title: Oxidative metabolism enhances the cytotoxic and genotoxic properties of the soy isoflavone daidzein.
abstract: METHODS
  Oxidative metabolism of daidzein (DAI) might result in the formation of hydroxylated metabolites. Here, we address the question whether these metabolites differ in their biological activity from the parent isoflavone, exemplified for the epidermal growth factor receptor and topoisomerase II, potentially resulting in an enhanced toxic profile.
  
  
  RESULTS
  In contrast to DAI, 6-hydroxydaidzein (6-HO-DAI) and 8-hydroxydaidzein (8-HO-DAI) were found to inhibit the tyrosine kinase activity of the epidermal growth factor receptor in an ELISA-based test system, but showed no effects within cells. Further, the oxidative metabolites suppressed the catalytic activity of topoisomerase II in the decatenation assay. In the in vivo complexes of enzyme to DNA (ICE) bioassay, 6-HO-DAI and 8-HO-DAI did not affect the level of covalent topoisomerase II-DNA intermediates within HT29 cells, thus arguing for a catalytic inhibition of topoisomerase II rather than poisoning activity. In contrast to DAI, 6-HO-DAI and 8-HO-DAI significantly increased the rate of DNA strand breaks in HT29 cells after 24-h incubation and caused a cell cycle delay in S-phase. Differences were also observed between the oxidative metabolites, with only 6-HO-DAI inducing apoptosis but not 8-HO-DAI.
  
  
  CONCLUSIONS
  These data indicate that oxidative metabolism of DAI generates metabolites with genotoxic properties where interference with topoisomerase II might play a role.
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Vienna, Austria.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Baechler
authors.forename: Anika
authors.initials: A
authors.lastname: Schroeter
authors.forename: Jessica
authors.initials: J
authors.lastname: Walker
authors.forename: Georg
authors.initials: G
authors.lastname: Aichinger
authors.forename: Doris
authors.initials: D
authors.lastname: Marko
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D019073:HT29 Cells; D006801:Humans; D007529:Isoflavones / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013025:Glycine max / Q000737:chemistry*; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology
chemical_list: C498104:8-hydroxydaidzein; D007529:Isoflavones; D059005:Topoisomerase II Inhibitors; C004742:daidzein; D011505:Protein-Tyrosine Kinases; D004250:DNA Topoisomerases, Type II; C476812:6-hydroxydaidzein
keywords: DNA damage; Daidzein; Isoflavone; Oxidative metabolism; Topoisomerase