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

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.

Natural Compound Library Screening Identifies Oroxin A for the Treatment of Myocardial Ischemia/Reperfusion Injury

“…Myocardial enzymes, such as cTnI, cTnT, CK-MB, LDH and AST produced in cardiomyocytes, can be released from damaged tissue into the blood circuit under pathological conditions ( Zhu et al, 2021 ). This serum myocardial zymogram can be used as a reliable index to determine the integrity of the myocardial membrane and the degree of myocardial injury ( Zhou et al, 2021 ). Combined with the observation of myocardial infarct size in rats, these results confirm the protective effect of OA on MI/RI.…”

Alkaloids as Natural NRF2 Inhibitors: Chemoprevention and Cytotoxic Action in Cancer

“…The structure labeled as number 2 in this study, a rare rearranged aconitine-type C-19 diterpenoid alkaloid, showed a slight inhibitory effect (10% inhibition rate) on the expression of NRF2-regulated genes at concentration of 10 µM and therefore promoted cytotoxic activity [ 139 ]. Apart from the promising NRF2-inhibitory activity, the present research in this field is limited concerning risk factors, particularly regarding the possible cardiac toxicity [ 141 , 142 ]. Thus, future studies should focus on increasing the selectivity of the cytotoxic action on cancer cells while sparing the healthy cells.…”

Assessing Drug-Induced Mitochondrial Toxicity in Cardiomyocytes: Implications for Preclinical Cardiac Safety Evaluation

“…Drugs inducing cardiotoxicity by targeting mitochondria invariably proceed to MMP collapse and mPTP opening ( Table 3 ). Antineoplastic agents, including DOX [ 73 , 81 , 164 ], As 2 O 3 [ 84 , 229 ], and imatinib [ 91 ]; β adrenergic receptor blockers, such as propranolol and atenolol [ 119 ]; antiarrhythmic drugs dronedarone and amiodarone [ 139 ]; antibiotics erythromycin and clarithromycin; NSAIDs such as naproxen, diclofenac, and celecoxib [ 60 ]; and diabetes drug pioglitazone [ 122 ] have all been reported to cause these harmful effects. mPTP opening and MMP decrease consequently induce loss of respiratory control and imbalance in ATP production, and loss of mitochondrial components such as ATP, NAD+, and glutathione, leading to water accumulation in the matrix, which causes mitochondrial osmotic swelling, IMM unfolding, and the rupture of the OMM [ 230 , 231 ].…”