Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Clinical Trial
. 2010 Oct 1;70(19):7392-9.
doi: 10.1158/0008-5472.CAN-10-2027. Epub 2010 Sep 14.

Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients

Ketan R Patel  1 , Victoria A Brown, Donald J L Jones, Robert G Britton, David Hemingway, Andrew S Miller, Kevin P West, Tristan D Booth, Marjorie Perloff, James A Crowell, Dean E Brenner, William P Steward, Andreas J Gescher, Karen Brown
Affiliations
Clinical Trial

Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients

Ketan R Patel et al. Cancer Res. .

Abstract

Resveratrol is a phytochemical with chemopreventive activity in preclinical rodent models of colorectal carcinogenesis. Antiproliferation is one of the many chemopreventive modes of action it has been shown to engage in. Concentrations of resveratrol, which can be achieved in human tissues after p.o. administration, have not yet been defined. The purpose of this study was to measure concentrations of resveratrol and its metabolites in the colorectal tissue of humans who ingested resveratrol. Twenty patients with histologically confirmed colorectal cancer consumed eight daily doses of resveratrol at 0.5 or 1.0 g before surgical resection. Resveratrol was found to be well tolerated. Normal and malignant biopsy tissue samples were obtained before dosing. Parent compound plus its metabolites resveratrol-3-O-glucuronide, resveratrol-4'-O-glucuronide, resveratrol-3-O-sulfate, resveratrol-4'-O-sulfate, resveratrol sulfate glucuronide, and resveratrol disulfate were identified by high-performance liquid chromatography (HPLC) with UV or mass spectrometric detection in colorectal resection tissue. Quantitation was achieved by HPLC/UV. Cell proliferation, as reflected by Ki-67 staining, was compared in preintervention and postintervention tissue samples. Resveratrol and resveratrol-3-O-glucuronide were recovered from tissues at maximal mean concentrations of 674 and 86.0 nmol/g, respectively. Levels of resveratrol and its metabolites were consistently higher in tissues originating in the right side of the colon compared with the left. Consumption of resveratrol reduced tumor cell proliferation by 5% (P = 0.05). The results suggest that daily p.o. doses of resveratrol at 0.5 or 1.0 g produce levels in the human gastrointestinal tract of an order of magnitude sufficient to elicit anticarcinogenic effects. Resveratrol merits further clinical evaluation as a potential colorectal cancer chemopreventive agent.

PubMed Disclaimer

Conflict of interest statement

Disclosure of Potential Conflicts of Interest

T Booth, employment, Pharmascience, Montreal Canada. The other authors declared no potential conflict of interest.

Figures

Figure 1
Figure 1
Figure 1 A. HPLC/UV chromatograms of extracts of normal colon tissue resected from a patient who had received resveratrol 1.0g daily for 8 days (solid line) and a patient who had refrained from resveratrol ingestion during the 7 days prior to resection (broken line). Identity of resveratrol-derived species as established by co-chromatography with authentic reference material and LC/MS/MS analysis is indicated above the peaks. Insert shows structures of resveratrol and its metabolites: R1, R2=H: resveratrol “7”, R1=sulfate R2=H: resveratrol-3-O-sulfate “6”, R1=H, R2=sulfate: resveratrol-4′-O-sulfate “5”, R1=glucuronide, R2=H: resveratrol-3-O-glucuronide “4”, R1=H, R2=glucuronide: resveratrol-4′-O-glucuronide “2”. Positions of the sulfonic and glucuronic acid moieties in resveratrol disulfate “3” and resveratrol sulfate glucuronide “1” are probably 3 and 4′, but this needs confirmation by 1H-NMR. Naringenin “8” was the internal standard. For details of tissue procurement, extraction and chemical analysis see Materials and Methods. Figure 1 B. LC/MS selected reaction monitoring (SRM) of transitions for the identification of resveratrol metabolites in extracts of colon tissue taken from a patient who had received 0.5g of resveratrol for 8 days. Metabolites identified were resveratrol sulfate glucuronide (m/z 483>227), resveratrol disulfate (m/z 387>227) resveratrol-3-O-glucuronide and resveratrol-4′-O-glucuronide (m/z 403>227), resveratrol-3-O-sulfate and resveratrol-4′-O-sulfate (307>227). Resveratrol was also identified (m/z 227>184). The total ion current from the analysis of a mixture of authentic standards is also shown for comparison. The mixture contained resveratrol-4′-O-glucuronide (1), resveratrol-3-O-glucuronide (2), dehydrated resveratrol glucuronide (exhibits the transition 385>227 and is not present in the patient samples) (3), resveratrol-4′-O-sulfate (4), resveratrol-3-O-sulfate (5) and resveratrol (6).
Figure 2
Figure 2
Concentrations of resveratrol and resveratrol-3-O-sulfate in normal colon and tumor tissue of a patient with a cecal (right-sided) and a sigmoid colonic tumor (left-sided), who had received resveratrol at a dose of 1.0g daily for 8 days. Normal tissue samples were taken at a distance of 5cm proximal or distal from tumor, and from the distal resection margin (RM). Differences in levels between the left and right side, similar to those shown here, were observed for resveratrol disulfate and the two resveratrol monoglucuronides, but not for resveratrol sulfate glucuronide.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nature Rev Drug Discov. 2006;5:493–506. - PubMed
    1. Tessitore L, Davit A, Sarotto I, Caderni G. Resveratrol depresses the growth of colorectal aberrant crypt foci by affecting bax and p21(CIP) expression. Carcinogenesis. 2000;21:1619–22. - PubMed
    1. Sengottuvelan M, Viswanathan P, Nalini N. Chemopreventive effect of trans-resveratrol - a phytoalexin against colonic aberrant crypt foci and cell proliferation in 1,2-dimethylhydrazine induced colon carcinogenesis. Carcinogenesis. 2006;27:1038–46. - PubMed
    1. Sengottuvelan M, Nalini N. Dietary supplementation of resveratrol suppresses colonic tumour incidence in 1,2-dimethylhydrazine-treated rats by modulating biotransforming enzymes and aberrant crypt foci development. Brit J Nutr. 2006;96:145–53. - PubMed
    1. Schneider Y, Duranton B, Gosse F, Schleiffer R, Seiler N, Raul F. Resveratrol inhibits intestinal tumorigenesis and modulates host-defense-related gene expression in an animal model of human familial adenomatous polyposis. Nutr Cancer. 2001;39:102–7. - PubMed

Publication types

MeSH terms