NEW PATHWAYS OF CORTICOSTEROID METABOLISM

皮质类固醇代谢的新途径

• 批准号: 3229869
• 负责人: CARL MONDER
• 金额: $ 27.57万
• 依托单位: POPULATION COUNCIL
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-10-01 至 1990-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3229869
• 关键词: adrenal hyperplasia; carboxylate; chromatography; corticosteroid analog; corticosteroids; cortisol; electrofocusing; gas chromatography mass spectrometry; genetic mapping; glucocorticoids; human subject; hydroxylation; isomerase; liver; major histocompatibility complex; orphan disease /drug; oxidation reduction reaction; radioimmunoassay; stereochemistry; steroid hormone metabolism; urinalysis

Our goals are to elaborate the details of and evaluate the significance of new pathways of corticosteroid metabolism. We have shown in all species studied, including man, that the ketol side chain is reversibly converted by an isomerase to an aldol configuration that can undergo further changes. Interconversion of the 20Alpha and 20Beta epimeric forms of the aldol is catalyzed by an epimerase. Either epimer is oxidized to the hydroxy acid side chain (cortic acids in man) by aldehyde dehydrogenases or reduced to glycols (cortols and cortolones in man) by aldo reductase. The properties of the enzymes that catalyze these changes, isolated from the livers of hamsters and mice, are being studied in detail in order to develop a basis for understanding how the various pathways of corticosteroid metabolism are controlled and coordinated. In parallel studies in humans, metabolic pathways corresponding to those in animals are inferred from the urinary metabolites derived from intravenously injected precursors. The metabolic and clinicophathological significance in man of the expanded pathways of corticosteroid metabolism are under study. In humans, we will use methods that we have developed in order to study how a variety of physiological conditions affect the urinary excretion of the cortoic acids. We will especiallly study infant and juvenile urine in order to establish what other steroid acid metabolites are excreted, and to isolate and identify them. The physiological fractions of the acid end-products of cortisol metabolism and the aldol intermediates will be evaluated by standard anti-inflammatory assays and by induction of specific enzymes such as tyrosines aminotransferase and glycogen synthetase which are known to respond to glucocorticoids. We will continue our studies of side chain isomerase genetics in the mouse in order to specifically map the gene and to establish its multiplicity. Our intentions are to use these studies as models for possible genetic defects of corticosteroid metabolism in humans.

我们的目标是详细说明和评估以下内容的重要性 皮质类固醇代谢的新途径。我们已经在所有物种中展示了 包括MAN在内的研究表明，酮醇侧链是可逆转化的 通过羟醛构型的异构酶，可以进一步 改变。20Alpha和20Beta表观形式的相互转换 羟醛是由一种异构体酶催化的。其中一种同分异构体被氧化成 羟基酸侧链(人体中的皮质酸)由乙醛脱氢酶或 被醛还原酶还原为二醇(人体中的皮质醇和皮质酮)。这个 催化这些变化的酶的性质，从 仓鼠和小鼠的肝脏，正在进行详细的研究，以便 为理解不同的途径如何 皮质类固醇代谢受到控制和协调。并行的 在人类的研究中，与动物的代谢途径相对应的是 从静脉注射产生的尿代谢物推断 先驱物。男性老年性痴呆的代谢和临床病理意义 皮质类固醇代谢的扩展途径正在研究中。在……里面 人类，我们将使用我们开发的方法来研究 各种生理条件影响尿液排泄量 可坏血酸。我们将特别研究婴儿和青少年的尿液 以确定其他类固醇酸代谢物的排泄情况，并 隔离并识别它们。酸的生理部分 皮质醇代谢的终端产品和羟醛中间体将是 通过标准抗炎试验和通过诱导特定的 酪氨酸转氨酶和糖原合成酶等酶 已知对糖皮质激素有反应。我们将继续研究 小鼠的侧链异构酶遗传学以便特异地定位 并建立它的多样性。我们的意图是利用这些 作为皮质类固醇代谢可能遗传缺陷模型的研究 在人类身上。