Evaluation of the clastogenic, DNA intercalative, and topoisomerase II-interactive properties of bioflavonoids in Chinese hamster V79 cells.
Bioflavonoids are naturally occurring polyphenols with intriguing and varied therapeutic and chemoprotective activities generally ascribed to their antioxidant properties. However, many flavonoids have also been shown to be genotoxic in a variety of prokaryotic, eukaryotic, and in vivo systems. The mechanistic basis for this genotoxicity has not been fully elucidated, although structure-activity relationship studies have identified requisite flavonoid structural features. We utilized Chinese hamster V79 cells to evaluate the relationships between DNA intercalation ability, topoisomerase II interactions, reactive oxygen species (ROS) generation, and clastogenicity in a series of 14 bioflavonoids. Five of the flavonoids examined, luteolin, quercetin, genistein, apigenin, and acacetin, were strongly clastogenic. This clastogenicity was shown to require DNA intercalation (with the exception of genistein) and was substantially reduced by catalytic inhibitors of DNA topoisomerase II. The transition metals Cu(II) and Mn(II) formed chelates with and/or modified the structure and biological activity of some flavonoids but no consistent relationship could be demonstrated between metal reactivity and clastogenicity. There was no clear association between generation of ROS and clastogenicity. The data presented herein are consistent with a model in which the genotoxicity of most flavonoids arises via DNA intercalation and topo II poisoning, likely mediated through metabolism to flavonoid quinones. Interestingly, other flavonoids such as myricetin, daidzein, baicalein, fisetin, and galangin were catalytic topo II inhibitors, rather than poisons. These studies further validate the use of cell-based approaches for detecting drug/topo II interactions and raise interesting questions relating to biological and chemical mechanisms of flavonoids.
Snyder
Ronald D
RD
Bristol-Myers Squibb Pharma Company, Newark, DE, USA. ronald.snyder@spcorp.com
Gillies
Peter J
PJ
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D004247:DNA / Q000378:metabolism*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004996:Ethidium / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology*; D007364:Intercalating Agents / Q000494:pharmacology / Q000633:toxicity*; D015162:Micronucleus Tests; D008956:Models, Chemical; D009153:Mutagens / Q000633:toxicity*; D017382:Reactive Oxygen Species; D013053:Spectrophotometry; D013997:Time Factors; D014466:Ultraviolet Rays
D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007364:Intercalating Agents; D009153:Mutagens; D017382:Reactive Oxygen Species; D001761:Bleomycin; D005047:Etoposide; D004317:Doxorubicin; D004247:DNA; D004250:DNA Topoisomerases, Type II; D004996:Ethidium