MAMMALIAN METABOLISM OF 4-HYDROXYBUTYRIC ACID

4-羟基丁酸的哺乳动物代谢

• 批准号: 3450073
• 负责人: K Michael GIBSON
• 金额: $ 5.36万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1989-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3450073
• 关键词: Krebs' cycle; brain metabolism; chromatography; electrophoresis; enzyme complex; fatty acid metabolism; gamma hydroxybutyrate; gas chromatography mass spectrometry; high performance liquid chromatography; inborn metabolism disorder; ion exchange chromatography; liver metabolism; molecular pathology; neurochemistry; oxidation; radioassay

4-Hydroxybutyric acid, an analog of the well known inhibitory neurotransmitter GABA, is a compound known to display both neuropharmacologic and neurophysiologic properties. A recently expanding body of evidence suggests that 4-hydroxybutyric acid, much like L-glutamate and GABA, functions in mammalian brain as a neurotransmitter. Furthermore, 4-hydroxybutyric acid is known to accumulate in the brain of patients with Huntington's chorea, Parkinson's disease and is excreted in large quantities in the urine of patients with a recently described inborn error of metabolism, 4-hydroxybutyric aciduria. In this latter pathological state, due to a deficiency of the GABA degradative enzyme succinic semialdehyde dehydrogenase, the six known patients have displayed a severe clinical picture of neurological deterioration, presumably due to the accumulation of 4-hydroxybutyric acid. Although known to exert neuropharmacologic activity, there is very little evidence concerning the mechanism by which 4-hydroxybutyric acid is metabolized. Initial studies suggest a mechanism of Beta-oxidation in peripheral organs and oxidation to the level of citric acid cycle intermediates in the brain. It is proposed to carry out a systematic investigation of the metabolism of 4-hydroxybutyric acid in the liver and brain of the rat. Radiolabeled and deuterated materials will be employed with quantification and metabolite identification by reverse phase HPLC and GCMS. In vivo characterization of 4-hydroxybutyric acid metabolism will be afforded by monitoring whole body metabolism in the intact rat. The probable role of 4-hydroxybutyric acid as neurotransmitter in mammalian brain warrants a systematic study of this molecule's degradative pathway. This fact alone should justify the proposed basic research investigation. However, clinical implications may also be involved. It remains possible that a thorough knowledge of the degradative pathway will afford a mechanism for stimulation. Evidence in this direction could be of therapeutic value to patients with severe pathologies such as Huntington's chorea, Parkinson's disease and 4-hydroxybutyric aciduria.

4-羟基丁酸，一种众所周知的抑制剂的类似物， 神经递质GABA是一种已知的化合物， 神经药理学和神经生理学特性。 一个最近不断扩大的 大量证据表明，4-羟基丁酸，很像L-谷氨酸 和GABA，在哺乳动物大脑中作为神经递质发挥作用。 此外，委员会认为， 4-已知羟丁酸在患有以下疾病的患者的大脑中积累： 亨廷顿舞蹈病、帕金森氏病和大排特 最近描述的先天性缺陷患者尿液中的含量 4-羟丁酸尿症 在后一种病理学中， 状态，由于缺乏GABA降解酶琥珀酸 半醛脱氢酶，六个已知的患者表现出严重的 神经功能恶化的临床表现，可能是由于 4-羟基丁酸的积累。 虽然众所周知， 神经药理学活性，很少有证据表明， 4-羟基丁酸的代谢机制。 初步研究 提示外周器官中β-氧化和氧化至 大脑中柠檬酸循环中间产物的水平。 拟 进行系统的代谢研究， 4-羟丁酸在大鼠的肝脏和大脑中。 放射性标记和 氘代材料将用于定量和代谢物 通过反相HPLC和GCMS鉴定。 的体内表征 4-羟丁酸代谢将通过监测全身来提供 在完整大鼠中的代谢。 4-羟丁酸的可能作用 作为哺乳动物大脑中的神经递质， 分子的降解途径。 仅这一事实就足以证明 提出基础研究调查。 然而，临床意义可能 也参与其中。 但仍然有可能， 降解途径将提供刺激机制。 证据 这一方向可能对严重的 例如亨廷顿舞蹈病、帕金森病和 4-羟丁酸尿症