle extract (Dong et al, 2014)

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CONCLUSION