Selective Induction of Estrogen Conjugative Metabolism

描述（由申请人提供）：该提案旨在验证一个新的假设，即能够优先刺激雌二醇（E2）及其羟基化代谢物（如4-OH-E2和16 α - oh - e1）代谢转化为非活性水溶性偶联物的化学物质比雌激素氧化代谢诱导剂更好、更安全地抑制E2诱导的癌症。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，我们提出了以下四个具体目标来初步验证这一新假设。目的1：通过生化分析和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）和氧化的活性。目的2：研究目的1中确定的强膳食诱导剂诱导雌性ACI大鼠肝脏、乳房和子宫雌激素结合的活性。目的3：比较雌激素与吲哚-3-甲醇（一种典型的雌激素氧化膳食诱导剂）结合的强诱导剂对雌性ACI大鼠血液和靶器官中E2和4-OH-E2（一种代表性的生物活性羟雌激素代谢物）代谢命运的影响。目的4：比较已鉴定的雌激素结合代谢诱导剂与吲哚-3-甲醇对雌性大鼠乳腺和子宫内E2和4- oh -E2促有丝分裂作用的影响，并比较其对雌性ACI大鼠雌激素诱导乳腺肿瘤的预防作用。我们预测，在雌激素的激素活性同样受到抑制的条件下，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预防功效。这些假设驱动的，基于机制的研究将导致开发一种有效的，基于饮食或植物化学的预防雌激素诱导的人类癌症的新策略。这些研究还将检验生物活性雌激素代谢物（如4-OH-E2和16 α - oh - e2）在雌激素诱导的癌症中的重要作用。

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.