Abstract
Background and aims:
Resveratrol, the most investigated dietary compound in studies aimed at linking wine consumption to human health, is an extremely minor component of this beverage and it is generally studied in vitro as the unconjugated aglycone at concentrations largely exceeding those found in the human circulatory system after dietary intake. Moreover, following intestinal absorption, trans-resveratrol and its glucoside, which are naturally present in wine and other food sources, are converted to sulphate and glucuronide metabolites. An estrogenic activity has previously been documented for resveratrol, yet nothing is known about the activity of its blood-circulating metabolic derivatives.
Methods and results:
Using a yeast two-hybrid detection system relying on the interaction between the ligand-binding domain of the human oestrogen receptors α and β and the human coactivator Tif2, we have systematically examined the oestrogen agonist and antagonist activities of the two main resveratrol forms present in planta (trans-resveratrol and trans-resveratrol-3-O-glucoside) and of the three main metabolites found in human plasma (trans-resveratrol-3-O-sulphate, trans-resveratrol-3-O-glucuronide and trans-resveratrol-4'-O-glucuronide). Only resveratrol-3-O-sulphate was found to display a fairly strong and oestrogen receptor α-preferential antagonistic activity, which was confirmed in a human breast adenocarcinoma cell line containing a luciferase reporter gene under the control of an oestrogen-responsive promoter.
Conclusions:
We show, for the first time, that resveratrol-3-O-sulphate, but neither of its metabolites, is endowed with anti-estrogenic activity and how human metabolism of phenolic substances plays a pivotal role in modulating their biological effect.
Keywords:
Phytoestrogen; Red wine; Resveratrol; Resveratrol metabolism.
Copyright © 2013 Elsevier B.V. All rights reserved.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma / drug therapy
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Adenocarcinoma / metabolism
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Antineoplastic Agents, Phytogenic / chemistry
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Antineoplastic Agents, Phytogenic / metabolism
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Antineoplastic Agents, Phytogenic / pharmacology*
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Binding Sites
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Cell Line, Tumor
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Clone Cells
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Estrogen Antagonists / chemistry
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Estrogen Antagonists / metabolism
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Estrogen Antagonists / pharmacology*
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Estrogen Receptor alpha / agonists
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Estrogen Receptor alpha / antagonists & inhibitors*
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Estrogen Receptor alpha / genetics
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Estrogen Receptor alpha / metabolism
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Estrogen Receptor beta / agonists
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Estrogen Receptor beta / antagonists & inhibitors*
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Estrogen Receptor beta / genetics
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Estrogen Receptor beta / metabolism
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Female
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Glucosides / chemistry
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Glucosides / metabolism
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Glucosides / pharmacology
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Glucuronides / chemistry
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Glucuronides / metabolism
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Glucuronides / pharmacology
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Humans
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MCF-7 Cells
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Neoplasm Proteins / agonists
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Neoplasm Proteins / antagonists & inhibitors*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Nuclear Receptor Coactivator 2 / agonists
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Nuclear Receptor Coactivator 2 / antagonists & inhibitors
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Nuclear Receptor Coactivator 2 / genetics
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Nuclear Receptor Coactivator 2 / metabolism
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Peptide Fragments / agonists
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Peptide Fragments / antagonists & inhibitors
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Peptide Fragments / genetics
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Peptide Fragments / metabolism
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Phytoestrogens / chemistry
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Phytoestrogens / metabolism
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Phytoestrogens / pharmacology
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Recombinant Proteins / chemistry
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Recombinant Proteins / metabolism
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Resveratrol
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Stereoisomerism
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Stilbenes / chemistry
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Stilbenes / metabolism
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Stilbenes / pharmacology*
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Sulfates / chemistry
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Sulfates / metabolism
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Sulfates / pharmacology
Substances
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Antineoplastic Agents, Phytogenic
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ESR1 protein, human
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Estrogen Antagonists
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Estrogen Receptor alpha
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Estrogen Receptor beta
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Glucosides
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Glucuronides
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NCOA2 protein, human
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Neoplasm Proteins
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Nuclear Receptor Coactivator 2
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Peptide Fragments
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Phytoestrogens
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Recombinant Proteins
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Stilbenes
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Sulfates
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Resveratrol