title: Inhibition of topoisomerase II by phase II metabolites of resveratrol in human colon cancer cells.
abstract: METHODS
  The cytotoxic and genotoxic potential of phase II metabolites of resveratrol (RSV) was investigated in human colon cells with special emphasis on human topoisomerase (TOP) II.
  
  
  RESULTS
  Cell-free screening of topoisomerase II (TOPII) inhibition by the decatenation assay showed inhibitory potential for RSV (≥200 μM) and for the first time for the three human phase II metabolites RSV-3-sulfate (≥200 μM), RSV-3-glucuronide (≥100 μM) and RSV-disulfate (≥100 μM). Conjugation at the C4'-position (RSV-4'-sulfate and RSV-4'-glucuronide) resulted in loss of the inhibitory potential in this assay. Cell-based experiments with RSV and the most abundant metabolite in humans, RSV-3-Sulf, revealed no TOP poisoning in HT29 and Caco-2 cells up to 250 μM. Further, the phase II metabolite exhibited only minor effects in the comet assay and showed negligible cytotoxic effects and apoptotic potential after 1 and 24 h incubation. Fluorescence microscopy and HPLC-DAD analysis identified cellular uptake of RSV and of RSV-3-Sulf although to a lesser extent when compared to RSV. Furthermore, within the cells fractional deconjugation of RSV-3-Sulf to the parent compound was observed.
  
  
  CONCLUSIONS
  Sulfate- and glucuronide-phase II metabolites might contribute to the genotoxic potential of RSV by inhibition of TOPII activity. By deconjugation at the target site RSV-3-Sulf might serve as a pool of the parent compound.
authors.affiliation: Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Anika
authors.initials: A
authors.lastname: Schroeter
authors.affiliation: Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Isabel Anna Maria
authors.initials: IA
authors.lastname: Groh
authors.affiliation: Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Del Favero
authors.affiliation: Department of Nutritional and Physiological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Marc
authors.initials: M
authors.lastname: Pignitter
authors.affiliation: Department of Nutritional and Physiological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schueller
authors.affiliation: Department of Nutritional and Physiological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Veronika
authors.initials: V
authors.lastname: Somoza
authors.affiliation: Department of Food Chemistry and Toxicology, Faculty of Chemistry, University of Vienna, Vienna, Austria.
authors.forename: Doris
authors.initials: D
authors.lastname: Marko
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells / Q000187:drug effects; D002474:Cell-Free System; D003110:Colonic Neoplasms / Q000188:drug therapy; D020552:Comet Assay; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D020719:Glucuronides / Q000494:pharmacology; D019073:HT29 Cells / Q000187:drug effects; D006801:Humans; D000077185:Resveratrol; D013267:Stilbenes / Q000378:metabolism* / Q000494:pharmacology*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*
chemical_list: D020719:Glucuronides; D013267:Stilbenes; D059005:Topoisomerase II Inhibitors; C000599822:resveratrol-3-O-4'-disulfate; C499731:resveratrol-4'-O-glucuronide; D000077185:Resveratrol
keywords: Colon cancer cells; DNA damage; Resveratrol; Resveratrol metabolites; Topoisomerase