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Genotoxicity of dietary, environmental and therapeutic topoisomerase II poisons is uniformly correlated to prolongation of enzyme DNA residence.
MedLine Citation:
PMID:  21520487     Owner:  NLM     Status:  Publisher    
Scope: 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). Methods and 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.
Faiza M Kalfalah; Christian Mielke; Morten O Christensen; Simone Baechler; Doris Marko; Fritz Boege
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-3-24
Journal Detail:
Title:  Molecular nutrition & food research     Volume:  -     ISSN:  1613-4133     ISO Abbreviation:  -     Publication Date:  2011 Mar 
Date Detail:
Created Date:  2011-4-26     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101231818     Medline TA:  Mol Nutr Food Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Institute of Clinical Chemistry and Laboratory Diagnostics, Heinrich-Heine-University, Medical Faculty, Düsseldorf, Germany.
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