Effects of Tryptophan 2,3-Dioxygenase Inhibitors in the Rat

  • M. Salter
  • R. M. Beams
  • M. A. E. Critchley
  • H. F. Hodson
  • R. Iyer
  • R. G. Knowles
  • D. J. Madge
  • C. I. Pogson
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 294)

Abstract

Tryptophan is an essential amino acid and is therefore, under normal conditions, only supplied net from the diet (see Fig. 1). Although tryptophan is metabolized through several pathways in the body, it is thought that the catabolism of tryptophan in the liver through the kynurenine pathway is of greatest quanitative significance (Young et al., 1978). However, under certain conditions, enzymes which control other pathways elsewhere in the body, such as indoleamine 2,3-dioxygenase, are induced to such an extent that their respective pathways become quantitatively significant (Brown et al., 1987; Knowles et al., 1989). Under normal conditions, the concentration of tryptophan in the blood will be regulated by the activity of the kynurenine pathway of the liver (Knowles et al., 1989) because there is little regulation of dietary input of tryptophan, apart from substrate supply. Until recently, it has been thought that the activity of the kynurenine pathway of the liver is controlled exclusively by its first step, tryptophan 2,3-dioxygenase (TDO); however, studies with isolated liver cells have shown that significant control resides in the transport of the amino acid across the plasma membrane (Salter et al., 1985; Salter et al., 1986a). Upon induction of TDO, control moves from TDO to transport until transport becomes the major controlling step in the pathway (Salter et al., 1986a). Tryptophan is transported across the liver plasma membrane by two transport systems, systems L and T (Salter et al., 1986b). Because these systems are not subject to regulation, apart from competition effects of other amino acids (Salter et al., 1986b), changes in plasma tryptophan will usually be caused by changes in TDO activity.

Keywords

Depression Serotonin Tryptophan Leucine Diazepam 

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References

  1. Brown, R.R., Borden, E.C., Sondel, P.M., and Lee, C., 1987, Effects of interferons and interleukin-2 as tryptophan metabolism in humans, in: “Progress in Tryptophan and Serotonin Research 1986”, Bender, D.A., Joseph, M.H., Kochen W., and Steinhart, H., eds., de Gruyter, Berlin, pp. 19–26.Google Scholar
  2. Green, A.R., Aronson, J.K., Curzon, G., and Woods, H.F., 1980, Metabolism of an oral tryptophan load, Br. J. Pharmacology, 10: 611–618.Google Scholar
  3. Hjorth, S., Soderpalm, B., and Engel, J.A., 1987, Biphasic effect of 5-HTP in the Vogel conflict model, Psychopharmacology, 92: 96–99.PubMedCrossRefGoogle Scholar
  4. Knowles, R.G., and Pogson, C.I., 1984, Characteristics of tryptophan accumulation by isolated rat forebrain synaptosomes, J. Neurochem., 42: 663–669.PubMedCrossRefGoogle Scholar
  5. Knowles, R.G., Pogson, C.I., and Salter, M., 1989, Application of control analysis to the study of amino acid metabolism, in: “Control of Metabolic Processes”, Cornish-Bowden, A., Ricard, J., Westerhoff, H.V., and Goldbeter, A., eds., Plenum, New York, pp. 377–384.Google Scholar
  6. Moller, S.E., 1981, Pharmacokinetics of tryptophan, renal handling of kynurenine and the effect of nicotinamide on its appearance in plasma and urine following L-tryptophan loading of healthy subjects, Eur. J. Clin. Pharmacol., 21: 137–142.PubMedCrossRefGoogle Scholar
  7. Naito, J., Ishiguro, I., and Nagamura, Y., 1989, Tryptophan 2,3-dioxygenase activity in rat skin, Arch. Biochem. Biophys., 270: 236–241.PubMedCrossRefGoogle Scholar
  8. Pogson, C.I., Knowles, R.G., and Salter, M., 1989, The control of aromatic amino acid catabolism and its relationship to neurotransmitter amine synthesis, Crit. Rev. Neurobiol., pp. 29–64.Google Scholar
  9. Salter, M., Bender, D.A., and Pogson, C.I., 1985, Leucine and tryptophan metabolism in rats, Biochem. J., 225: 277–280.PubMedGoogle Scholar
  10. Salter, M., Knowles, R.G., and Pogson, C.I., 1986a, Quantification of the importance of individual steps in the control of aromatic amino acid metabolism, Biochem. J., 234: 635–647.PubMedGoogle Scholar
  11. Salter, M., Knowles, R.G., and Pogson, C.I., 1986b, Transport of the aromatic amino acids into isolated liver cells, Biochem. J., 233: 499–506.PubMedGoogle Scholar
  12. Spano, P.F., Szyszka, K., Galli, C.L., and Ricci, A., 1974, Effect of clofibrate on free and total tryptophan in serum and brain tryptophan metabolism, Pharmacol. Res. Commun., 6: 163–173.PubMedCrossRefGoogle Scholar
  13. Taylor, D.P., 1988, Buspirone, a new approach to the treatment of anxiety, FASEB J., 2: 2445–2452.PubMedGoogle Scholar
  14. Thomson, J., Rankin, H., Ashcroft, G.W., Yates, C.M., McQueen, J.K., and Cummings, S.W., 1982, The treatment of depression in general practice: a comparison of L-tryptophan, amitriptyline and combination of L-tryptophan and amitriptyline with placebo, Psychol. Med., 12: 741–751.PubMedCrossRefGoogle Scholar
  15. Yaryura-Tobias, J.A., and Bhagavan, H.N., 1977, L-tryptophan in obsessivecompulsive disorders, Am. J. Psychiat., 134: 1298–1299.PubMedGoogle Scholar
  16. Young, S.N., 1986, The clinical psychopahrmacology of tryptophan, in: “Nutrition and the Brain”, Wurtman, R.J., and Wurtman, J.J., eds., Raven Press, New York, pp. 49–88.Google Scholar
  17. Young, S.N., St. Arnaud-McKenzie, D., and Sourkes, T.L., 1978, Importance of tryptophan pyrrolase and aromatic amino acid decarboxylase in the catabolism of tryptophan, Biochem. Pharmacol., 27: 763–767.PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1991

Authors and Affiliations

  • M. Salter
    • 2
  • R. M. Beams
    • 3
  • M. A. E. Critchley
    • 1
  • H. F. Hodson
    • 3
  • R. Iyer
    • 3
  • R. G. Knowles
    • 2
  • D. J. Madge
    • 3
  • C. I. Pogson
    • 2
  1. 1.PharmacologyThe Wellcome Research LaboratoriesBeckenhamUK
  2. 2.Biochemical SciencesThe Wellcome Research LaboratoriesBeckenhamUK
  3. 3.Medicinal ChemistryThe Wellcome Research LaboratoriesBeckenhamUK

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