Chemopreventive Actions of Equol Enantiomers

雌马酚对映体的化学预防作用

• 批准号: 7126735
• 负责人: KENNETH DAVID SETCHELL
• 金额: $ 32.37万
• 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/7126735
• 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（由申请人提供）：大豆饮食及其成分异黄酮、染料木黄酮和最近的大豆黄酮的抗癌作用已在化学诱导乳腺癌的啮齿动物模型中得到充分证实。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黄酮，成为主要的循环异黄烷，占血清中总异黄酮的 85% 以上。很大程度上由于缺乏足够的商业数量的雌马酚用于喂养实验，雌马酚的化学预防特性从未得到检验。雌马酚是独特的，与大豆苷元或金雀异黄酮不同，其分子中具有手性中心，因此以非对映异构体、S-牛尿酚和R-牛尿酚存在。我们最近发现，人类和大鼠的肠道细菌只合成 S-牛尿酚。人类产生 S-牛尿酚的能力与改善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-牛尿酚对雌激素受体 ER(3 但不是 ERa) 具有相对较高的亲和力，而相比之下，R-牛尿酚对两种受体的结合亲和力较低。因此，具有两个雌激素活性显着不同的“相同”分子使得通过允许比较分子雌激素特性在化学预防中的相关性，我们能够通过生产大量的对映体纯 S- 和 R-牛尿酚，获得独特的资助提案。通过不对称化学合成，我们首次研究了雌马酚对映体的化学预防特性，初步数据表明，雌马酚在刺激乳腺生长和分化方面的效力比染料木黄酮强 5 倍以上，这非常重要。发育效应与化学预防密切相关，因此预计 S-牛尿酚将在乳腺癌的 DMBA 动物模型中具有化学预防作用。将表明，大豆蛋白在该大鼠模型中已确立的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，并通过与金雀异黄素的效果类比，相信较早暴露于雌马酚将增强化学预防效果。最后，我们将研究 S-牛尿酚对生殖毒性的影响，因为如果将牛尿酚开发为潜在的化学预防剂，这对于定义这一点很重要。鉴于 FDA 目前正在审查大豆和降低癌症风险的健康声明的修订版，这些研究与人类相关。