权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MECHANISM AND CONTROL OF ESTROGEN BIOSYNTHESIS

雌激素生物合成的机制和控制

基本信息

批准号：
3315389
负责人：
JACK FISHMAN
金额：
$ 14.42万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-02-01 至 1991-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3315389
关键词：
N hydroxylation aromatase brain metabolism cyclization estrogens hormone biosynthesis hormone regulation /control mechanism laboratory rabbit laboratory rat liver disorder radiotracer scintillation spectrometry stereochemistry tritium

项目摘要

Knowledge of the mechanism of estrogen biosynthesis and of the enzyme or enzymes involved in it is critical to an understanding of this essential biotransformation and to its rational control in diseases where estrogen formation needs to be limited. We will study the aromatization of androgens from several directions. The nature of the three oxidative steps participating in the process will be explored using novel specifically labeled substrates which allow examination both of the initial two hydroxylations at C-19 and the terminal hydroxylation leading to aromatization. Experimental evidence supports the 2Beta carbon as the site of the final hydroxylation, but other observations cast doubt on that location. Experiments are proposed to resolve the difficulty and to define the nature of the terminal enzymatic step in estrogen biosynthesis. The nature of estrogen biosynthesis. The nature of estrogen biosynthesis will be studied in tissues other than the placenta including the ovaries, testes, brain and other non-gonadal sites. Evidence has already been obtained that the process is different in the ovaries and brain and new tools will be used to probe the mechanism of aromatization in these tissues and to study the role of pituitary hormones and other agents in its control. New affinity media and specific radiolabeled irreversible ligands will be used to purify and separate the placental aromatase complex into its catalytic components. Immunocytochemical and autoradiographic methods will be used to study the localization of the enzymes in the various sites or aromatization. Information obtained in these studies will be used in the modification of the already synthesized new high affinity inhibitors of estrogen biosynthesis to generate new categories of those agents which will be expected to exhibit high in vivo potency in diminishing estrogenic levels in diseases such as breast cancer and prostatic hyperplasia and in controlling reproductive processes.

了解雌激素的生物合成机制和酶或参与这一过程的酶对于理解这一关键因素至关重要雌激素在疾病中的生物转化及其合理控制编队需要受到限制。我们将研究甲苯的芳构化来自多个方向的雄激素。三个氧化步骤的性质参与这一进程将特别使用NORICE进行探索带标签的底物，允许检查最初的两个 C-19上的羟基化和末端羟基化导致芳构化。实验证据支持2Beta碳作为站点最终的羟化作用，但其他观察结果对此表示怀疑地点。为了解决这一难题，我们提出了实验方案。雌激素生物合成中末端酶步骤的性质。这个雌激素生物合成的本质。雌激素生物合成的本质将在胎盘以外的组织中进行研究，包括卵巢，睾丸、脑和其他非性腺部位。证据已经被证明得出在卵巢和脑中的过程是不同的和新的将使用工具来探索这些组织中芳构化的机制并研究垂体激素和其他因素在其发病中的作用控制力。新型亲和介质和特定的放射性标记不可逆配体将用于纯化和分离胎盘芳香酶复合体它的催化成分。免疫细胞化学和放射自显影方法将用于研究酶在不同部位的定位或者芳构化。从这些研究中获得的信息将用于已合成的新型高亲和力抑制剂的修饰雌激素生物合成产生新类别的这些制剂，这将有望在体内显示出降低雌激素的高效力乳腺癌和前列腺增生症等疾病的水平控制生殖过程。

项目成果

期刊论文数量（6）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The nature of the final oxidative step in the aromatization sequence.

芳构化序列中最终氧化步骤的性质。

DOI：
10.1016/0039-128x(87)90023-7
发表时间：
1987
期刊：
Steroids
影响因子：
2.7
作者：
Fishman,J;Hahn,EF
通讯作者：
Hahn,EF

Estrogen formation in human prostatic tissue from patients with and without benign prostatic hyperplasia.

患有或不患有良性前列腺增生的患者前列腺组织中雌激素的形成。

DOI：
10.1002/pros.2990090402
发表时间：
1986
期刊：
The Prostate
影响因子：
0
作者：
Stone,NN;Fair,WR;Fishman,J
通讯作者：
Fishman,J

19-Hydroxylation of androgens by rat granulosa cells.

19-大鼠颗粒细胞对雄激素的羟基化。

DOI：
10.1210/endo-122-3-1047
发表时间：
1988
期刊：
Endocrinology
影响因子：
4.8
作者：
Norton,BI;Miyairi,S;Fishman,J
通讯作者：
Fishman,J

Stereochemistry of 1,2-hydrogen loss during aromatization in the brain.

大脑芳构化过程中 1,2-氢损失的立体化学。

DOI：
10.1016/0022-4731(85)90211-0
发表时间：
1985
期刊：
Journal of steroid biochemistry
影响因子：
0
作者：
Hahn,EF;Fishman,J
通讯作者：
Fishman,J

19-Hydroxylation of androgens in the rat brain.

大鼠大脑中雄激素的 19-羟基化。

DOI：
10.1073/pnas.82.9.2728
发表时间：
1985
期刊：
Proceedings of the National Academy of Sciences of the United States of America
影响因子：
11.1
作者：
Hahn,EF;Miyairi,S;Fishman,J
通讯作者：
Fishman,J