Abstract
Tryptophan hydroxylase is the initial and rate-limiting enzyme in the biosynthesis of the neurotransmitter serotonin. A variety of drugs are known to diminish the function of this enzyme, and possibly cause damage to serotonin neurons. These include the substituted amphetamines methamphetamine and 3,4-methylenedioxy-methamphetamine, as well as L-DOPA, the most common therapy for Parkinsons Disease. In view of the important role for dopamine in the effects of these drugs on tryptophan hydroxylase and on serotonin neurons, we tested whether dopamine could alter the activity of this important enzyme. We found that dopamine-derived quinones, but not dopamine, inactivate tryptophan hydroxylase and convert the protein to a redox-cycling quinoprotein. This posttranslational modification of tryptophan hydroxylase could play a role in the drug-induced reduction in serotonin synthesis.
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Cohen, G., Farooqui, R., and Kesler, N., 1997, Parkinson disease: A new link between monoamine oxidase and mitochondrial electron flow, Proc. Natl. Acad. Sci. USA 94:4890–4894.
Dahlstrom A. and Fuxe K., 1964, Evidence for the existence of monoamine-containing neurons in the central nervous system, Acta Physiol. Scand. 62(Suppl 232):1–55.
D’Sa, C., Arthur, R.E. Jr., States, J.C., and Kuhn, D.M., 1996a, Tryptophan hydroxylase: Cloning and expression of the rat brain enzyme in mammalian cells, J. Neurochem. 67:900–906.
D’Sa, C., Arthur, R.E. Jr., and Kuhn, D.M., 1996b, Expression and deletion mutagenesis of tryptophan hydroxylase fusion proteins: Delineation of the enzyme catalytic core, J. Neurochem. 67:917–926.
Fahn, S., 1998, Welcome news about levodopa, but uncertainty remains, Ann. Neurol. 43:551–554.
Fleckenstein, A.E., Beyeler, M.L., Jackson, J.C., Wilkins, D.G., Gibb, J.W., and Hanson, G.R., 1997, Metham-phetamine-induced decrease in tryptophan hydroxylase activity: role of 5-hydroxytryptamine transporters, Eur. J. Pharmacol. 324:179–186.
Gartside, S.E., Cowen, P.J., and Sharp, T., 1992, Evidence that the large neutral amino acid L-valine decreases electrically-evoked release of 5-HT in rat hippocampus in vivo, Psychopharmacology 109:251–253.
Gibb, J.W., Johnson, M., Elayan, I., Lim, H.K., Matusda, L., and Hanson, G.R., 1997, Neurotoxicity of amphetamines and their metabolites, NIDA Res. Monogr. 173:128–145.
Gibb, J.W., Johnson, M., Stone, D.M., and Hanson, G.R., 1993, Mechanisms mediating biogenic amine deficits induced by amphetamine and its congeners, NIDA Res. Monogr. 136:226–236.
Graham, D.G., 1978, Oxidative pathways for catecholamines in the genesis of neuromelanin and cytotoxic quinones, Mol. Pharmacol. 14:633–643.
Halliday, G.M., Blumbergs, P.C., Cotton, R.G., Blessing, W.W., and Geffen, L.B., 1990, Loss of brain serotonin-and substance P-containing neurons in Parkinsons Disease, Brain Res. 510:104–107.
Halliday, G.M., Li, Y.W., Blumbers, P.C., Joh, T.H., Cotton, R.G.H., Howe, P.R.C., Blessing, W.W., and Geffen, L.B., 1990, Neuropathology of immunohistochemically identified brainstem neurons in Parkinsons Disease, Ann. Neurol. 27:373–385.
Ishida, Y., Hashiguchi, H., Todaka, K., Kuwahara, I., and Mitsuyama, Y., 1996, Dopaminergic transplants alter in vivo activity of tryptophan hydroxylase in the striatum in a rat model of Parkinson’s disease, Neurosci. Lett. 210:75–78.
Jequier, E., Lovenberg, W., and Sjoerdsma, A., 1967, Tryptophan hydroxylase inhibition: the mechanism by which p-chlorophenylalanine depletes brain serotonin, Mol. Pharmacol. 3:274–278.
Johansen, P.A., Wolf, W.A., and Kuhn, D.M., 1991, Inhibition of tryptophan hydroxylase by benserazide and other catechols, Biochem. Pharmacol. 41:625–628.
Kuhn, D.M. and Arthur, R.E. Jr., 1996, Inactivation of brain tryptophan hydroxylase by nitric oxide, J. Neurochem. 67:1072–1077.
Kuhn, D.M. and Arthur, R.E. Jr., 1997a, Inactivation of tryptophan hydroxylase by nitric oxide: Enhancement by tetrahydrobiopterin, J. Neurochem. 68:1495–1502.
Kuhn, D.M. and Arthur, R.E. Jr., 1997b, Molecular mechanism of the inactivation of tryptophan hydroxylase by nitric oxide: Attack on critical sulfhydryls that spare the enzyme iron center, J. Neurosci. 17:7245–7251.
Kuhn, D.M., Ruskin, B., and Lovenberg, W., 1980, Tryptophan hydroxylase: The role of oxygen, iron, and sulfhydryl groups as determinants of stability and catalytic activity, J. Biol. Chem. 255:4137–4143.
Melamed, E., Zoldan, J., Friedberg, G., Ziv, I., and Weizmann, A., 1996, Involvement of serotonin in clinical features of Parkinsons disease and complications of L-DOPA therapy, Adv. Neurol. 69:545–550.
Melamed, E., Offen, D., Shirvan, A., Djaldetti, R., Barzilai, A., and Ziv, I., 1998, Levodopa toxicitiy and apoptosis, Ann. Neurol. 44(suppl 1):S149–S154.
Metzger, R., Hanson, G.R., Gibb, J.W., and Fleckenstein, A.E., 1998, 3,4-methylenedioxy-methamphetamine-induced acute changes in dopamine transporter function, Eur. J. Pharmacol. 349:205–210.
Murray, J.B., 1996, Depression in Parkinson’s Disease. J. Psychol. 130:659–667.
Naoi, M., Marayuma, W., Takahashi, T., Ota, M., and Parvez, H., 1994, Inhibition of tryptophan hydroxylase by dopamine and the precursor amino acids, Biochem. Pharmacol. 48:207–211.
Paz, M.A., Fluckiger, R., Boak, A., Kagan, H.M., and Gallop, P.M., 1991, Specific detection of quinoproteins by redox-cycling staining, J. Biol. Chem. 266:689–692.
Schmidt, C.J. and Lovenberg, W., 1985, In vitro demonstration of dopamine uptake by neostriatal serotonergic neurons of the rat, Neurosci. Lett. 59:9–14.
Stone, D.M., Hanson, G.R., and Gibb, J.W., 1989, In vitro reactivation of rat cortical tryptophan hydroxylase following in vivo inactivation by methylenedioxymethamphetamine, J. Neurochem. 53:572–581.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1999 Springer Science+Business Media New York
About this chapter
Cite this chapter
Kuhn, D.M. (1999). Tryptophan Hydroxylase Regulation Drug-Induced Modifications that Alter Serotonin Neuronal Function. In: Huether, G., Kochen, W., Simat, T.J., Steinhart, H. (eds) Tryptophan, Serotonin, and Melatonin. Advances in Experimental Medicine and Biology, vol 467. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-4709-9_3
Download citation
DOI: https://doi.org/10.1007/978-1-4615-4709-9_3
Publisher Name: Springer, Boston, MA
Print ISBN: 978-1-4613-7133-5
Online ISBN: 978-1-4615-4709-9
eBook Packages: Springer Book Archive