MAMMALIAN METABOLISM OF 4-HYDROXYBUTYRIC ACID

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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.