CORTICOSTEROID METABOLISM IN JUVENILE HYPERTENSION

我们正在研究一种最近发现的青少年高血压。在……里面 在这种情况下，受影响的儿童无法将皮质醇氧化到 可的松。我们计划提供进一步的证据证明患有这种疾病的儿童 这种情况被称为表观矿质皮质激素过剩(AME)， 以低肾上腺素血症和低醛固酮血症为特征， 皮质类固醇11β-脱氢酶缺乏症是潜在的缺陷。我们 我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 将可的松还原为皮质醇。这些互补性的存在 条件使我们提出了11β-羟基类固醇脱氢酶 (11-HSD)，催化11-氧代和可逆的相互转化 皮质类固醇的11-羟基是由不同的 相互依赖的11β-脱氢酶和11-还原酶组分。 文献中有关11-HSD性质的信息是一致的 具有多酶结构。我们将从鸡或鸭中提纯酶 肝脏，含有11-还原酶，没有检测到11-脱氢酶，以及 来自猴子胎盘，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 成年大鼠肝脏中氧化酶和还原酶的分离 组件。脱氢酶将通过高纯度的组合进行纯化 高效层析技术与亲和沉淀 双官能团配体。对容易失活的人的稳定 用甘油或其他试剂进行11-还原酶的初步尝试 它的净化。11-脱氢酶和11-还原酶的分离 通过层析和电泳法实现。11-还原酶 将通过类似于11-脱氢酶的程序进行纯化 净化。酶的动力学和物理化学性质 将进行详细研究，以确定 环境对其行为的影响，并确定其多样性。这些 调查将有助于(A)了解氧化和 C-11处皮质类固醇的减少在代谢过程中受到控制； (B)深入了解人类疾病中11-HSD干扰的根源。

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.