Hormonal and genotoxic activity of resveratrol

doi:10.1016/S0378-4274(02)00290-4

Toxicology Letters

Volume 136, Issue 2, 15 December 2002, Pages 133-142

https://doi.org/10.1016/S0378-4274(02)00290-4 Get rights and content

Abstract

Resveratrol (RES) is a natural polyphenol present in red wines and various human food items. The estrogenic activity of RES was demonstrated in two in vitro assay systems, i.e. binding to human estrogen receptor α and stimulation of MCF-7 cell proliferation. To investigate the inhibition of cell proliferation observed at high concentrations of RES, we analyzed the compound for genotoxic potential. RES induced cellular toxicity, micronuclei, and metaphase chromosome displacement in L5178Y mouse lymphoma cells. Likewise, the induction of micronuclei was observed in Chinese hamster V79 cells. Determination of kinetochore signals in micronuclei and cell cycle analysis suggested that RES did not cause a direct disturbance of mitosis. In support of this notion, cell-free tubulin polymerization studies indicated no direct effect of RES on microtubule assembly. According to an estimation of daily intake and bioavailability, concentrations that were found genotoxic in vitro might be reached in human exposure. On the other side, the estrogenic acitivity might be beneficial. Therefore, further investigations of mechanisms, possibly including animal models, would be desirable to clarifiy a potential risk for humans.

Introduction

Resveratrol (RES, Fig. 1) is a natural polyphenol present in red wines and various human foods. It is synthesized by a variety of plant species in response to injury, UV irradiation and fungal attack. Since it is only synthesized in the skin of the grape berries, red wine contains more RES than white wine. It has been suggested that RES may be the main active principle involved in the ‘French Paradox’, the inverse correlation between red wine consumption and the incidence of cardiovascular disease (Wu et al., 2001).

RES has been shown to exhibit estrogenic activity (Gehm et al., 1997, Ashby et al., 1999, Bowers et al., 2000). The observation that RES is an effective radical-scavenger suggested that it acts as a natural antioxidant against oxidative DNA-damage (Cadenas and Barja, 1999, Lin and Tsai, 1999). In addition to these anti-initiating properties, RES exhibits anti-inflammatory effects. For example, it suppresses cyclooxgenase activity and the induction of the transcription factor NF kappa B by other agents (Bhat and Pezzuto, 2002). RES shows antimutagenic and anticarcinogenic activities. Benzo[a]pyrene-induced cancerogenesis could be reduced by RES by inhibition of CYP1A1 (El Attar and Virji, 1999, Ciolino and Yeh, 1999, Chun et al., 1999). RES also inhibited the 7, 12-dimethylbenz[a]anthracene (DMBA)-induced cancerogenesis in a mouse-model (Jang et al., 1997). In another model RES reduced the intestinal tumorigenesis in genetically predisposed mice (Schneider et al., 2001). Furthermore, RES is a known inducer of apoptosis. Interestingly, the pro-apoptotic effect may be limited to tumor cells, while normal cells remain unharmed (Lu et al., 2001). Therefore, great interest in RES as a cancer chemopreventive or even cancer therapeutic agent has evolved (Gusman et al., 2001, Savouret and Quesne, 2002). Opposite to this view, we demonstrate here that RES exhibits a genotoxic potential in vitro.

Section snippets

Test substances

RES (3,4′,5-Trihydroxy-trans-stilbene), 17β-estradiol (E2), and diethylstilbestrol (DES) of the highest available purity (⩾98%) were obtained from Sigma Chemie GmbH (Deisenhofen, Germany).

Cell culture

MCF-7, MDA-MB-231 and V79 cells were purchased from American Type Culture Collection (ATTC, Hanassas, USA). MCF-7 and MDA-MB-231 cells were cultured in phenol red-free RPMI 1640 medium supplemented with antibiotics, l-glutamine (0.25 mg/ml), sodium pyruvate (107 mg/ml), human insulin (0.2 ng/ml), and 5% fetal

Results and discussion

By using two different in vitro assays, our studies demonstrate that the phytochemical RES (Fig. 1) is estrogenic. In agreement with data published in the literature (Gehm et al., 1997, Ashby et al., 1999, Bowers et al., 2000) RES competed with [³H]-E2 for binding to the human estrogen receptor α under cell-free conditions (Fig. 2) and induced proliferation of the estrogen receptor-positive cell line MCF-7 in a dose-dependent manner at concentrations ranging from 10 nM to 10 μM (Fig. 3); at

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Hormonal and genotoxic activity of resveratrol

Abstract

Introduction

Section snippets

Test substances

Cell culture

Results and discussion

J. Chromat. B Biomed. Sci. Appl.

Free Radical Biol. Med.

Biochem. Biophys. Res. Commun.

Mutat. Res.

Nutr. Res.

Chem. -Biol. Interact.

Biomed. Pharmacother.