Regulation of cerebral kynurenine and 5-hydroxyindole pathways during tryptophan loading

Cerebral tryptophan metabolism was studied in rat brain slices. The results show that serotonin production was inhibited at high levels of tryptophan or 5-oxo-L-prolyltryptophan. In contrast, kynurenine formation showed a dose dependent increase at the various concentrations of tryptophan or 5-oxo-L-prolyltryptophan. Measurements of the activities of Tryptophan Hydroxylase (TH) and indoleamine 2,3-dioxygenase (IDOase) in crude brain homogenates showed that serotonin formation was linear in the presence of dithiothreitol, whereas kynurenine production was inhibited in the presence of dithiothreitol or superoxide dismutase. These results suggest an inverse relationship in the regulation of 5-hydroxyindole and kynurenine pathways. The former being inhibited in the presence of high tryptophan concentration while the latter is enhanced. Furthermore, a high intracellular thiol-disulphide ratio appears to favour serotonin formation, whereas a highly reducing environment decreases kynurenine production.