Chemopreventive Actions of Equol Enantiomers

雌马酚对映体的化学预防作用

• 批准号: 7021647
• 负责人: KENNETH DAVID SETCHELL
• 金额: $ 41.72万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7021647
• 关键词: antineoplastics; breast neoplasms; cancer prevention; cell differentiation; cell proliferation; chemical carcinogen; chemoprevention; dimethylbenzanthracene; disease /disorder model; flavones; gas chromatography mass spectrometry; genistein; laboratory rat; mammary gland; nutrition aspect of cancer; reproductive development; soybeans; stereoisomer

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.

描述（由申请方提供）：大豆饲料和成分异黄酮、染料木素和最近的大豆苷元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黄酮或大豆苷元成为主要的循环异黄烷，占血清中总异黄酮的>85%。由于缺乏足够的商业数量的牛尿酚用于喂养实验，牛尿酚的化学预防性质从未被检查过。雌马酚是独特的，与大豆苷元或染料木黄酮的不同之处在于在分子中具有手性中心，因此以非对映异构体S-雌马酚和R-雌马酚的形式存在。我们最近已经表明，肠道细菌合成专门的S-雌马酚在人类和大鼠。人类产生S-雌马酚的能力与改善对大豆饮食的临床反应显着相关，包括降低乳腺癌风险。更重要的是，S-雌马酚对雌激素受体ER β具有相对高的亲和力，但对ER α没有亲和力，而相反，R-雌马酚以低亲和力结合两种受体。因此，具有两个在雌激素活性方面显著不同的“相同”分子使得该资助提案通过允许比较该分子在化学预防中的雌激素性质的相关性而变得独特。通过我们的能力，大量的对映体纯S-和R-雌马酚的不对称化学合成，我们建议调查，第一次，化学预防性能的雌马酚的对映体。基于显示雌马酚在刺激乳腺生长和分化（其是与化学预防强烈相关的重要发育作用）方面的效力比染料木黄酮高>5倍的初步数据，因此预期S-雌马酚将在乳腺癌的DMBA动物模型中具有化学预防性。此外，这些研究将有助于表明，大豆蛋白在该大鼠模型中的明确化学预防作用是该物种产生的高浓度雌马酚的结果。我们建议检查暴露于膳食雌马酚的时间的影响，并通过类比染料木素的效果，相信早期暴露于雌马酚将放大化学预防作用。最后，我们将研究S-雌马酚对生殖毒性的影响，因为这对于确定雌马酚是否被开发为潜在的化学预防剂很重要。这些研究与人类有关，因为FDA目前正在审查大豆和癌症风险降低的修正健康声明。