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Comparison of dose-dependent outcomes in induction of cytogenotoxic responses by novel glucosyl flavonoids




Engen, Anya, author
Kato, Takamitsu, advisor
Hanneman, William, advisor
Legare, Marie, committee member
Bouma, Gerrit, committee member

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The flavonoids quercetin, and its glucosides isoquercetin and rutin, are phytochemicals commonly consumed in plant-derived foods. They are associated with potential health-promoting effects such as anti-inflammation, anti-viral, anti-carcinogenesis, neuro- and cardio-protection, etc. Semi-synthetic water soluble quercetin glucosides, maltooligosyl isoquercetin (MI), monoglucosyl rutin (MO) and maltooligosyl rutin (MA) were developed to overcome solubility challenges for improved incorporation in food and medicinal applications. Quercetin and its glucosides are known to induce genetic instability and decrease cell proliferation, which are possible mechanisms of anti-carcinogenesis in in vitro and animal studies. Using an in vitro system of Chinese hamster ovary (CHO) cells, this thesis project examined the differences in cytogenotoxic responses induced by natural and novel flavonoids. Treatments with flavonoids at a concentration range of 0.1 and 1,000 ppm induced sister chromatid exchanges (SCE) and micronuclei (MN) in CHO cells. Compared to spontaneous occurrences, significant increases in SCE and MN were observed in both natural and synthetic flavonoid-treated cells in a dose-dependent manner. The natural flavonoids exhibited greater potency than the synthetic compounds, where quercetin was most potent. An analysis of the effects of flavonoids on DNA repair via the poly(ADP ribose) polymerase (PARP) pathway using ELISA showed that all three natural flavonoids along with MI and MO were capable of inhibiting PARP activity by 50%. Quercetin was observed to be the strongest natural inhibitor of PARP. In growth studies using the same treatment dosages as the SCE-MN experiments, colony formation data corroborate those of the growth inhibition studies, in which all flavonoids exerted varying inhibitory effects on cell proliferation. These cytogenetic studies demonstrated that quercetin, isoquercetin and rutin generally exerted more potency than the synthetic compounds, requiring lower doses to achieve efficacy. The ability of both the natural and the synthetic flavonoids to cause genomic instability and impair cell growth may have human health implications for chemoprevention.


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