MECHANISM AND CONTROL OF ESTROGEN BIOSYNTHESIS

雌激素生物合成的机制和控制

• 批准号: 3315384
• 负责人: JACK FISHMAN
• 金额: $ 15.2万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-02-01 至 1990-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3315384
• 关键词: N hydroxylation; brain metabolism; cyclization; estrogens; hormone biosynthesis; hormone regulation /control mechanism; liver disorder; radiotracer; scintillation spectrometry; stereochemistry; tritium

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.

了解雌激素生物合成的机制和酶或 参与其中的酶对于理解这种重要的 生物转化及其在疾病中的合理控制， 必须限制形成。 我们将研究的芳构化 雄激素从几个方向。 三个氧化步骤的性质 参与这一进程将探讨使用新的具体 标记的底物，其允许检查最初的两个 C-19位的羟基化和末端羟基化， 芳构化 实验证据支持2 β碳作为 最终羟基化，但其他观察结果对此表示怀疑 位置. 提出了实验来解决困难，并定义 雌激素生物合成中末端酶促步骤的性质。 的 雌激素生物合成的性质。 雌激素生物合成的性质将 在胎盘以外的组织（包括卵巢）中进行研究， 睾丸、大脑和其他非性腺部位。 证据已经 得到的过程是不同的卵巢和大脑和新的 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药物在其 控制 新的亲和介质和特异性放射性标记的不可逆配体 将用于纯化和分离胎盘芳香酶复合物， 其催化成分。 免疫细胞化学和放射自显影方法 将用于研究酶在不同位点的定位 或芳构化。 这些研究中获得的信息将用于 已经合成的新的高亲和力抑制剂的修饰 雌激素生物合成产生新类别的那些药剂， 预期在体内表现出高的减少雌激素 在乳腺癌和前列腺增生等疾病中， 控制生殖过程。