MAMMALIAN METABOLISM OF 4-HYDROXYBUTYRIC ACID

4-羟基丁酸，一种众所周知的抑制性物质的类似物 神经递质GABA是一种已知的化合物，它既可以显示 神经药理学和神经生理学特性。一家最近扩张的 大量证据表明，4-羟基丁酸很像L-谷氨酸 和GABA，在哺乳动物的大脑中作为神经递质发挥作用。此外， 已知4-羟基丁酸在慢性阻塞性肺疾病患者的大脑中积聚 亨廷顿舞蹈症，帕金森氏病，大量排泄 最近描述的一种先天错误患者的尿量 代谢方面，4-羟基丁酸尿症。在后一种病态中 状态，由于缺乏GABA降解酶琥珀酸 半醛脱氢酶，已知的六名患者都表现出严重的 神经恶化的临床表现，可能是由于 4-羟基丁酸的积累。尽管已知的是 神经药理活性，几乎没有证据表明 4-羟基丁酸的代谢机制。初步研究 提示外周器官中的β-氧化和氧化为 大脑中柠檬酸循环中间产物的水平。有建议说 对新陈代谢进行系统的研究 大鼠肝脏和脑中的4-羟基丁酸。放射性标记和 氢化材料将用于定量和代谢物。 反相高效液相色谱和气相色谱-质谱法鉴定。在体表征性 4-羟基丁酸代谢将通过全身监测来提供 完整大鼠体内的代谢。4-羟基丁酸的可能作用 因为哺乳动物大脑中的神经递质需要对此进行系统的研究 分子的降解途径。仅这一事实就应该证明 建议进行基础研究调查。然而，临床意义可能 也要参与其中。仍然有可能的是，彻底了解 降解途径将为刺激提供一种机制。证据在 这个方向可能对重症患者有治疗价值。 亨廷顿舞蹈症、帕金森氏病和 4-羟基丁酸尿症。

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.