Metabolism of l‐Tryptophan to Kynurenate and Quinolinate in the Central Nervous System: Effects of 6‐Chlorotryptophan and 4‐Chloro‐3‐Hydroxyanthranilate

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.