alpha-asarone and Cardiotoxicity

Asarone isomers are naturally occurring in Acorus calamus Linné, Guatteria gaumeri Greenman, and Aniba hostmanniana Nees. These secondary plant metabolites belong to the class of phenylpropenes (phenylpropanoids or alkenylbenzenes). They are further chemically classified into the propenylic trans- and cis-isomers α-asarone and β-asarone and the allylic γ-asarone. Flavoring, as well as potentially pharmacologically useful properties, enables the application of asarone isomers in fragrances, food, and traditional phytomedicine not only since their isolation in the 1950s. However, efficacy and safety in humans are still not known. Preclinical evidence has not been systematically studied, and several pharmacological effects have been reported for extracts of Acorus calamus and propenylic asarone isomers. Toxicological data are rare and not critically evaluated altogether in the 21st century yet. Therefore, within this review, available toxicological data of asarone isomers were assessed in detail. This assessment revealed that cardiotoxicity, hepatotoxicity, reproductive toxicity, and mutagenicity as well as carcinogenicity were described for propenylic asarone isomers with varying levels of reliability. The toxicodynamic profile of γ-asarone is unknown except for mutagenicity. Based on the estimated daily exposure and reported adverse effects, officials restricted or published recommendations for the use of β-asarone and preparations of Acorus calamus. In contrast, α-asarone and γ-asarone were not directly addressed due to a limited data situation.

Topics: Allylbenzene Derivatives; Animals; Anisoles; Carcinogens; Cardiotoxicity; Chemical and Drug Induced Liver Injury; Humans; Isomerism; Reproduction

α-asarone is a natural phenylpropene found in several plants, which are widely used for flavoring foods and treating diseases. Previous studies have demonstrated that α-asarone has many pharmacological functions, while some reports indicated its toxicity. However, little is known about its cardiovascular effects. This study investigated developmental toxicity of α-asarone in zebrafish, especially the cardiotoxicity. Zebrafish embryos were exposed to different concentrations of α-asarone (1, 3, 5, 10, and 30 μM). Developmental toxicity assessments revealed that α-asarone did not markedly affect mortality and hatching rate. In contrast, there was a concentration-dependent increase in malformation rate of zebrafish treated with α-asarone. The most representative cardiac defects were increased heart malformation rate, pericardial edema areas, sinus venosus-bulbus arteriosus distance, and decreased heart rate. Notably, we found that α-asarone impaired the cardiac function of zebrafish by prolonging the mean QTc duration and causing T-wave abnormalities. The expressions of cardiac development-related key transcriptional regulators tbx5, nkx2.5, hand2, and gata5 were all changed under α-asarone exposure. Further investigation addressing the mechanism indicated that α-asarone triggered apoptosis mainly in the heart region of zebrafish. Moreover, the elevated expression of puma, cyto C, afap1, caspase 3, and caspase 9 in treated zebrafish suggested that mitochondrial apoptosis is likely to be the main reason for α-asarone induced cardiotoxicity. These findings revealed the cardiac developmental toxicity of α-asarone, expanding our knowledge about the toxic effect of α-asarone on living organisms.

Topics: Abnormalities, Drug-Induced; Allylbenzene Derivatives; Animals; Anisoles; Apoptosis; Cardiotoxicity; Electrocardiography; Embryo, Nonmammalian; Heart Defects, Congenital; Mitochondria, Heart; Zebrafish