Selective Induction of Estrogen Conjugative Metabolism

选择性诱导雌激素结合代谢

• 批准号: 6853607
• 负责人: BAO-TING ZHU
• 金额: $ 20.73万
• 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 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6853607
• 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）：本提案旨在测试一个新的假设，即化学物质可以优先刺激雌二醇（E2）及其羟基化代谢物（如4-OH-E2和16α-OH-E1）代谢转化为与雌激素氧化代谢的诱导剂相比，无活性的水溶性结合物是 E2 诱导的癌症更好、更安全的抑制剂。根据我们最近关于膳食二苯甲酰甲烷 (DAM) 对人类乳腺细胞和动物 E2 结合代谢的优先刺激作用的数据，我们提出以下四个具体目标来初步测试这一新假设。目标 1：通过生化测定和 Northern blot 分析，研究膳食 DBM 及其类似物在非肿瘤性 AG11134 人乳腺上皮细胞中诱导雌激素结合酶（葡萄糖醛酸化、硫酸化和 O-甲基化）与氧化的活性。目标 2：研究目标 1 下确定的强膳食诱导剂在诱导雌性 ACI 大鼠的肝脏、乳房和子宫中雌激素结合的活性。目标 3：比较强雌激素诱导剂与吲哚-3-甲醇（一种典型的雌激素氧化膳食诱导剂）结合对血液中 E2 和 4-OH-E2（一种代表性生物活性羟基雌激素代谢物）代谢命运的影响。雌性 ACI 大鼠的靶器官。目的 4：比较已确定的雌激素结合代谢诱导剂与吲哚-3-甲醇对雌性大鼠乳房和子宫中 E2 和 4-OH-E2 促有丝分裂作用的影响，并比较其预防效果雌性 ACI 大鼠中雌激素诱发的乳腺肿瘤的研究。我们预测，在雌激素激素活性受到同等抑制的条件下，雌激素结合代谢诱导剂比雌激素氧化代谢诱导剂具有更高的防癌功效。这些假设驱动、基于机制的研究将导致开发一种有效的、新颖的策略，用于通过饮食或植物化学物质预防雌激素诱发的人类癌症。这些研究还将检验生物活性雌激素代谢物（例如 4-OH-E2 和 16α-OH-E2）在雌激素诱发的癌症中的重要作用。