Kynurenine Pathway Metabolism in Human Astrocytes

  • Gilles J. Guillemin
  • Stephen J. Kerr
  • George A. Smythe
  • Patricia J. Armati
  • Bruce J. Brew
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 467)


The involvement of astrocytes in Kynurenine pathway (KP) metabolism is still poorly understood. In the present study, we investigated the ability of human fetal astrocytes in vitro to produce quinolinic and picolinic acids using mass spectrometry. In parallel, we estimated the level of expression of five major KP enzymes using RT-PCR. The results demonstrated that astrocytes express most KP enzymes, except for kynurenine-hydroxylase. This in vitro study provides novel informations regarding the ability of human fetal astrocytes to degrade L-tryptophan along the KP.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bender D.A. and McCreanor, G.M., 1982, The preferred route of kynurenine metabolism in the rat, Biochem. Biophys. Acta 717:56–60.PubMedCrossRefGoogle Scholar
  2. Bignami A., Eng L.F., Dahl D., and Uyeda C.T., 1972, Localization of glial fibrillary acidic protein in astrocytes by immunofluorescence, Brain Res 43:429–435.PubMedCrossRefGoogle Scholar
  3. Brew B.J., Wesselingh S.L., Gonzales M., Heyes M.P., and Price R.W., 1996, How HIV leads to neurological disease, Med. J. Aust. 164:233–234.PubMedGoogle Scholar
  4. Espey M.G., Chernyshev O.N., Reinhard J.J., Namboodiri M.A., and Colton C.A., 1997, Activated human microglia produce the excitotoxin quinolinic acid, Neuroreport 8:431–434.PubMedCrossRefGoogle Scholar
  5. Foster A.C., White R.J., and Schwarcz R., 1986, Synthesis of quinolinic acid by 3-hydroxyanthranilic acid oxygenase in rat brain tissue in vitro, J. Neurochem. 47:23–30.PubMedCrossRefGoogle Scholar
  6. Fukui S., Schwarcz R., Rapaort S.I., Takada Y., and Smith Q.R., 1991, Blood-Brain Barrier transport of Kynurenines: Implications for brain synthesis and metabolism., J. Neurochem. 56:2007–2017.PubMedCrossRefGoogle Scholar
  7. Guillemin G., Boussin F., Croitoru J., Le Grand R., and Dormont D., 1997, Obtention and characterization of astrocytes and microglia from adult monkey brains., J. Neurosc. Res. 49:576–591.CrossRefGoogle Scholar
  8. Heyes M.P., Saito K., and Crowley J.S., et al., 1992, Quinolinic acid and kynurenine pathway metabolism in inflammatory and non-inflammatory neurological disease, Brain. 115:1249–1273.PubMedCrossRefGoogle Scholar
  9. Heyes M.P., Saito K., and Markey S.P., 1992, Human macrophages convert L-tryptophan into the neurotoxin quinolinic acid, Biochem. J. 283:633–635.PubMedGoogle Scholar
  10. Heyes M.P., 1993, Metabolism and neuropathologic significance of quinolinic acid and kynurenic acid, Biochemical Soc. Trans. 21:83–89.Google Scholar
  11. Heyes M.P., Achim C.L., Wiley C.A., Major E.O., Saito K., and Markey S.P., 1996, Human microglia convert L-tryptophan into the neurotoxin quinolinic acid, Biochem. J. 320:595–597.PubMedGoogle Scholar
  12. Heyes M.P., Chen C.Y., Major E.O., and Saito K., 1997, Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types, Biochem. J. 326:351–356.PubMedGoogle Scholar
  13. Heyes M.P., Saito K., and Chen C.Y., et al., 1997, Species heterogeneity between gerbils and rats: quinolinate production by microglia and astrocytes and accumulations in response to ischemic brain injury and systemic immune activation, J. Neurochem. 69:1519–1529.PubMedCrossRefGoogle Scholar
  14. Kohler C., Peterson A., Eriksson L.G., Okuno E., and Schwarcz R., 1988, Immunohistochemical identification of quinolinic acid phosphoribosyltransferase in glial cultures from rat brain, Neurosci Lett 84:115–9.PubMedCrossRefGoogle Scholar
  15. Koide Y. and Yoshida A., 1994, The signal transduction mechanism responsible for γ-IFN-induced indoleamine 2.3-dioxygenase gene expression, Infect. Immunity 62:948–955.Google Scholar
  16. Pemberton A.L., Kerr S.J., Smythe G., and Brew B.J., 1997, Quinolinic acid production by macrophages stimulated with IFN-γ, TNF-α and IFN-α. J. Interferon & Cytokine Res. 17:589–595.CrossRefGoogle Scholar
  17. Roberts R.C., McCarthy K.E., Du F., Okuno E., and Schwarcz R, 1994, Immunocytochemical localization of the quinolinic acid synthesizing enzyme, 3-hydroxyanthranilic acid oxygenase, in the rat substantia nigra, Brain Res 650:229–238.PubMedCrossRefGoogle Scholar
  18. Saito K., Nowak T.S., and Suyama K., et al., 1993, Kynurenine pathway enzymes in brain: responses to ischaemic brain injury versus systemic immune activation, J. Neurochem. 61:2061–2070.PubMedCrossRefGoogle Scholar
  19. Saito K., Crowley J.S., Markey S.P., and Heyes M.P., 1993, A mechanism for increased quinolinic acid formation following acute systemic immune stimulation, J. Biol. Chem. 268:15496–15503.PubMedGoogle Scholar
  20. Sanni L.A., Thomas S.R., and Tattam B.N., et al., 1998, Dramatic changes in oxidative tryptophan metabolism along the kynurenine pathway in experimental cerebral and non-cerebral malaria, Am. J. Pathol. 152:611–619.PubMedGoogle Scholar
  21. Schwarcz R., Whetsell W.O.J., and Mangano R.M., 1983, Quinolinic acid: an endogenous metabolite that produces axon-sparing lesions in rat brain, Science 219:316–318.PubMedCrossRefGoogle Scholar
  22. Villinger F., Hunt D., Mayne A., Vuchetiv M., Findley H., and Ansari A.A., 1993, Qualitative and quantitative studies of cytokines synthetized and secreted by non-human primate peripheral blood mononuclear cells., Cytokine 5:169–179.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Gilles J. Guillemin
    • 1
  • Stephen J. Kerr
    • 1
  • George A. Smythe
    • 3
  • Patricia J. Armati
    • 4
  • Bruce J. Brew
    • 1
    • 2
  1. 1.Centre for ImmunologyAustralia
  2. 2.Departments of Neurology and HIV MedicineSt Vincent’s HospitalSydneyAustralia
  3. 3.Biomedical Mass Spectrometry UnitUniversity of New South WalesSydneyAustralia
  4. 4.School of Biological SciencesUniversity of SydneyAustralia

Personalised recommendations