posted on 2011-11-24, 10:18authored byKetan R. Patel
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.