NEW PATHWAYS OF CORTICOSTEROID METABOLISM

皮质类固醇代谢的新途径

• 批准号: 3229870
• 负责人: CARL MONDER
• 金额: $ 29.08万
• 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/3229870
• 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.

我们的目标是阐述细节并评估其重要性 new pathways of corticosteroid metabolism. We have shown in all species 包括人类在内的研究表明，酮醇侧链是可逆转换的 通过异构酶形成羟醛构型，可以进一步进行 变化。 20Alpha 和 20Beta 差向异构体形式的相互转化 aldol is catalyzed by an epimerase. 任一差向异构体被氧化成 羟基酸侧链（人的皮质酸）通过醛脱氢酶或 醛还原酶将其还原为乙二醇（人类可托醇和可托酮）。 这 催化这些变化的酶的特性，从 正在对仓鼠和小鼠的肝脏进行详细研究，以便 为理解各种途径如何 皮质类固醇代谢得到控制和协调。 并联 在人类研究中，与动物的代谢途径相对应的是 从静脉注射产生的尿液代谢物推断 前体。 男性的代谢和临床病理学意义 皮质类固醇代谢的扩展途径正在研究中。 在 人类，我们将使用我们开发的方法来研究 各种生理状况都会影响尿中的排泄 皮质酸。 我们将特别研究婴儿和青少年的尿液 为了确定哪些其他类固醇酸代谢物被排泄，并 隔离并识别他们。 The physiological fractions of the acid 皮质醇代谢的最终产物和羟醛中间体将 通过标准抗炎测定和特异性诱导进行评估 酪氨酸转氨酶、糖原合成酶等酶 are known to respond to glucocorticoids. We will continue our studies of 小鼠侧链异构酶遗传学，以便特异性绘制 gene and to establish its multiplicity. Our intentions are to use these 作为皮质类固醇代谢可能遗传缺陷模型的研究 在人类中。