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Methyleugenol and oxidative metabolites induce DNA damage and interact with human topoisomerases

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Abstract

Methyleugenol is a substituted alkenylbenzene found in several herbs and spices. It is classified by the European Union’s Scientific Committee on Food as a genotoxic carcinogen. We addressed the biological mechanism of the genotoxic properties of methyleugenol and its oxidative metabolites. Methyleugenol and the oxidative metabolites significantly enhanced the DNA damage in human colon carcinoma cells (HT29). Methyleugenol did not affect the protein status of γH2AX, a biomarker of DNA double-strand breaks, whereas its metabolites methyleugenol-2′,3′-epoxide and 3′-oxomethylisoeugenol significantly increased the cellular phosphorylated H2AX level. Both of these metabolites also showed a significant induction of micronuclei in HT29 cells. Furthermore, we investigated whether topoisomerase interaction contribute to the observed effect on DNA integrity. Methyleugenol-2′,3′-epoxide and 3′-oxomethylisoeugenol inhibited the activity of recombinant topoisomerase I. In HT29 cells, neither methyleugenol nor the metabolites affected the level of topoisomerase protein bound to DNA, excluding a topoisomerase poisoning mode of action. In addition, 3′-oxomethylisoeugenol potently diminished the level of camptothecin-stabilized topoisomerase I/DNA intermediates and camptothecin-induced DNA strand breaks. In conclusion, it could be suggested that 3′-oxomethylisoeugenol may also interact with classical or food-borne topoisomerase I poisons, diminishing their poisoning effectiveness.

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Acknowledgments

The study was supported by Boehringer Ingelheim Fonds which financed the research habitation at the University of Vienna by a travel grant. The study was also supported by the grant ES419/2-1 of the Deutsche Forschungsgemeinschaft.

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Authors and Affiliations

  1. Institute of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Kaiserslautern, Germany

    Isabel Anna Maria Groh & Olga Rudakovski

  2. Department of Food Chemistry and Toxicology, University of Vienna, Vienna, Austria

    Isabel Anna Maria Groh, Anika Schroeter & Doris Marko

  3. Institute of Food Chemistry, Westfälische Wilhelms-Universität Münster, Münster, Germany

    Malte Gründken & Melanie Esselen

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  1. Isabel Anna Maria Groh
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  2. Olga Rudakovski
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Correspondence to Melanie Esselen.

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Groh, I.A.M., Rudakovski, O., Gründken, M. et al. Methyleugenol and oxidative metabolites induce DNA damage and interact with human topoisomerases. Arch Toxicol 90, 2809–2823 (2016). https://doi.org/10.1007/s00204-015-1625-3

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  • DOI: https://doi.org/10.1007/s00204-015-1625-3

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