title: Methyleugenol and oxidative metabolites induce DNA damage and interact with human topoisomerases.
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.
authors.affiliation: Institute of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Kaiserslautern, Germany.|Department of Food Chemistry and Toxicology, University of Vienna, Vienna, Austria.
authors.forename: Isabel Anna Maria
authors.initials: IA
authors.lastname: Groh
authors.affiliation: Institute of Chemistry, Division of Food Chemistry and Toxicology, University of Kaiserslautern, Kaiserslautern, Germany.
authors.forename: Olga
authors.initials: O
authors.lastname: Rudakovski
authors.affiliation: Institute of Food Chemistry, Westfälische Wilhelms-Universität Münster, Münster, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Gründken
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Vienna, Austria.
authors.forename: Anika
authors.initials: A
authors.lastname: Schroeter
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Vienna, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Marko
authors.affiliation: Institute of Food Chemistry, Westfälische Wilhelms-Universität Münster, Münster, Germany. esselen@uni-muenster.de.
authors.forename: Melanie
authors.initials: M
authors.lastname: Esselen
mesh_terms: D014408:Biomarkers, Tumor / Q000819:agonists / Q000378:metabolism; D001711:Biotransformation; D002274:Carcinogens, Environmental / Q000032:analysis / Q000378:metabolism / Q000633:toxicity*; D002277:Carcinoma / Q000139:chemically induced / Q000201:enzymology; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000378:metabolism; D020552:Comet Assay; D004249:DNA Damage; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004852:Epoxy Compounds / Q000032:analysis / Q000378:metabolism / Q000633:toxicity; D005054:Eugenol / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism / Q000633:toxicity; D005506:Food Contamination; D019073:HT29 Cells; D006657:Histones / Q000819:agonists / Q000378:metabolism; D006801:Humans; D015162:Micronucleus Tests; D009153:Mutagens / Q000032:analysis / Q000378:metabolism / Q000633:toxicity*; D009363:Neoplasm Proteins / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017365:Spices / Q000009:adverse effects / Q000032:analysis; D059004:Topoisomerase I Inhibitors / Q000032:analysis / Q000378:metabolism / Q000633:toxicity*
chemical_list: C000614725:3'-oxomethylisoeugenol; D014408:Biomarkers, Tumor; D002274:Carcinogens, Environmental; D004852:Epoxy Compounds; C468783:H2AX protein, human; D006657:Histones; D009153:Mutagens; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D059004:Topoisomerase I Inhibitors; C000614724:methyleugenol-2',3'-epoxide; C005223:methyleugenol; D005054:Eugenol; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human
keywords: DNA damage; DNA double-strand breaks; Methyleugenol; Micronucleus induction; Oxidative metabolites; Topoisomerase inhibition