Chemopreventive Actions of Equol Enantiomers

描述（由申请人提供）：大豆饮食及其成分异黄酮，染料木素和最近的大豆黄酮的抗癌作用在化学诱导乳腺癌的啮齿动物模型中得到了很好的证实。然而，当啮齿类动物喂食大豆时，肠道细菌衍生的代谢物雌马酚，而不是染料木素或大豆黄酮，成为主要的循环异黄酮，占血清中总异黄酮的85%。很大程度上由于缺乏足够商业数量的马酚用于饲养实验，马酚的化学预防特性从未被研究过。雌马酚与大豆苷元或染料木素的独特之处在于在分子中有一个手性中心，因此以非对映异构体s -雌马酚和r -雌马酚的形式存在。我们最近的研究表明，人类和大鼠的肠道细菌只合成s -雌马酚。人类产生s -雌马酚的能力与改善大豆饮食的临床反应显著相关，包括降低乳腺癌的风险。更重要的是，s -雌马酚对雌激素受体ER(3)的亲和力相对较高，而对雌激素受体ERa没有亲和力，而R-雌马酚对这两种受体的亲和力都较低。因此，有两个“相同”的分子在雌激素性上有明显的不同，这使得这项拨款申请是独一无二的，因为它允许比较分子在化学预防中的雌激素特性的相关性。通过不对称化学合成，我们能够生产大量的纯S-和r -马雌酚对映体，我们首次提出研究马雌酚对映体的化学预防特性。根据初步数据显示，雌马酚在刺激乳腺生长和分化方面的效力是染料木黄酮的5倍，这是与化学预防密切相关的重要发育效应，因此预计s -雌马酚将在乳腺癌DMBA动物模型中具有化学预防作用。此外，这些研究将有助于表明，大豆蛋白在该大鼠模型中的化学预防作用是该物种产生高浓度马雌酚的结果。我们建议研究暴露于膳食雌马酚的时间效应，并通过类比染料木黄酮的效应，认为早期暴露于雌马酚将放大化学预防效应。最后，我们将检查s -雌马酚对生殖毒性的影响，因为如果要将雌马酚开发为潜在的化学预防剂，这一点很重要。鉴于修订后的大豆健康声明和降低癌症风险目前正在接受FDA的审查，这些研究与人类有关。

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.