alpha-asarone and Chemical-and-Drug-Induced-Liver-Injury

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 (αA) and β-asarone (βA) are often used as flavoring agents for alcoholic beverages and food supplements. They possess a double bond in the side chain with different configurations. Double bonds are a class of alert chemical group, due to their metabolic epoxidation to the corresponding epoxides eliciting liver injury. Little is known about changes of configuration on metabolic activation and related toxicity. Here, we report the insight into the mechanisms of hepatotoxicity of asarone with different configurations. In vitro and in vivo comparative studies demonstrated βA displayed higher metabolic activation effectiveness. Apparently, the major metabolic pathway of βA underwent epoxidation at C-1' and C-2', while αA was mainly metabolized to the corresponding alcohol resulting from the hydroxylation of C-3'. CYP1A2 dominated the metabolism of αA and βA. The molecular simulation studies showed that the orientation of βA at the active site of CYP1A2 favored the epoxidation of βA over that of αA. These findings not only remind us that configuration is another important factor for toxicities but also facilitate the understanding of the mechanisms of toxic action of asarone. Additionally, these findings would benefit the risk assessment of αA and βA exposure from foods.

Topics: Allylbenzene Derivatives; Anisoles; Chemical and Drug Induced Liver Injury; Cytochrome P-450 CYP1A2; Humans

Acorus calamus is a swamp herb, which is widely spread in northern hemisphere. It is used in infusions and in bitters but also in food supplements and in traditional herbal medicine. However, the main A. calamus ingredients, propenylic 2,4,5-trimethoxyphenylpropene isomers, termed alpha- (trans) and beta- (cis) asarone, are known carcinogens in rodents. Genotoxic and mutagenic properties are proposed. The presented in vitro cytotoxicity study focused on time-dependent and combinatory exposure scenarios. All experiments performed in HepG2 cells show moderate (in middle micromolar range) cytotoxicity with a time-dependent increase in effectiveness. The combination of the two asarone isomers in short time experiments (1 h) did not show any effect, whereas asarone isomer interaction changes from synergistic to antagonistic with an extended duration of exposure up to 72 h. The antagonism occurred predominantly in the naturally occurring trans/cis-asarone ratio of approximately 1:10. Combinatory cytotoxicity of asarones and selected, dietary relevant flavonoids in constant ratios was mainly attributed to flavonoid toxicity.

Topics: Allylbenzene Derivatives; Anisoles; Chemical and Drug Induced Liver Injury; Drug Synergism; Flavonoids; Hep G2 Cells; Humans; Isomerism