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Title: Potential cancer chemopreventive properties of resveratrol metabolites
Authors: Patel, Ketan R.
Supervisors: Brown, Karen
Award date: 1-Oct-2011
Presented at: University of Leicester
Abstract: Resveratrol (trans-3,5,4′-trihydroxystilbene), a naturally occurring polyphenol present in grapes and red wine has undergone investigation as a potential cancer chemopreventive agent. Resveratrol is rapidly and extensively metabolised to its major phase II metabolites, including resveratrol sulfates and glucuronides. It is not yet known whether resveratrol metabolites contribute to the beneficial effects attributed to resveratrol, or whether resveratrol regeneration can occur from the metabolites. Resveratrol and metabolite pharmacokinetics were investigated in the plasma of healthy human volunteers receiving 0.5, 1.0, 2.5 and 5.0 g resveratrol daily. Concentrations were also quantified in malignant and non-malignant colon tissue removed from colorectal cancer patients, who received 0.5 or 1.0 g resveratrol daily. A mixture of resveratrol monosulfates and individual monoglucuronide isomers were synthesised. Resveratrol monosulfates were administered to mice to determine their pharmacokinetics. The effects of the metabolites on proliferation in HCA-7, HT-29 and HCEC colon cell lines were assessed. In healthy volunteers, resveratrol metabolites were shown to be the major species recovered from plasma. Average volunteer plasma AUClast for resveratrol-4′-O-glucuronide and resveratrol-3-O-sulfate were approximately 36- and 81-fold greater respectively than for resveratrol, following 0.5 g resveratrol dosing. In colon tissues from cancer patients resveratrol generally predominated, with resveratrol sulfate glucuronide being the most prominent metabolite. In mice administered monosulfates, resveratrol formation was found to occur, with measurable concentrations in plasma, mucosa, liver, lung and pancreas. The conversion of resveratrol sulfates to resveratrol was also observed in cells in vitro. Uptake of the metabolites and intracellular resveratrol correlated with effects on proliferation. Whilst resveratrol monoglucuronides had a limited inhibitory effect on cell proliferation, monosulfates caused a more pronounced reduction, with the greatest effect in HT-29 followed by HCA-7 cells, and little or no effect in HCEC cells. Further investigations will improve our understanding of the role of resveratrol metabolites in chemoprevention.
Type: Thesis
Level: Doctoral
Qualification: PhD
Rights: Copyright © the author, 2011.
Appears in Collections:Theses, Dept. of Cancer Studies & Molecular Medicine
Leicester Theses

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