title: Genotoxicity of dietary, environmental and therapeutic topoisomerase II poisons is uniformly correlated to prolongation of enzyme DNA residence.
abstract: METHODS
  DNA damage by genistein and etoposide is determined by the half-life of topoisomerase II-DNA linkage induced [Bandele O. J. and Osheroff N., Biochemistry 2008, 47, 11900]. Here, we test whether this applies generally to dietary flavonoids and therapeutic compounds enhancing topoisomerase II-DNA cleavage (Topo II poisons).
  
  
  RESULTS
  We compared the impact of Topo II poisons on DNA residence kinetics of biofluorescent human topoisomerases IIα and IIβ (delineating duration of the DNA-linked enzyme state) with histone 2AX phosphorylation (delineating DNA damage response). Prolongation of topoisomerase II-DNA residence was correlated to DNA damage response, whereas topoisomerase II-DNA linkage was not. Catalytic inhibitors stabilizing topoisomerase II on unbroken DNA also exhibited such a correlation, albeit at a lower level of DNA damage response. Therapeutic Topo II poisons had stronger and more durable effects on enzyme II DNA residence and elicited stronger DNA damage responses than natural or dietary ones.
  
  
  CONCLUSIONS
  Topoisomerase II-mediated DNA damage appears related to the prolongation of enzyme DNA residence more than to enzyme-DNA cleavage. Due to this reason, genistein and other tested natural and dietary Topo II poisons have a much lower genotoxic potential than therapeutic ones under the conditions of equal topoisomerase II-DNA linkage.
authors.affiliation: Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich-Heine-University, Medical Faculty, Moorenstrasse 5, Düsseldorf, Germany.
authors.forename: Faiza M
authors.initials: FM
authors.lastname: Kalfalah
authors.forename: Christian
authors.initials: C
authors.lastname: Mielke
authors.forename: Morten O
authors.initials: MO
authors.lastname: Christensen
authors.forename: Simone
authors.initials: S
authors.lastname: Baechler
authors.forename: Doris
authors.initials: D
authors.lastname: Marko
authors.forename: Fritz
authors.initials: F
authors.lastname: Boege
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D053837:DNA Cleavage; D004249:DNA Damage; D004250:DNA Topoisomerases, Type II / Q000187:drug effects / Q000378:metabolism*; D005047:Etoposide / Q000009:adverse effects; D005419:Flavonoids / Q000009:adverse effects; D019833:Genistein / Q000009:adverse effects; D006207:Half-Life; D006657:Histones / Q000378:metabolism; D006801:Humans; D016014:Linear Models; D010636:Phenols / Q000009:adverse effects; D059808:Polyphenols; D059005:Topoisomerase II Inhibitors / Q000378:metabolism
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D005419:Flavonoids; D006657:Histones; D010636:Phenols; D059808:Polyphenols; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004247:DNA; D019833:Genistein; D004250:DNA Topoisomerases, Type II