MECHANISM AND CONTROL OF ESTROGEN BIOSYNTHESIS

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。

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.