SpringerLink
Log in

The metabolic fate of infusedl-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites

  • Original Investigations
  • Published:
Psychopharmacology Aims and scope Submit manuscript

Abstract

l-Tryptophan (Trp) was widely used as a natural tool for the support of serotonin-mediated brain functions and as a challenge probe for the assessment of serotonin-mediated neuroendocrine responses. The metabolic fate of the administered Trp and the kinetics of the accumulation of Trp metabolites in the circulation, however, have never thoroughly been investigated.

This study describes the time- and dose-dependent alterations in the plasma levels of various Trp metabolites and large neutral amino acids after the infusion of Trp to healthy young men (1, 3 and 5 g; placebo-controlled, double-blind, cross-over study during day- and night-time).

The major Trp metabolites (kynurenine, indole acetic acid and indole lactic acid) in plasma increased dose-dependently but rather slowly after Trp administration to reach their maximal plasma levels (up to 10-fold after the 5 g dose) at about 3 h p.i., and remained at an elevated level (about 5-fold) for up to 8 h. N-acetyl-Trp and 5-hydroxy-Trp rose rapidly and massively after Trp infusions, at the 5 g dose more than 200- and 20-fold, respectively, and declined rapidly to about 5-fold baseline levels within 2 h. Whole blood serotonin levels were almost unaffected by the Trp infusions. A rather slow increase of 5-hydroxyindole acetic acid was seen, reaching maximum values (3-fold at the 5 g dose) at about 2 h after the infusion of Trp. Additionally, a dose-dependent rise of circulating melatonin was observed afterl-Trp infusions. The administration ofl-Trp caused a depletion of the concentrations of the other large neutral amino acids and a dose dependent decrease of the ratio between plasma tyrosine and the sum of the plasma concentrations of the other large neutral amino acids. Apparently, none of the existing pathways of peripheral Trp metabolism is saturated by its substrate, Trp in men. At least some of the central effects reported afterl-Trp administration may be mediated by the Trp-stimulated formation of neuroactive metabolites or by the decreased availability of tyrosine for catecholamine synthesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Aizenstein ML, Scavone C (1984) The urinary excretion of 5-hydroxyindoleacetic acid does not reflect brain levels of this metabolite of 5-hydroxytryptamine. Braz J Med Biol Res 17:323–327

    Google Scholar 

  • Ashcroft GW, Eccleston D, Crawford TBB (1965) 5-Hydroxyindole metabolism in rat brain. A study of intermediate metabolism using the technique of tryptophan loading. J Neurochem 12:483–492

    Google Scholar 

  • Aviram M, Cogan U, Modady S (1991) Excessive dietary tryptophan enhances plasma-lipid peroxidation in rats. Atherosclerosis 88:29–34

    Google Scholar 

  • Belongia EA, Hedberg CW, Gleich GJ (1990) An investigation of the cause of the eosinophilia-myalgia syndrome associated with tryptophan use. N Engl J Med 323:357–365

    Google Scholar 

  • Brainard GC, Lewy AJ, Menaker M, Fredrikson RH, Miller LS, Wellber RG, Caryone V, Hudson D (1988) Dose-response relationship between light irridance and the suppression of plasma melatonin in human volunteers. Brain Res 454:212–218

    Google Scholar 

  • Brown RR, Lee CM, Kohler PC, Hank JA, Storer BE, Sondel PM (1989) Altered tryptophan and neopterin metabolism in cancerpatients treated with recombinant interleukin-2. Cancer Res 49:4941–4944

    Google Scholar 

  • Byrne GJ, Lehmann LK, Kirschbaum JG, Borden EC, Lee CM, Brown RR (1986) Induction of tryptophan-degradation in vitro and in vivo: a γ-interferon-stimulated activity. J Interferon Res 6:389–396

    Google Scholar 

  • Carboni E, Cadoni C, Tanda GL, Dichiara G (1989) Calcium-dependent, tetrodotoxin-sensitive stimulation of cortical serotonin release after a tryptophan load. J Neurochem 53:976–978

    Google Scholar 

  • Charlton KG, Johnson TD, Mamed AT, Clarke DE (1983) Cardiovascular actions of kynuramine and 5-hydroxykynuramine in pithed rats. J Neural Transm 57:199–211

    Google Scholar 

  • Christen S, Peterhans E, Stocker R (1990) Antioxidant activities of some tryptophan metabolites: possible implication for inflammatory diseases. Proc Natl Acad Sci USA 87:2506–2510

    Google Scholar 

  • Cowen PJ (1988) Neuroendocrine responses to tryptophan as an index of brain serotonin function. In: Huether G (ed) Amino acid availability and brain function in health and disease. NATO ASI Series, vol H20, Springer, Berlin Heidelberg, New York, pp 285–290

    Google Scholar 

  • Fernstrom JD, Wurtman RJ (1971) Brain serotonin content: physiological dependence on plasma tryptophan levels. Science 173:149–151

    Google Scholar 

  • Gal EM, Young RB, Sherman AD (1978) Tryptophan loading: consequent effects on the synthesis of kynurenine and 5-hydroxy-indoles in rat brain. J Neurochem 31:237–244

    Google Scholar 

  • Gearney DP, Soper N, Shepstone BJ, Goodwin GM, Cowen PJ (1991) Intravenousl-tryptophan and regional cerebral blood-flow. Biol Psychiatry 29:508–509

    Google Scholar 

  • George CFB, Millar TW, Hanly PJ, Kryger MH (1989) The effect ofl-trytophan on daytime sleep latency in normals—correlation with blood-levels. Sleep 12:345–353

    Google Scholar 

  • Gessa GL, Biggio G, Fadda F, Corsini GU, Tagliamonte A (1974) Effect of the oral administration of Trp-free amino acid mixtures on serum tryptophan, brain tryptophan and serotonin metabolism. J Neurochem 22:869–870

    Google Scholar 

  • Goodwin GM, Shapiro CM, Bennie J, Dick H, Carroll S, Fin KG (1989) The neuroendocrine responses and psychological effects of infusion ofl-tryptophan in anorexia nervosa. Psychol Med 19:857–864

    Google Scholar 

  • Hajak G, Huether G, Blanke J, Bloemer M, Freyer C, Poeggeler B, Reimer A, Rodenbeck A, Schulz-Varszegi M, Rüther E (1991) The influence of intravenousl-tryptophan on plasma melatonin and sleep in men. Pharmacopsychiatry 24:17–20

    Google Scholar 

  • Hajak G, Huether G, Rodenbeck A, Rüther E (1992) Endocrine and sleep-inducing properties ofl-tryptophan in men In: Lehnert H et al (eds) Endocrine and nutritional control of basic biological functions. Hogrefe and Huber, Bern, Stuttgart, Toronto (in press)

    Google Scholar 

  • Hartmann EL (1986) Effect ofl-tryptophan and other amino-acids on sleep. Nutr Rev 44:70–73

    Google Scholar 

  • Heyes MP, Markey SP (1988) Quantification of quinolinic acid in rat brain, whole blood and plasma by GCMS: effects of systemicl-Trp administration on brain and blood quinolinic acid concentrations. Anal Biochem 174:349–359

    Google Scholar 

  • Huether G, Lajtha A (1991) Changes in free amino acid concentrations in serum, brain, and CSF throughout embryogenesis. Neurochem Res 16:145–150

    Google Scholar 

  • Huether G, Poeggeler B, Reimer A, George A (1992) Effect of tryptophan administration on circulating melatonin levels in chicks and rats: Evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract. Life Sci 51:945–953

    Google Scholar 

  • Hussain MN, Sirek A, Cukerman E, Sirek OV (1985) The effect of tryptophan on biogenic amines in the hepatic portal circulation of the dog. Can J Physiol 63:863–866

    Google Scholar 

  • Idzikowski C, Mills FJ, Glennard R (1986) 5-Hydroxytryptamine-2 antagonist increases human slow wave sleep. Brain Res 378 164–168

    Google Scholar 

  • Jones ML, Kimbrough TD, Weekley LB (1985) Disturbances of tryptophan metabolism in mice acutely deprived of tryptophan. Ann Nutr Metab 29:209–215

    Google Scholar 

  • Juorio AV, Paterson IA (1990) Tryptamine may couple dopaminergic and serotonergic transmission in the brain. Gen Pharmacol 21:613–616

    Google Scholar 

  • Körner E, Bertha G, Flooh E, Reinhart B, Wolf R, Lechner H (1986) Sleep-inducing effect ofl-tryptophan. Eur Neurol 25:75–81

    Google Scholar 

  • Lapin JP (1988) Behavioral and convulsant effects of kynurenines. In: Stone TW (ed) Quinolinic acid and the kynurenines. CRC Press, Boca Raton, Florida, pp 193–211

    Google Scholar 

  • Lee MA, Nash JF, Barnes M, Meltzer HY (1991) Inhibitory effect of ritanserin on the 5-hydroxytryptophan-mediated cortisol, ACTH and prolactin secretion in humans. Psychopharmacology 103:258–264

    Google Scholar 

  • Liebermann HR (1986) Behavior, sleep and melatonin. J Neural Transm (Suppl) 21:233–241

    Google Scholar 

  • Maestroni GJ, Conti MA, Pierpalle W (1987) The pineal gland and the circadian opiatergic, immunoregulatory role of melatonin. Ann NY Acad Sci 496:67–77

    Google Scholar 

  • Marsden CA, Curzon G (1978) The contribution of tryptamine to the behavioural effects ofl-Trp in tranylcypramine-treated rats. Psychopharmacology 57:71–76

    Google Scholar 

  • Marsden CA, Curzon G (1979) The role of tryptamine in behavioural effects of tranylcypramine plusl-tryptophan. Neuropharmacology 18:159–164

    Google Scholar 

  • Masiello P, Balestrere E, Bacciola D, Bergamini E (1987) Influence of experimental diabetes on brain levels of monoamine neurotransmitters and their precursor amino acids during tryptophan loading. Acta Diabetol Lat 24:43–50

    Google Scholar 

  • Mason R, Brooks A (1988) The electrophysiological effects of melatonin and a putative melatonin antagonist (N-acetyltryptamine) on rat suprachiasmatic neurones in vitro. Neurosci Lett 95:296–301

    Google Scholar 

  • Mirmian M, Pevet P (1986) Effect of melatonin and 5-methoxytryptamine on sleep-wake-patterns in the male rat. J Pineal Res 3:135–141

    Google Scholar 

  • Moir ATB, Eccleston D (1968) The effects of precursor loading in the cerebral metabolism of 5-hydroxyindoles. J Neurochem 15:1093–1108

    Google Scholar 

  • Moja EA, Restani P, Corsii E, Stacchezzini MC, Assereto R, Galli CL (1991) Cycloheximide blocks the fall of plasma and tissue tryptophan levels after tryptophan-free amino-acid mixtures. Life Sci 49:1121–1128

    Google Scholar 

  • Morand C, Young SN, Ervin FR (1983) Clinical response of aggressive schizophrenics to oral tryptophan. Biol Psychiatry 18:575–578

    Google Scholar 

  • Poeggeler B, Huether G (1991) A versatile homogenous one-tube scintillation proximity radioimmunoassay for melatonin. Clin Chem 38:314–315

    Google Scholar 

  • Poeggeler B, Reimer A, Huether G (1992) The origin of elevated plasma melatonin after administration ofl-tryptophan. In: Lehnert H et al (eds) Endocrine and nutritional control of basic biological functions. Hogrefe and Huber, Bern, Stuttgart, Toronto (in press)

    Google Scholar 

  • Pomfret DW, Schenck KW, Fudzinski P, Cohen ML (1987) Interaction of 5-OH-kynurenamine,l-kynurenine, and kynuramine with multiple serotonin receptors in smooth muscle. J Pharmacol Exp Ther 241:465–471

    Google Scholar 

  • Price LH, Charney DS, Delgado PL, Heninger GR (1991) Serotonin function and depression—neuroendocrine and mood responses to intravenousl-tryptophan in depressed patients and healthy comparison subjects. Am J Psychiatry 148:1518–1525

    Google Scholar 

  • Renson J, Weissbach H, Udenfriend S (1962) Hydroxylation of tryptophan by phenylalanine hydroxylase. J Biol Chem 237:2261–2264

    Google Scholar 

  • Rizza V, Bousquet E, Guerrera F, De Regis M (1983) Regulation of cerebral kynurenine and 5-hydroxyindole pathways during tryptophan loading. Cephalalgia 3:139–142

    Google Scholar 

  • Schaechter JD, Wurtman RJ (1990) Serotonin release varies with brain tryptophan levels. Brain Res 532:203–210

    Google Scholar 

  • Schneider-Helmert D, Spinweber CL (1986) Evaluation ofl-tryptophan for treatment of insomnia: a review. Psychopharmacology 89:1–7

    Google Scholar 

  • Schwarcz T, Whetsell WO, Mangano RM (1983) Quinolonic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain. Science 219:316–318

    Google Scholar 

  • Schwartz DH, Hernandez L, Hoebel BG (1990) Tryptophan increases extracellular serotonin in the lateral hypothalamus of food-deprived rats. Brain Res Bull 25:803–807

    Google Scholar 

  • Sidransky H, Sarma DSR, Bongiorno M, Berney E (1968) Effect of dietary tryptophan on hepatic ribosomes and protein synthesis in fasted mice. J Biol Chem 243:1123–1132

    Google Scholar 

  • Sleight AJ, Marsden CA, Martin KF, Palfreyman MG (1988) Relationship between extracellular 5-hydroxytryptamine and behavior following monoamine-oxidase inhibition andl-tryptophan. Br J Pharmacol 93:303–310

    Google Scholar 

  • Slutsker L, Hoesley FC, Miller L (1990) Eosinophilia-myalgia syndrome associated with exposure to tryptophan from a single manufacturer JAMA 264:213–217

    Google Scholar 

  • Stone TW, Connick JH (1985) Quinolinic acid and other kynurenines in the central nervous system. Neuroscience 15:597–617

    Google Scholar 

  • Sved AF, Van Itallie DM, Fernstrom JD (1982) Studies on the antihypertensive action ofl-tryptophan. J Pharmacol Exp Ther 221:329–333

    Google Scholar 

  • Teff KL, Young SN (1988) Effects of carbohydrate and protein administration on rat tryptophan and 5-hydroxytryptamine—differential effects on the brain, intestine, pineal, and pancreas. Can J Physiol Pharmacol 66:683–688

    Google Scholar 

  • Thomson E, Rankin H, Ashcroft GW, Yates CM, McQueen JK, Cummings SW (1982) The treatment of depression in general practice: a comparison ofl-tryptophan, amitryptiline, and a combination ofl-tryptophan and amitryptiline with placebo. Psychol Med 12:741–751

    Google Scholar 

  • Träskman-Bendz L, Haskett RF, Zis AP (1986) Neuroendocrine effects ofl-tryptophan and dexamethasone. Psychopharmacology 89:85–88

    Google Scholar 

  • Van Praag HM, Lemus C, Kahn R (1987) Hormonal probes of central serotonergic activity: do they really exist. Biol Psychiatry 22:86–98

    Google Scholar 

  • Waldhauser F, Saletu B, Trinchard-Lugan I (1990) Sleep laboratory investigations of hypnotic properties of melatonin. Psychopharmacology 100:222–226

    Google Scholar 

  • Weissbach H, King W, Sjoersdsma A, Udenfriend S (1959) Formation of indole-3-acetic acid and tryptamine in animals. J Biol Chem 234:81–86

    Google Scholar 

  • Werner-Felmayer G, Werner ER, Fuchs D, Hausen A, Reibnegger G, Wachter H (1989) Characteristics of interferon induced tryptophan-metabolism in human-cells in vitro. Biochim Biophys Acta 1012:140–147

    Google Scholar 

  • Winokur A, Lindberg ND, Lucki I, Phillips J, Amsterdam JD (1986) Hormonal and behavioral effects associated with intravenousl-tryptophan administration. Psychopharmacology 88:213–219

    Google Scholar 

  • Wurtman RJ, Fernstrom JD (1976) Control of brain neurotransmitter synthesis by precursor availability and nutritional state. Biochem Pharmacol 25:1691–1696

    Google Scholar 

  • Woolf PD, Lee L (1976) Effect of the serotonin precursor, tryptophan, on pituitary hormone secretion. J Clin Endocrinol Metab 45:123–133

    Google Scholar 

  • Yasui H, Takai K, Yoshida R, Hayaishi OP, Nas US (1986) Interferon enhances tryptophan-metabolism by inducing pulmonary indoleamine 2,3-dioxygenase—its possible occurrence in cancer-patients. Proc Natl Acad Sci USA 83:6622–6626

    Google Scholar 

  • Yoshida R, Urade Y, Tokuda M, Hayashi O (1979) Induction of indoleamine 2, 3-dioxygenase in mouse lung during virus infection. Proc Natl Acad Sci USA 76:4084–4086

    Google Scholar 

  • Young SN (1986) The clinical psychopharmacology of tryptophan. In: Wurtman RJ, Wurtman JJ (eds) Nutrition and the brain, vol 7 Raven Press, New York, pp 49–88

    Google Scholar 

  • Young SN, Gauthier S (1981) Tryptophan availability and the control of 5-hydroxytryptamine and tryptamine synthesis in human CSF. Adv Exp Med Biol 133:221–230

    Google Scholar 

  • Young SN, St-Arnaud-McKenzie D, Sourkes TL (1978) Importance of tryptophan pyrrolase and aromatic amino acid decarboxylase in the catabolism of tryptophan. Biochem Pharmacol 27:763–767

    Google Scholar 

  • Yuwiler A, Brammer GL, Morley JE et al. (1981) Short-term and repetitive administration of oral tryptophan in normal men. Arch Gen Psychiatry 38:619–626

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Psychiatry, University of Göttingen, V. Siebold-Strasse 5, W-3400, Göttingen, Federal Republic of Germany

    G. Huether, G. Hajak, A. Reimer, B. Poeggeler, M. Blömer, A. Rodenbeck & E. Rüther

Authors
  1. G. Huether
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. Hajak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Reimer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. Poeggeler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Blömer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. Rodenbeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. E. Rüther
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

Part of this work was presented at the International Symposium on Future Prospects ofl-Tryptophan in Medicine, Heidelberg, Germany, November 22–23, 1991

Rights and permissions

Reprints and permissions

About this article

Cite this article

Huether, G., Hajak, G., Reimer, A. et al. The metabolic fate of infusedl-tryptophan in men: possible clinical implications of the accumulation of circulating tryptophan and tryptophan metabolites. Psychopharmacology 109, 422–432 (1992). https://doi.org/10.1007/BF02247718

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02247718

Key words

Search

Navigation