Chemopreventive Actions of Equol Enantiomers

描述(申请人提供)：在化学诱发乳腺癌的啮齿动物模型中，大豆饮食及其组成成分异黄酮染料木素和最近的大豆苷元的抗癌作用得到了很好的证实。然而，当啮齿动物喂食大豆时，肠道细菌衍生的代谢物Equol，而不是染料木素或大豆苷元，成为主要的循环异黄酮类，占血清中总异黄酮类的85%。很大程度上是由于缺乏足够的商业数量的马醇喂养实验，马醇的化学预防特性从未被检查过。马儿是独一无二的，与大豆苷元或染料木素不同，它在分子中有一个手性中心，因此以非对映异构体、S-马儿和R-马儿的形式出现。我们最近已经证明，肠道细菌在人和大鼠身上只能合成S-马酚。人类产生S-马酚的能力与改善对大豆饮食的临床反应显著相关，包括降低乳腺癌风险。更重要的是，S-马酚对雌激素受体ER(3)有较高的亲和力，而不是Era，而R-马酚与两种受体的亲和力都较低。因此，拥有两个在雌激素活性上明显不同的“相同”分子，通过允许比较分子的雌激素特性在化学预防中的相关性，使这项赠款提案变得独特。通过我们通过不对称化学合成大量生产S-和R-马酚对映体的能力，我们建议第一次研究马醇对映体的化学预防性质。根据初步数据显示，马兜铃醇在刺激乳腺生长和分化方面的效力是金雀异黄素的5倍，这是与化学预防密切相关的重要发育效应，因此有望在DMBA乳腺癌动物模型中起到化学预防作用。此外，这些研究将有助于证明，大豆蛋白在这种大鼠模型中良好的化学预防作用是这种物种产生的高浓度木醇的结果。我们建议研究饮食中马胆醇暴露的时机的影响，通过类比染料木素的作用，我们认为更早地接触马兜铃醇将放大化学预防作用。最后，我们将检验S-马酚对生殖毒性的影响，因为如果马马酚要被开发为潜在的化学预防药物，这一点的确定是很重要的。考虑到目前FDA正在审查的关于大豆和降低癌症风险的修正健康声明，这些研究与人类相关。

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.