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

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

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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）：大豆饮食的抗癌作用和成分的异黄酮，染料木黄酮和大戴兹因在化学诱导的乳腺癌的啮齿动物模型中已很好地确立。然而，当啮齿动物被喂食大豆时，它是细菌衍生的代谢物雌激素，而不是染料黄酮或大豆，它变成了占血清中总异黄酮的85％的主要循环异黄体。在很大程度上，由于缺乏足够的商业量为饲料实验，从未研究过Equol的化学预防特性。 Equol是独特的，与大泽蛋白或染料黄素的不同，在分子中拥有手性中心，因此作为非映异构体，S- Equol和R-Equol发生。我们最近表明，肠道细菌在人类和大鼠中仅合成S-Equol。人类产生S-Equol的能力与改善对大豆饮食的临床反应显着相关，包括降低乳腺癌的风险。更重要的是，S-Equol对雌激素受体ER具有相对较高的亲和力（3但不是ERA，而相比之下，Requol与两个受体的亲和力低。因此，具有两个“相同的”分子在雌激素中明显不同的分子在雌激素中明显不同，从而使该授予的赠款提案通过允许与雌激素的相关性与雌激素的相关性相关性，而化学量与雌激素的相关性与我们的雌激素相关性。通过不对称化学合成的对映体纯S-和R equol，我们提议首次研究Equol的对映异构体的化学预防特性。在乳腺癌的DMBA动物模型中进行化学预防，这些研究将表明大豆模型中大豆蛋白的化学预防作用是该物种产生的高浓度的结果。我们建议检查暴露于饮食的时间的时间，并类似于染料碱性的作用，认为早期暴露于雌激素会扩大化学预防作用。最后，我们将检查S-Equol对生殖毒性的影响，因为这对于定义equol将作为潜在的化学预防剂开发，这一点很重要。这些研究与人类有关，鉴于FDA目前正在审查大豆的健康索赔和降低癌症风险的索赔。