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Grant Abstract

Grant Number: 5R01AT003313-02
PI Name: SETCHELL, KENNETH DAVID.
Project Title: Chemopreventive Actions of Equol Enantiomers

Abstract: DESCRIPTION (provided by applicant): The anticancer actions of soy diets and the constituent isoflavones, genistein and more recently daidzein, are well established in rodent models of chemically induced breast cancer. However, when rodents are fed soy it is the intestinal bacterially derived metabolite equol, and not genistein or daidzein, that becomes the major circulating isoflavan accounting for >85% of the total isoflavones in serum. Largely due to a lack of sufficient commercial quantities of equol for feeding experiments, the chemopreventive properties of equol have never been examined. Equol is unique and differs from daidzein or genistein in possessing a chiral center in the molecule and therefore occurs as diastereoisomers, S-equol and R-equol. We have recently shown that intestinal bacteria synthesize exclusively S-equol in humans and rats. The ability of humans to produce S-equol is significantly associated with improved clinical responses to soy diets, including reduced risk of breast cancer. More importantly, S-equol has a relatively high affinity for estrogen receptor ER(3 but not ERa, while by contrast, R- equol binds with low affinity to both receptors. Thus, having two 'identical' molecules differing markedly in estrogenicity makes this grant proposal unique by permitting a comparison of the relevance of the estrogenic properties of the molecule in chemoprevention. Through our ability to produce bulk amounts of enantiomeric pure S- and R-equol by an asymetric chemical synthesis, we propose to investigate, for the first time, the chemopreventive properties of equol's enantiomers. Based on preliminary data showing that equol is >5-fold greater in potency than genistein in stimulating mammary gland growth and differentiation, which are important developmental effect strongly associated with chemoprevention, it is therefore expected that S-equol will be chemopreventive in the DMBA animal model of mammary cancer. Furthermore, these studies will serve to show that the well established chemopreventive actions of soy protein in this rat model are the result of high concentrations of equol produced by this species. We propose to examine the effect of timing of exposure to dietary equol, and by analogy to genistein's effect believe that earlier exposure to equol will amplify the chemopreventive effect. Finally, we will examine S-equol's effects on reproductive toxicity since this is important to define, if equol is to be developed as a potential chemopreventive agent. These studies are relevant to humans given the ammended health claim for soy and cancer risk-reduction currently being reviewed by the FDA.

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