The Journal of Physiological Sciences

, Volume 67, Issue 3, pp 361–372 | Cite as

Effect of water-immersion restraint stress on tryptophan catabolism through the kynurenine pathway in rat tissues

  • Yoshiji Ohta
  • Hisako Kubo
  • Koji Yashiro
  • Koji Ohashi
  • Yuji Tsuzuki
  • Naoya Wada
  • Yasuko Yamamoto
  • Kuniaki Saito
Original Paper


The aim of this study was to clarify the effect of water-immersion restraint stress (WIRS) on tryptophan (Trp) catabolism through the kynurenine (Kyn) pathway in rat tissues. The tissues of rats subjected to 6 h of WIRS (+WIRS) had increased tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) activities and increased TDO and IDO1 (one of two IDO isozymes in mammals) mRNA expression levels, with decreased Trp and increased Kyn contents in the liver. +WIRS rats had unchanged TDO and IDO activities in the kidney, decreased TDO activity and unchanged IDO activity in the brain, and unchanged IDO activity in the lung and spleen, with increased Kyn content in all of these tissues. Pretreatment of stressed rats with RU486, a glucocorticoid antagonist, attenuated the increased TOD activity, but not the increased IDO activity, with partial recoveries of the decreased Trp and increased Kyn contents in the liver. These results indicate that WIRS enhances hepatic Trp catabolism by inducing both IDO1 and TDO in rats.


Water-immersion restraint stress (rats) Liver tryptophan catabolism Tryptophan 2,3-Dioxygenase Indoleamine 2,3-Dioxygenase 1 Glucocorticoid Interferon-γ 



This study was partially supported by a grant from the Research Foundation of Fujita Health University, Grants-in-Aids for Scientific Research (24592734, 26860368) from the Japan Society for the Promotion of Science (JSPS), and a Research Grant from the Smoking Research Foundation (SRF).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest concerning this article.


  1. 1.
    Kolodziej LZ, Paleolog EM, Williams RO (2011) Kynurenine metabolism in health and disease. Amino Acids 41:1173–1183CrossRefPubMedGoogle Scholar
  2. 2.
    Braidy N, Guilemin GJ, Mansour H, Chan-Ling T, Grant R (2011) Changes in kynurenine pathway metabolism in the brain, liver and kidney of aged female Wistar rats. FEBS J 278:4425–4434CrossRefPubMedGoogle Scholar
  3. 3.
    Li D, Cai H, Hou M, Fu D, Ma Y, Luo Q, Yuan X, Lv M, Zhang X, Cong X, Lv Z (2012) Effects of indoleamine 2,3-dioxygenases in carbon tetrachloride-induced hepatitis model of rats. Cell Biochem Funct 30:309–314CrossRefPubMedGoogle Scholar
  4. 4.
    Siddiqi NJ (2014) Effect of gold nanoparticles on superoxide dismutase and indoleamine 2,3-dioxygenase in various rat tissues. Indian J Biochem Biophys 51:156–159PubMedGoogle Scholar
  5. 5.
    Dai X, Zhu BT (2010) Indoleamine 2,3-dioxygenase tissue distribution and cellular localization in mice: implications for its biological functions. J Histochem Cytochem 58:17–28CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Gál E (1974) Cellular tryptophan 2,3-dioxygenase (pyrrolase) and its induction in rat brain. J Neurochem 22:861–863CrossRefPubMedGoogle Scholar
  7. 7.
    Haber R, Besstte D, Hulihan-Giblin B, Durcan MJ, Goldman D (1993) Identification of tryptophan 2,3-dioxygenase RNA in rodent brain. J Neurochem 60:1159–1162CrossRefPubMedGoogle Scholar
  8. 8.
    Kanai M, Nakamura T, Funakoshi H (2009) Identification and characterization of novel variants of tryptophan 2.3-dioxygenase gene: differential regulation in the mouse nervous system during development. Neurosci Res 64:111–117CrossRefPubMedGoogle Scholar
  9. 9.
    Nomura J (1965) Effect of stress and psychotropic drugs on rat liver tryptophan dioxygenase. Endocrinology 76:1190–1194CrossRefPubMedGoogle Scholar
  10. 10.
    Németh Š, Vigaš M (1975) Adrenal hormones and increase of liver tyrosine aminotransferase and tryptophan pyrrolase activity after immobilization in rats. Endocrinol Exp 9:100–104PubMedGoogle Scholar
  11. 11.
    Sitaraman V, Ramasarma T (1975) Nature of induction of tryptophan pyrrolase in cold exposure. J Appl Physiol 58:245–249Google Scholar
  12. 12.
    Németh Š (1977) The effect of stress on the activity of hepatic tryptophan pyrrolase, of tyrosine aminotransferase in various organs and on the level of tryptophan in the liver and plasma of rats. Physiol Biochem 26:557–563Google Scholar
  13. 13.
    Gibney SM, Fagan EM, Waldron A-M, O’Byrne J, Connor TJ, Harkin A (2014) Inhibition of stress-induced hepatic tryptophan 2,3-dioxygenase exhibits anti-depressant activity in an animal model of depressive behavior. Int J Neuropsychopharmacol 17:917–928CrossRefPubMedGoogle Scholar
  14. 14.
    Schutz G, Killewich L, Chen G, Feigelson P (1975) Control of the mRNA for hepatic tryptophan oxygenase during hormonal and substrate induction. Proc Natl Acad Sci USA 72:1017–1020CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Danesch U, Hashimoto S, Renkawitz R, Schütz G (1983) Transcriptional regulation of the tryptophan oxygenase gene in rat liver by glucocorticoids. J Biol Chem 258:4750–4753PubMedGoogle Scholar
  16. 16.
    Danesch U, Gloss B, Schmid W, Schütz G, Schüle R, Renkawitz R (1991) Glucocorticoid induction of the rat tryptophan oxygenase gene us mediated by two widely separated glucocorticoid-responsive elements. EMBO J 6:625–630Google Scholar
  17. 17.
    Taylor MW, Feng G (1991) Relationship between interferon-γ, indoleamine 2,3-dioxygenase, and tryptophan catabolism. FASEB J 5:2516–2522PubMedGoogle Scholar
  18. 18.
    King NJC, Thomas SR (2007) Molecules in focus: indoleamine 2,3-dioxygenase. Int J Biochem Cell Biol 39:2167–2172CrossRefPubMedGoogle Scholar
  19. 19.
    Murakami Y, Saito K (2013) Species and cell type differences in tryptophan metabolism. Int J Tryptophan Res 6[Suppl 1]:47–54CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Yeung AW, Terentis AC, King NJ, Thomas SR (2015) Role of indoleamine 2,3-dioxygenase in health and disease. Clin Sci 129:601–672CrossRefPubMedGoogle Scholar
  21. 21.
    Kiank C, Zeden J-P, Drude S, Domanska G, Fusch G, Otten W, Schuett C (2010) Psychological stress-induced, IDO1-dependent tryptophan catabolism: implications on immunosuppression in mice and humans. PLoS One 5(7):e11825. doi: 10.1371/journal.pone.001185 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Hamaguchi M, Watanabe T, Higuchi H, Tominaga K, Fujiwara Y, Arakawa T (2001) Mechanisms and roles of neutrophil infiltration in stress-induced gastric injury in rats. Dig Dis Sci 46:2708–2715CrossRefPubMedGoogle Scholar
  23. 23.
    Brzozowski T, Konturek PC, Konturek SJ, Kwiecień S, Sliwowski Z, Pajdo R, Duda A, Ptak A (2003) Implication of reactive oxygen species and cytokines in gastroprotection against stress-induced gastric damage by nitric oxide releasing aspirin. Int J Colorectal Dis 18:320–329PubMedGoogle Scholar
  24. 24.
    Jia Y-T, Ma B, Wei W, Xu Y, Wang Y, Tang H-T, Xia Z-F (2007) Sustained activation of nuclear factor-κB by reactive oxygen species is involved in the pathogenesis of stress-induced gastric damage in rats. Crit Care Med 35:1582–1591CrossRefPubMedGoogle Scholar
  25. 25.
    Jia Y-T, Wei W, Ma B, Xu Y, Liu W-J, Wang Y, Lv K-Y, Tang H-T, Wei D, Xia Z-F (2007) Activation of p38 MARK by reactive oxygen species is essential in a rat model of stress-induced gastric mucosal injury. J Immunol 179:7808–7819CrossRefPubMedGoogle Scholar
  26. 26.
    Takada Y, Urano T, Ihara H, Takada A (1995) Changes in the central and peripheral serotonergic system in rats exposed to water-immersion restraint stress and nicotine administration. Neurosci Res 23:305–311CrossRefPubMedGoogle Scholar
  27. 27.
    Nishida K, Ohta Y, Kobayashi T, Ishiguro I (1997) Involvement of the xanthine-xanthine oxidase system and neutrophils in the development of acute gastric mucosal lesions in rats water immersion restraint stress. Digestion 58:340–351CrossRefPubMedGoogle Scholar
  28. 28.
    Ohta Y, Kaida S, Chiba S, Tada M, Teruya A, Imai Y, Kawanishi M (2009) Involvement of oxidative stress in increases in serum levels of various enzymes and components in rats with water-immersion restraint stress. J Clin Biochem Nutr 45:347–354CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Ohta Y, Yashiro K, Ohashi K, Imai Y (2012) Disruption of non-enzymatic antioxidant defense systems in the brain of rats with water-immersion restraint stress. J Clin Biochem Nutr 51:36–42CrossRefGoogle Scholar
  30. 30.
    Ohta Y, Yashiro K, Kiada S, Imai Y, Ohashi K, Kitagawa A (2013) Water-immersion restraint stress disrupts nonenzymatic antioxidant defense systems through rapid and continuous ascorbic acid depletion in the adrenal gland. Cell Biochem Funct 31:254–262CrossRefPubMedGoogle Scholar
  31. 31.
    Mailliet F, Qi H, Rocher C, Spending M, Svenningsson P, Jay TM (2008) Protection of stress-induced impairment of hippocampal/prefrontal LTP through blockade of glucocorticoid receptors. Implication of MEK signaling. Exp Neurol 21:593–596CrossRefGoogle Scholar
  32. 32.
    Guillemin R, Clayton GW, Lipscomb HS, Smith JD (1959) Fluorometric measurement of rat plasma and adrenal corticosterone. A note on technical details. J Lab Clin Med 53:830–832PubMedGoogle Scholar
  33. 33.
    Fujigaki S, Saito K, Takemura M, Fujii H, Wasa H, Noma A, Seishima M (1998) Species differences in l-tryptophan-kynurenine pathway metabolism: quantification of anthranilic acid and its related enzymes. Arch Biochem Biophys 358:329–335CrossRefPubMedGoogle Scholar
  34. 34.
    Fujigaki S, Saito K, Takemura M, Maekawa N, Yamada Y, Wasa H, Seishima M (2002) l-Tryptophan-l-kynurenine pathway metabolism accelerated by toxoplasma gondii infection is abolished in gamma interferon-gene-deficient mice: cross-regulation between inducible nitric oxide synthase and indoleamine 2,3-dioxygenase. Infect Immun 70:779–786CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Yuasa HJ, Mizuno K, Ball HJ (2015) Low efficiency IDO2 enzymes are conserved in lower vertebrates, whereas higher efficiency IDO1 enzymes are dispensable. FEBS J 282:2735–2745CrossRefPubMedGoogle Scholar
  36. 36.
    Ball HJ, Yuasa HJ, Austin CJD, Weiser S, Hunt NH (2009) Indoleamine 2,3-dioxygenase-2: a new enzyme in the kynurenine pathway. Int J Biochem Cell 41:467–471CrossRefGoogle Scholar
  37. 37.
    Fukunaga M, Yamamoto Y, Kawasoe M, Arioka Y, Murakami Y, Hoshi M, Saito K (2012) Studies on tissue and cellular distribution of indoleamine 2,3-dioxygenase 2: the absence of IDO1 upregulates IDO2 expression in the epididymis. J Histochem Cytochem 60:854–960CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Fracesconi RP, Boyd AE III, Mager M (1972) Human tryptophan and tyrosine metabolism: effects of acute exposure to cold stress. J Appl Physiol 33:165–169Google Scholar
  39. 39.
    Okamoto H, Ishikawa A, Nishimuta M, Kodama N, Yoshitake Y, Furwatari T, Shibata K (2002) Effects of stress on the urinary excretory pattern of niacin catabolites, the most reliable index of niacin status, in humans. J Nutr Sci Vitaminol 48:417–419CrossRefPubMedGoogle Scholar
  40. 40.
    Saito K, Ohta Y, Nagamura Y, Sasaki E, Ishiguro I (1990) Relationship between l-tryptophan uptake and l-tryptophan 2.3-dioxygenase activity in rat hepatocytes. Biochem Int 20:71–80PubMedGoogle Scholar
  41. 41.
    Pawlfak D, Takada Y, Urano T, Takada A (2000) Serotonegic and kynurenic pathways in rats exposed to foot shock. Brain Res Bull 52:197–205CrossRefGoogle Scholar
  42. 42.
    Young SN (1981) Mechanism of decline in rat brain 5-hydrozytryptamine after induction of liver tryptophan pyrrolase by hydrocortisone: roles of tryptophan catabolism and kynurenine synthesis. Br J Pharmacol 74:695–700CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Ramanarayanan-Murthy L, Colman PD, Feigelson P (1978) Studies on the glucocorticoid receptor and the hormonal modulation of the mRNA for tryptophan oxygenase. Adv Exp Med Biol 96:73–107CrossRefPubMedGoogle Scholar
  44. 44.
    Hirota T, Hirota K, Sanno Y, Tanaka T (1985) A new glucocorticoid receptor species: relation to induction of tryptophan dioxygenase by glucocorticoid. Endocrinology 117:1788–1795CrossRefPubMedGoogle Scholar
  45. 45.
    Al-Safadi S, Branchaud M, Rutherford S, Amir S (2015) Glucocorticoids and stress-induced changes in the expression of PERIOD1 in the rat forebrain. PLoS One 10(6):e0130085. doi: 10.1371/journal.pone.0130085 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Sim Y-B, Park S-H, Kang Y-J, Kim S-M, Lee J-K, Jung J-S, Suh H-W (2010) The regulation of blood glucose level in physical and emotional stress models: possible involvement of adrenergic and glucocorticoid systems. Arch Pharm Res 33:1679–1683CrossRefPubMedGoogle Scholar
  47. 47.
    Jeffrey R, Plescia MG, Anastasio GD (1998) Mifepristone (RU 486). Current knowledge and future prospects. Arch Fam Med 7:219–222CrossRefGoogle Scholar
  48. 48.
    Charmandari E, Tsigos C, Chrousos G (2005) Endocrinology of the stress response. Annu Rev Physiol 67:259–284CrossRefPubMedGoogle Scholar
  49. 49.
    Arakawa H, Kodama H, Matsuoka N, Yamaguchi I (1997) Stress increases plasma enzyme activity in rats: differential effects of adrenergic and cholinergic blockers. J Pharmacol Exp Ther 280:1296–1303PubMedGoogle Scholar
  50. 50.
    Yamada F, Inoue S, Saitoh T, Tanaka K (1993) Glucoregulatory hormones in the immobilization stress-induced increase in plasma glucose in fasted and fed rats. Endocrinology 132:2199–2205PubMedGoogle Scholar
  51. 51.
    Elenkov IJ, Chroudsos GF (2002) Stress hormones, proinflammatory and antiinflammatory cytokines, and autoimmunity. Ann NY Acad Sci 966:290–303CrossRefPubMedGoogle Scholar

Copyright information

© The Physiological Society of Japan and Springer Japan 2016

Authors and Affiliations

  • Yoshiji Ohta
    • 1
  • Hisako Kubo
    • 2
  • Koji Yashiro
    • 1
  • Koji Ohashi
    • 3
  • Yuji Tsuzuki
    • 2
  • Naoya Wada
    • 2
  • Yasuko Yamamoto
    • 2
    • 4
  • Kuniaki Saito
    • 2
    • 4
  1. 1.Department of ChemistryFujita Health University School of MedicineToyoakeJapan
  2. 2.Human Health Sciences, Graduate School of Medicine and Faculty of MedicineKyoto UniversityKyotoJapan
  3. 3.Department of Clinical Biochemistry, Faculty of Medical TechnologyFujita Health University School of Health SciencesToyoakeJapan
  4. 4.Department of Disease Control and PreventionFujita Health University Graduate School of Health SciencesToyoakeJapan

Personalised recommendations