Abstract
Brain GABA transaminase is inactivated by preincubation with antidepressant/antipanic drug phenelzine (β-ethylphenylhydrazine) (mixing molar ratio 10∶1) at pH 7.4. The reaction of enzyme with phenelzine was monitored by absorption and fluorescence spectroscopic methods. The inactive enzyme was fully reconstituted by addition of cofactor pyridoxal-5-phosphate. This result implies that the blocking of 1 mol of pyridoxal-5-phosphate per enzyme dimer is needed for inactivation of the enzyme. The time course of the reaction is significantly affected by the substrate α-ketoglutarate, which afforded complete protection against the loss of catalytic activity. The kinetic studies shows that phenelzine reacts with the cofactor of enzyme with a second-order rate constant of 2.1×103 M−1s−1. It is postulated that the antidepressant/antipanic drug phenelzine is able to elevate the neurotransmitter GABA levels in central nervous system by inhibitory action on GABA degradative enzyme GABA transaminase.
Similar content being viewed by others
References Cited
Berrettini, W. H., Goldin, L. R., Nurnberger, J. I. Jr., and Gershon, E. S., Genetic factors in affective illness.J. Psychiatr. Res., 18, 329–350 (1984).
Berrettini, W. H., Umberkoman-Wiita, B., Nurnberger, J. I., Jr., Vogel, W. H., Gershon, E. S. and Post, R. M., Platelet GABA transaminase in affective illness.Psychiatry Res., 7, 255–260 (1980).
Bowers, M. B., Jr., Gold, B. I. and Roth, R. H., CSF GABA in psychotic disorders.Psychopharmacology (Berlin), 70, 279–282 (1980).
Bradford, M. M., A rapid and sensitive method for the quantitation of microgram quantities of protein using the principle of protein-dye binding.Anal. Biochem. 72, 248–254 (1976).
Breslow, M. R., Faukhauser, M. P. Potter, R. L., Meredith, K. E., Misiaszek, J. and Hope, D. G., Role of γ-aminobutyric acid in antipanic drug efficacy.Am. J. Psychiatry, 146, 353–356 (1989).
Choi, S. Y., Kim, I., Jang, S. H., Lee, S. J., Song, M. S., Lee, Y. S. and Cho, S. W., Purification and properties of GABA transaminase from bovine brain.Mol. Cells, 3, 397–401 (1993).
Davis, B. J., Disc gel eletrophoresis II. Method and application to human serum proteins.Ann. NY Acad. Sci., 121, 404–427 (1964).
Fletcher, A. and Fowler, L. J., 4-Arninobutyric acid metabolism in rat brain following chronic oral administration of ethanolamine-O-sulfate.Biochem. Pharmacol., 29, 1451–1454 (1980).
Frederick, P., Kramer, G. L., Dunnam, D. and Rush, J., Plasma GABA in mood disorders.Psychopharmacol. Bull., 26, 157–161 (1990).
Gerner, R. H., Fairbanks, L., Anderson, G. M., Young, J. G., Scheinin, M., Linnoila, M., Hare, T. A., Shaywitz, B. A. and Cohen, D. J., CSF neurochemistry in depressed, manic and schizophrenic patients compared with that of normal controls.Am. J. Psychiatry, 141, 1533–1540 (1984).
Gerner, R. H., and Hare, T. A., CSF GABA in normal subjects and patients with depression, schizophrenia, mania, and anorexia nervosa.Am. J. Psychiatry, 138, 1098–1101 (1981).
Gold, B. I., Bowers, M. B., Jr., Roth, R. H. and Sweeney, D. W., GABA levels in CSF of patients with psychiatric disorders.Am. J. Psychiatry, 137, 362–364 (1980).
Kaiya, H., Namba, M., Yoshida, H., and Nakamura, S., Plasma glutamate decarboxylase activity in neuropsychiatry.Psychiatry Res., 6, 335–343 (1982).
Kasa, K., Otsuki, S., Yamamoto, M., Sato, M., Kuroda, H., and Ogawa, N., Cerebrospinal fluid γ-aminobutyric acid and homovanillic acid in depressive disorders.Biol. Psychiatry, 17, 877–883 (1982).
Korf, J. and Venema, K., Desmethylimipramine enhances the release of endogenous GABA and other neurotransmitter amino acids from the rat thalamus.J. Neurochem., 40, 946–950 (1983).
Laemmli, U. K., Cleavage of structural proteins during the assembly of the head of bacteriophage T4.Nature, 227, 680–685 (1970).
Lee, B. R., Hong, J. W., Yoo, B. K., Lee, S. J., Cho, S. W. and Choi, S. Y., Bovine brain succinic semialdehyde dehydrogenase; Purification, kinetics and reactivity of lysyl residues connected with catalytic activity.Mol. Cells, 5, 611–617 (1995).
Lippert, B., Metcalf, B. W., Jung, M. J. and Casara, P., 4-Aminohex-5-enoic acid; a selective catalytic inhibitor of 4-aminobutyrate aminotransferase in mammalian brain.Eur. J. Biochem., 74, 441–445 (1977).
Lloyd, K. G. and Pilc, A., Chronic antidepressants and GABA synapses.Neuropharmacology, 23(7B), 841–842 (1984).
Lloyd, K. G., Thuret, F. and Pilc, A., Up-regulation of gamma-aminobutyric acid (GABA)8 binding sites in rat frontal cortex: a common action of repeated adminitration of different calsses of antidepressants and electroshock,J. Pharmacol. Exp. Ther., 235, 191–199 (1985).
Lloyd, K. G., Zivkovic, B., Scatton, B., Morselli, P. L. and Bartholini, G., The GABAergic hypothesis of depression.Prog. Neuropsychopharmacol. Biol. Psychiatry, 13, 341–351 (1989).
Patel, G. J., Schatz, R. P. and Constantinides, S. M. Effect of desipramine and pargyline on brain gamma-aminobutyric acid.Biochem. Pharmacol., 24, 57–61 (1975).
Perry, J. L. and Hansen, S., Sustained drug-enduced elevation of brain GABA in the rat.J. Neurochem., 21, 1167–1175 (1973).
Popov, N. and Matthies, H., Some effects of monoamine oxidase inhibitors of the metabolism of γ-aminobutyric acid in rat brain.J. Neurochem., 16, 899–907 (1969).
Post, R. M., Ballenger, J. C., Hare, T. A., Goodwin, F. K., Lake, C. R., Jimerson, D. C. and Bunney, W. E., Jr., Cerebrospinal fluid GABA in normals and patients with affective disorders.Brain Res. Bull., 5, 755–759 (1980).
Riblet, L. A., Taylor, D. P. and Eison, M. S., Pharmacology and neurochemistry of buspirone.J. Clin. Psychiatry, 43(12, section 2), 11–16 (1982).
Sheehan, D. V., Delineation of anxiety and phobic disorders responsive to monoamine oxidase inhibitors: implications for classification.J. Clin. Psychiatry, 45 (7, section 2), 29–36 (1984).
Sheehan, D. V., Tricyclic antidepressant in the treatment of panic and anxiety disorders.Psychosomatics, 27 (Nov suppl): 10–16 (1986).
Sheehan, D. V., Ballenger, J. and Jacobsen, G., Treatment of endogenous anxiety with phobic, hysterical, and hypochondrical sympotoms.Arch. Gen. Psychiatry, 37, 51–59 (1980).
Sheehan, D. V., Ddavidson, J. and Manschreck, T., Lack of efficacy of a new antidepressant (bupropion) in the treatment of panic disorder with phobias.Clin. Psychopharmacol., 3, 28–31 (1983).
Zimmer, R., Teelken, A. W., Meier, K. D., Acken-Heil, M. and Zander, K. J., Preliminary studies on CSF gamma-aminobutyric acid levels in psychiatric patients before and during treatment with different psychotropic drugs.Prog. Neuropsychopharmacol. Biol. Psychiatry, 4, 613–620 (1981).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Yoo, B.K., Hong, J.W., Suk, J.W. et al. Inhibitory actions of the antidepressant/antipanic drug phenelzine on brain GABA transaminase. Arch. Pharm. Res. 19, 480–485 (1996). https://doi.org/10.1007/BF02986015
Received:
Issue Date:
DOI: https://doi.org/10.1007/BF02986015