Metabolism of L-tryptophan to kynurenate and quinolinate in the central nervous system: Effects of 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate

Dmitry B. Naritsin, Kuniaki Saito, S. P. Markey, Cai Y. Chen, Melvyn P. Heyes

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

The metabolism of L-tryptophan to the neuroactive kynurenine pathway metabolites, L-kynurenine, kynurenate and quinolinate, and the effects of two inhibitors of quinolinate synthesis (6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate) were investigated by mass spectrometric assays in cultured cells and in vivo. Cell lines obtained from astrocytoma, neuroblastoma, macrophage/monocytes, lung, and liver metabolized L-[13C6]-tryptophan to L-[13C6] kynurenine and [13C6]kynurenate, particularly after indoleamine-2,3-dioxygenase induction by interferon-γ. Kynurenine aminotransferase activity was measurable in all cell types examined but was unaffected by interferon-γ. These results suggest that many cell types can be sources of kynurenate following immune activation. In vivo synthesis of L-[13C6] kynurenine and [13C6] kynurenate from L-[13C6] tryptophan was studied in the CSF of macaques infected with poliovirus, as a model of inflammatory neurologic disease. The effects of 6-chlorotryptophan and 4-chloro-3-hydroxyanthranilate on the synthesis of kynurenate were different. 6-Chlorotryptophan attenuated formation of L-[13C6] kynurenine and [13C6] kynurenate and was converted to 4-chlorokynurenine and 7-chlorokynurenate. It may be an effective prodrug for the delivery of 7-chlorokynurenate, which is a potent antagonist of NMDA receptors. In contrast, 4-chloro-3-hydroxyanthranilate did not reduce accumulation of L-[13C6] kynurenine and [13C6] kynurenate. 6-Chlorotryptophan and 4-chloro-3-hydroxyanthranilate are useful tools to manipulate concentrations of quinolinate and kynurenate in the animal models of neurologic disease to evaluate physiological roles of these neuroactive metabolites.

Original languageEnglish
Pages (from-to)2217-2226
Number of pages10
JournalJournal of neurochemistry
Volume65
Issue number5
Publication statusPublished - 11-1995
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

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