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Chemopreventive Actions of Equol Enantiomers

雌马酚对映体的化学预防作用

基本信息

批准号：
7287768
负责人：
KENNETH DAVID SETCHELL
金额：
$ 30.77万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2009-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7287768
关键词：
Accounting Address Adenocarcinoma Adult Affinity Age Animal Cancer Model Animal Feed Animal Model Animal Testing Animals Anthracenes Antineoplastic Agents Appendix Applications Grants Area Bacteria Binding Biological Availability Birth Body Weight Breast Cancer Cell Breast Cancer Prevention Breeding Bromodeoxyuridine Cancer cell line Carcinogens Cell Line Chemoprevention Chemopreventive Agent Clinical Control Groups Data Data Analyses Development Diet Differentiation and Growth Dose Duct (organ) structure Ductal Ensure Estradiol Estrogen Receptors Estrogens Evaluation Exhibits Exposure to Female Frequencies Furans Genistein Growth Hand Health Human In Vitro Incidence Intestines Isoflavones Jordan Knowledge Late Effects Life Light Lobule MCF7 cell Malignant Neoplasms Mammary Neoplasms Mammary gland Measures Metabolism Modeling Monitor Neonatal Numbers Object Attachment Ovary Personal Satisfaction Pharmaceutical Preparations Pharmacodynamics Phenoxodiol Positioning Attribute Predisposition Principal Investigator Process Property Prostate Puberty Rate Rattus Reporting Research Research Design Research Personnel Risk Risk Reduction Rodent Rodent Model Role Sample Size Serum Soy Proteins Sprague-Dawley Rats Staining method Stains Structure Tamoxifen Testing Testis Time Tissues Toxic effect Transplantation Tumor Burden United States Food and Drug Administration United States National Institutes of Health Urine Uterus Vagina Weaning Week Work absorption anthracene base cancer risk chemical synthesis daidzein daidzin day dimethylbenzanthracene enantiomer equol estrogenic activity experience feeding fetal furan genistin improved in vivo interest male malignant breast neoplasm mouse model neonatal exposure neoplastic programs pup receptor reproductive research study response soy soy protein isolate success tumor tumorigenesis

项目摘要

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-牛尿酚以较低的亲和力与两种受体结合。因此，拥有两个雌激素活性显着不同的“相同”分子，通过允许比较该分子的雌激素特性在化学预防中的相关性，使该拨款提案独一无二。通过不对称化学合成对映体纯S-和R-牛尿酚，我们建议首次研究牛尿酚对映体的化学预防特性。初步数据显示，雌马酚在刺激乳腺生长和分化方面的效力比金雀异黄素高 5 倍以上，这是与化学预防密切相关的重要发育作用，因此预计 S-牛尿酚将在乳腺癌 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。