DNA double strand break repair as cellular response to genotoxic asarone isomers considering phase I metabolism

Römermann

Cramer

et al. 2021

J. Agric. Food Chem.

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α-Asarone and β-asarone are reported as bioactive constituents of Acorus calamus. Phase I metabolism of asarone isomers results in a multiple spectrum of genotoxic metabolites. Thus, the question arises whether structural analogues of the known phase I metabolites also naturally occur in A. calamus-based food products. A liquid chromatography−tandem mass spectrometry (LC−MS/MS) method was developed and validated for three product classes, herbal infusions, alcoholic beverages, and food supplements. High asarone contents were detected in herbal infusions (total mean 9.13 mg/kg, n = 8) and food supplements (total mean 14.52 mg/kg, n = 6); hence, these food products can highly contribute to human exposure to genotoxic asarone derivatives. Also, the occurrence of asarone oxidation products found in food and food supplements has to be taken under consideration because data on toxicity is limited so far.

Section: Resultsmentioning

confidence: 99%

Quantitative Analysis of β-Asarone Derivatives in Acorus calamus and Herbal Food Products by HPLC-MS/MS

Römermann

Cramer

et al. 2021

J. Agric. Food Chem.

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“…Considering the observed excretion rate of 42%, it is quite reasonable that the highly reactive epoxide intermediate is formed to a significant extent, which promotes its binding to macromolecules such as DNA or proteins. However, a fast repair of epoxide-derived genotoxic DNA-damage in liver tumor HepG2 cells and also a time-dependent decrease of DNA adducts in rat hepatocytes are reported [ 10 , 28 ]. Epoxide hydrolases catalyze the formation of less reactive dihydro-diol derivatives and they are suggested to play a major role in the detoxification of epoxides in vivo [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…Threo - and erythro -asarone diols were isolated from a decomposed epoxide solution. Further information can be found in the literature [ 10 ]. Additionally, 7′-hydroxycoumarin and 4-methylumbelliferyl-β-D-glucuronide were purchased from Sigma-Aldrich (Steinheim, Germany).…”

Section: Methodsmentioning

confidence: 99%

“…Besides all positive effects, these substances are also of toxicological concern. Among acute and chronic toxicity, hepatotoxic properties in rodents as well as cytotoxic, genotoxic and mutagenic effects in vitro are reported for parent compounds and several oxidative phase I metabolites [ 7 , 8 , 9 , 10 , 11 ]. Furthermore, DNA repair mechanisms are also activated in response to asarone-mediated genotoxic effects in cells [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Phase II Metabolism of Asarone Isomers In Vitro and in Humans Using HPLC-MS/MS and HPLC-qToF/MS

Römermann

Cramer

et al. 2021

Foods

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(1) Background: Metabolism data of asarone isomers, in particular phase II, in vitro and in humans is limited so far. For the first time, phase II metabolites of asarone isomers were characterized and human kinetic as well as excretion data after oral intake of asarone-containing tea infusion was determined. (2) Methods: A high pressure liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-qTOF-MS) approach was used to identify phase II metabolites using liver microsomes of different species and in human urine samples. For quantitation of the respective glucuronides, a beta-glucuronidase treatment was performed prior to analysis via high pressure liquid chromatography coupled with tandem mass spectrometry (HPLC-MS/MS). (3) Results: Ingested beta-asarone and erythro and threo-asarone diols were excreted as diols and respective diol glucuronide conjugates within 24 h. An excretion rate about 42% was estimated. O-Demethylation of beta-asarone was also indicated as a human metabolic pathway because a corresponding glucuronic acid conjugate was suggested. (4) Conclusions: Already reported O-demethylation and epoxide-derived diols formation in phase I metabolism of beta-asarone in vitro was verified in humans and glucuronidation was characterized as main conjugation reaction. The excretion rate of 42% as erythro and threo-asarone diols and respective asarone diol glucuronides suggests that epoxide formation is a key step in beta-asarone metabolism, but further, as yet unknown metabolites should also be taken into consideration.

“…A contribution of redox‐sensitive mechanisms to DNA‐damaging properties can be proposed from observed formamidopyrimidine‐DNA‐glycosylase‐sensitive sites after metabolic activation. Additionally, the induction of micronuclei by an aneugenic mechanism and the induction of DNA repair mechanisms were observed in in vitro experiments (Hermes, Haupenthal, Uebel, & Esselen, 2020).…”

Section: Toxicodynamicmentioning

confidence: 96%

α‐Asarone, β‐asarone, and γ‐asarone: Current status of toxicological evaluation

Uebel

J of Applied Toxicology

Haupenthal

et al. 2020

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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.