Xanthurenic acid distribution, transport, accumulation and release in the rat brain

*INSERM U-575 and Department of Biochemistry, Faculty of Medicine, Strasbourg, France CEA/Saclay, Department d’Inge´nierie et d’Etudes des prote´ines, Gif Sur Yvette, FranceThe kynurenine pathway is the principal metabolic route forcatabolism of tryptophan. Several intermediates of the path-way are active at central neurotransmitter sites, for example,the NMDA receptor agonist quinolinic acid and the gluta-mate receptor antagonist kynurenic acid. The latter is mainlysynthesized in rat brain astrocytes by kynurenine aminotrans-ferase and is released into the immediate vicinity of gluta-matergic synapses to possibly reduce the neurotoxic effectsof excitatory amino acid (Guidetti et al. 1995, 2007; Ceresoliet al. 1997). These findings raised the possibility that thekynurenine pathway and the metabolites of tryptophan couldbe involved in various neuroregulatory and neuropatholo-gical phenomenon in the CNS (Stone and Darlington 2002).Xanthurenic acid (Xa) is one metabolite of this kynureninepathway and could be considered as the parent compound ofkynurenic acid. Indoleamine 2,3 dioxygenase which ispresent in the brain transforms tryptophan into kynureninethat is either transaminated into kynurenic acid by kynure-nine aminotransferase or hydroxylated into 3-hydroxykynur-enine by kynurenine 3-hydroxylase. Transamination of3-hydroxykynurenine leads to xanthurenic acid (Fig. 1).The latter pathway is generally considered to be part of adetoxification process that reduces the concentration of 3-hydroxykynurenine because spontaneous oxidation of thissubstance induces free radical generation and apoptosis, bothin vitro and in vivo (Okuda et al. 1996; Wei et al. 2000).However, a transaminase specific for 3-hydroxykynureninehas not been identified in man. In mammals, it is generallythought that 3-hydroxykynurenine is transformed to Xa bythe same kynurenine transaminase isoenzymes that catalyzethe transamination of kynurenine to kynurenic acid (Urenjakand Obrenovitch 2000).