CORTICOSTEROID METABOLISM IN JUVENILE HYPERTENSION

青少年高血压中的皮质类固醇代谢

• 批准号: 3235800
• 负责人: CARL MONDER
• 金额: $ 9.1万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-07-01 至 1989-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3235800
• 关键词: Pongidae; adolescence (12-20); affinity chromatography; corticosteroids; cortisol; cortisone; enzyme complex; enzyme mechanism; high performance liquid chromatography; human subject; human tissue; hydroxysteroid dehydrogenases; hypertension; inborn metabolism disorder; laboratory rat; liver; microsomes; oxidation reduction reaction; placenta; steroid hormone metabolism

We are studying a recently discovered form of juvenile hypertension. In this condition the affected children are unable to oxidize cortisol to cortisone. We plan to provide further evidence that children with this condition, which has been named Apparent Mineralocorticoid Excess (AME), and is characterized by hyporeninemia and hypoaldosteronism, have corticosteroid 11Beta-dehydrogenase deficiency as an underlying defect. We also plan to study the metabolism of corticosteroids in a disease in which the underlying biochemical abnormality appears to be the inability to reduce cortisone to cortisol. The existence of these complementary conditions has led us to propose that 11Beta-hydroxysteroid dehydrogenase (11-HSD) which catalyzes the reversible interconversion of 11-oxo and 11-hydroxy groups of corticosteroids is a complex made up of separate, yet interdependent 11Beta-dehydrogenase and 11-reductase components. Information from the literature on the properties of 11-HSD is consistent with a multi-enzyme structure. We will purify enzyme from chicken or duck liver, which contains 11-reductase with no detectable 11-dehydrogenase, and from monkey placenta, which contains 11-dehydrogenase and no detectable 11-reductase. We will isolate 11-HSD which contains both activities from adult rat liver and attempt to separate the oxidase and reductase components. The dehydrogenases will be purified by a combination of high performance chromatographic techniques and affinity precipitation with bifunctional ligands. Stabilization of the readily inactivated 11-reductase by glycerol or other agents will be attempted preliminary to its purification. Separation of 11-dehydrogenase and 11-reductase will be achieved by chromatographic and electrophoretic methods. The 11-reductase will be purified by procedures similar to those used for 11-dehydrogenase purification. The kinetic and physico-chemical properties of the enzymes will be studied in detail, in order to define the effects of the environment on their behavior and to determine their multiplicity. These investigations will contribute (a) to an understanding of how oxidation and reduction of corticosteroids at C-11 are controlled during metabolism; and (b) to insight into the origin of disturbances in 11-HSD in human disease.

我们正在研究一种最近发现的青少年高血压。 在 这种情况下，受影响的儿童无法氧化皮质醇， 可的松 我们计划提供进一步的证据， 这种情况被称为明显的盐皮质激素过量（AME）， 并以低肾素血症和低醛固酮症为特征， 皮质类固醇11 β-脱氢酶缺乏症作为潜在缺陷。 我们 还计划研究皮质类固醇在一种疾病中的代谢， 潜在的生化异常似乎是无法 把可的松分解成皮质醇 这些互补性的存在 条件使我们提出11 β-羟基类固醇脱氢酶 （11-HSD），其催化11-氧代和 11-皮质类固醇的羟基是一种复合物， 相互依赖的11 β-脱氢酶和11 β-还原酶组分。 文献中关于11-HSD性质的信息一致 具有多酶结构。 我们将从鸡肉或鸭肉中纯化酶 肝脏，含有11-还原酶，但未检测到11-脱氢酶，和 从猴胎盘，其中含有11-脱氢酶，没有检测到 11-还原酶。 我们将分离出含有这两种活性的11-HSD， 成年大鼠肝脏，并尝试分离氧化酶和还原酶 件. 将通过组合高纯度的 高效液相色谱技术和亲和沉淀 双功能配体 稳定易失活的 11-甘油或其他试剂的还原酶将被初步尝试， 它的净化。 11-脱氢酶和11-还原酶的分离将是 通过色谱和电泳方法获得。 11-还原酶 将通过类似于用于11-脱氢酶的程序纯化 洁净. 酶的动力学和理化性质 将详细研究，以确定的影响， 环境对他们的行为，并确定其多样性。 这些 调查将有助于（a）了解氧化和 在代谢过程中控制C-11皮质类固醇的减少;和 (b)深入了解人类疾病中11-HSD紊乱的起源。