title: Topoisomerase poisoning by genistein in the intestine of rats.
abstract: The isoflavone genistein has been shown to act as topoisomerase II poison in various cell lines. Here, we address the question whether genistein is able to affect topoisomerase II in vivo. Juvenile male Wistar rats received either a single dose of genistein subcutaneously (s.c.; 10 mg/kg BW) or a lifelong isoflavone-rich diet encompassing in utero, lactation phase and 10 days of oral consumption, whereas genistein was mainly taken up as glycosides (25-50 mg/kg BW). The effects on the level of covalent topoisomerase II-DNA-complexes in the duodenum and colon were measured using the "Isolation of in vivo complexes of enzyme to DNA" (ICE)-bioassay. Simultaneously, serum as well as tissue concentrations of genistein and its metabolites were quantified by LC-MS. Genistein (s.c.) significantly increased the amount of covalent topoisomerase IIα and β-DNA complexes in the gut, showing more persistent effects in the colon than in the duodenum. In case of a lifelong dietary isoflavone exposure, no effects on the stabilization of cleavage complexes was observed, except a slight increase of topoisomerase IIα-DNA-complexes in the colon. The differences between the exposure routes might be attributed to the higher serum concentration of the genistein aglycon after subcutaneous treatment probably due to circumvention of first-pass metabolism compared to oral consumption of an isoflavone-rich diet. These data indicate that subcutaneously administrated genistein clearly possesses topoisomerase poisoning properties in vivo, whereas an isoflavone-rich diet containing genistein only caused a slight effect which relevance has to be clarified in further studies.
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Waehringerstr. 38, A-1090 Vienna, Austria.
authors.forename: Simone A
authors.initials: SA
authors.lastname: Baechler
authors.affiliation: Department of Safety and Quality of Fruit and Vegetables, Max Rubner-Institut, Haid-und-Neu-Straße 9, D-76131 Karlsruhe, Germany.
authors.forename: Sebastian T
authors.initials: ST
authors.lastname: Soukup
authors.affiliation: Institute of Cardiovascular Research and Sports Medicine, Department of Molecular and Cellular Sports Medicine, German Sports University Cologne, Am Sportpark Muengersdorf 6, D-50933 Cologne, Germany.
authors.forename: Almut F
authors.initials: AF
authors.lastname: Molzberger
authors.affiliation: Department of Safety and Quality of Fruit and Vegetables, Max Rubner-Institut, Haid-und-Neu-Straße 9, D-76131 Karlsruhe, Germany.
authors.forename: Sabine E
authors.initials: SE
authors.lastname: Kulling
authors.affiliation: Institute of Cardiovascular Research and Sports Medicine, Department of Molecular and Cellular Sports Medicine, German Sports University Cologne, Am Sportpark Muengersdorf 6, D-50933 Cologne, Germany.
authors.forename: Patrick
authors.initials: P
authors.lastname: Diel
authors.affiliation: Department of Food Chemistry and Toxicology, University of Vienna, Waehringerstr. 38, A-1090 Vienna, Austria. Electronic address: doris.marko@univie.ac.at.
authors.forename: Doris
authors.initials: D
authors.lastname: Marko
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004032:Diet / Q000662:veterinary; D004305:Dose-Response Relationship, Drug; D005260:Female; D019833:Genistein / Q000097:blood / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000951:Antigens, Neoplasm; D004268:DNA-Binding Proteins; D019833:Genistein; D004250:DNA Topoisomerases, Type II
keywords: Cleavage complex; Genistein; Intestine; Isoflavones; Topoisomerase poison