Formation of 5-hydroxykynurenine and 5-hydroxykynurenamine from 5-hydroxytryptophan in rabbit small intestine.
In order to clarify the role of indoleamine 2,3-dioxygenase [indole:oxygen 2,3-oxidoreductase (decyclizing), EC 1.13.11.17] in the metabolism of serotonin, DL-5-hydroxy[methylene-(14)C]tryptophan, a precursor of serotonin, was incubated with slices of rabbit ileum. Resulting metabolites were separated by DEAE-cellulose column and polyamide column chromatography and identified by various chromatographic techniques and enzymatic analysis. Metabolites obtained in significant amounts were serotonin, 5-hydroxyindoleacetic acid, 5-hydroxytryptophol, 5-hydroxykynurenine, 5-hydroxykynurenamine, and 4,6-dihydroxyquinoline, representing 13.2, 15.8, 7.0, 21.9, 1.3, and 2.6% of the total metabolites, respectively. The first three compounds were previously reported to be major metabolites produced from 5-hydroxytryptophan by the action of aromatic L-amino acid decarboxylase and monoamine oxidase, whereas the last three are formed by the cleavage of the indole ring by the action of indoleamine 2,3-dioxygenase. In the presence of pargyline, a monoamine oxidase inhibitor, the major metabolites obtained were serotonin, 5-hydroxykynurenine, and 5-hydroxykynurenamine, representing 29.6, 26.6, and 5.4% of the total metabolites, respectively. In the presence of RO4-4602, an aromatic amino acid decarboxylase inhibitor, 5-hydroxykynurenine was the sole major product. These results strongly suggest that the newly discovered metabolic pathway involving the cleavage of the indole ring of 5-hydroxytryptophan operates in vivo to a significant extent and that indoleamine 2,3-dioxygenase plays an important role in the regulation of serotonin levels in the small intestine of the rabbit.
D006916:5-Hydroxytryptophan / Q000378:metabolism*; D000818:Animals; D002250:Carbon Radioisotopes; D002855:Chromatography, Thin Layer; D004590:Electrophoresis, Paper; D007082:Ileum / Q000378:metabolism*; D007553:Isotope Labeling; D007735:Kynuramine / Q000031:analogs & derivatives / Q000096:biosynthesis*; D007737:Kynurenine / Q000031:analogs & derivatives* / Q000096:biosynthesis; D008297:Male; D011427:Propiophenones / Q000096:biosynthesis*; D011817:Rabbits
D002250:Carbon Radioisotopes; D011427:Propiophenones; D007737:Kynurenine; D007735:Kynuramine; C001402:5-hydroxykynuramine; C019420:5-hydroxykynurenine; D006916:5-Hydroxytryptophan