Selective Induction of Estrogen Conjugative Metabolism

选择性诱导雌激素结合代谢

• 批准号: 7024997
• 负责人: BAO-TING ZHU
• 金额: --
• 依托单位: UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-03-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7024997
• 关键词: benzoates; breast neoplasms; cancer prevention; chemical conjugate; enzyme activity; enzyme induction /repression; enzyme mechanism; estradiol; estrogens; high performance liquid chromatography; hormone metabolism; hormone related neoplasm /cancer; hydroxylation; immunocytochemistry; laboratory rat; northern blottings; oxidation; sulfation; tissue /cell culture

DESCRIPTION (provided by applicant): This proposal is aimed at testing a novel hypothesis that chemicals that can preferentially stimulate the metabolic conversion of estradiol (E2) and its hydroxylated metabolites (such as 4-OH-E2 and 16alpha-OH-E1) to inactive, water-soluble conjugates would be better and safer inhibitors of E2-induced cancer than inducers of estrogen oxidative metabolism. On the basis of our recent data on the preferential stimulatory effect of dietary dibenzoylmethane (DAM) on E2 conjugative metabolism in human mammary cells and in animals, we propose the following four Specific Aims for our initial testing of this novel hypothesis. Aim 1: To study dietary DBM and its analogs for their activity in inducing the enzymes for estrogen conjugation (glucuronidation, sulfation, and O-methylation) vs oxidation in non-neoplastic AG11134 human mammary epithelial cells by using biochemical assays and Northern blot analysis. Aim 2: To study strong dietary inducers identified under Aim 1 for their activity in inducing estrogen conjugation in liver, breast, and uterus of female ACI rats. Aim 3: To compare the effects of strong inducers of estrogen conjugation with indole-3-carbinol (a prototypical dietary inducer of estrogen oxidation) on the metabolic fate of E2 and 4-OH-E2 (a representative bioactive hydroxyestrogen metabolite) in blood and target organs of female ACI rats. Aim 4: To compare the effects of an identified inducer of estrogen conjugative metabolism with indole-3-carbinol on the mitogenic actions of E2 and 4-OH-E2 in the breast and uterus of female rats, and to compare their efficacies in the prevention of estrogen-induced mammary tumors in female ACI rats. We predict that an inducer of estrogen conjugative metabolism will have a much higher cancer-preventive efficacy than an inducer of estrogen oxidative metabolism under conditions where estrogen's hormonal activity is equally inhibited. These hypothesis-driven, mechanism-based studies will lead to the development of an effective, novel strategy for dietary or phytochemical-based prevention of estrogen-induced human cancers. These studies will also provide examinations of the important roles of bioactive estrogen metabolites (e.g., 4-OH-E2 and 16alpha-OH-E2) in estrogen-induced cancers.

描述（由申请人提供）：该提案旨在测试一种新的假设，即可以优先刺激雌二醇（E2）及其羟基代谢物的代谢转化的化学物质（例如4-OH-E2和16Alpha-OH-E1）比无效的，水的conjugate和Sajugation concointy和Sajugation相比，e eTRINIS的eTROINGER eTRINIS的eTCORTIONS比氧化代谢。根据我们最近关于饮食中二苯甲酰甲烷（DAM）对人类乳腺细胞和动物中E2结合代谢的优先刺激作用的数据，我们提出了以下四个特定目的，用于初步测试这一新假设。目的1：研究饮食DBM及其类似物，用于诱导雌激素结合酶的活性（葡萄糖醛酸化，硫酸化和O-甲基化）与非偏神经AG11134人类乳腺上皮细胞中的非肿瘤AG11134中的氧化相对于氧化。目标2：研究在AIM 1下鉴定出的强大饮食诱导剂，以使其在雌性ACI大鼠的肝脏，乳房和子宫中诱导雌激素结合的活性。目标3：要比较雌激素结合的强诱导剂与吲哚-3-甲醇（雌激素氧化的典型饮食诱导剂）对血液和靶标的Organs的E2和4-OH-E2代谢命运（一种代表性的生物活性羟基代谢物）的影响。目标4：比较鉴定出雌激素结合代谢的诱导剂与吲哚-3-甲醇对E2和4-OH-E2在雌性大鼠的乳房和子宫中的有丝分裂作用的影响，并比较其在预防雌激素诱导的雌性乳腺肿瘤中的效果。我们预测，在雌激素的激素活性同样抑制的情况下，雌激素结合代谢的诱导剂将比雌激素氧化代谢的诱导剂具有更高的癌症疗效。这些基于假设驱动的基于机制的研究将导致发展有效的，新的基于饮食或植物化学的预防雌激素诱导的人类癌症的策略。这些研究还将提供对生物活性雌激素代谢产物（例如4-OH-E2和16alpha-OH-e2）在雌激素诱导的癌症中的重要作用的检查。