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Xanthurenic acid 8-glucoside is a side metabolite of the tryptophan-xanthommatin pathway in Drosophila. From 3-hydroxykynurenine, two biosynthetic pathways can be envisaged, one via xanthurenic acid, and another via 3-O-glucoside of 3-hydroxykynurenine. In this report evidence is presented to show that the synthesis takes place via xanthurenic acid. (a) We have demonstrated that the Drosophila melanogaster vermilion purple mutant (unable to synthesize 3-hydroxykynurenine) synthesizes xanthurenic acid 8-glucoside when fed with xanthurenic acid; and (b) the activities required for its synthesis via xanthurenic acid have been found (3-hydroxykynurenine transaminase and xanthurenic acid:UDP-glucosyltransferase). This is the first time that a UDP-glucosyltransferase activity that utilizes xanthurenic acid has been demonstrated. The enzyme in crude extracts from Drosophila sordidula shows the following characteristics. (a) It has optimal activity at 35 degrees C at pH 7.1 (in buffer Tris-HCl), and in the presence of a divalent cation (Mg2+ or Mn2+); (b) the activity is inhibited by xanthurenic acid (above 1.5 mM), UDP, D-gluconic acid 1,5-lactone, and Triton X-100; (c) it is localized in both the microsomal and the soluble fractions; (d) the specific activity is two times higher in heads than in bodies; and (e) the activity is enhanced in flies fed with phenobarbital.

An unknown fluorescent metabolite has been isolated from heads of eye-color mutants of Drosophila melanogaster. Only a few mutations cause it to accumulate, viz. cardinal (cd), dark red brown (drb), Henna-recessive (Hnr), purple (pr), Punch2 (Pu2), Punch-Grape (PuGr), and scarlet (st). After purification by ion-exchange chromatography, the spectroscopic, chemical, and enzymatic analyses revealed that it is a novel quinoline derivative: xanthurenic acid 8-O-beta-D-glucoside. Feeding experiments suggest that this glucoside is synthesized from 3-hydroxykynurenine and that free xanthurenic acid is not a precursor. The results from the analysis for its occurrence in double mutants, together with the fact that xanthurenic acid 8-glucoside share the same precursor as xanthurenic acid and xanthommatin, suggest that xanthurenic acid 8-glucoside formation is closely related to the regulation of the last step in the biosynthesis of xanthommatin.

Tryptophan degradation in mice initiated by indoleamine 2,3-dioxygenase was characterized, taking advantage of its induction by bacterial lipopolysaccharide. Our results demonstrated that in various tissues, N-formylkynurenine produced by the dioxygenase from tryptophan was rapidly hydrolyzed into kynurenine by a kynurenine formamidase, but it was not further metabolized. The localization in the liver and kidney of the kynurenine-metabolizing enzymes suggested that kynurenine thus formed was transported by the bloodstream to those two organs to be metabolized. In fact, the plasma kynurenine level increased in parallel with the induction of the dioxygenase by lipopolysaccharide, and kinetic analysis indicated that at the maximal induction of the enzyme there was a 3-fold increase in the kynurenine production. The major metabolic route of kynurenine was excretion in urine as xanthurenic acid. This increase in the kynurenine production was not explained by L-tryptophan 2,3-dioxygenase in the liver, because during the induction of indoleamine 2,3-dioxygenase, the hepatic enzyme level was substantially suppressed. These findings indicated that indoleamine 2,3-dioxygenase actively oxidized tryptophan in mice and that its induction resulted in an increase in tryptophan degradation.

The metabolism of orally administered 8-methyl ether of xanthurenic acid-carboxy-14C and methoxy-14C was studied in rabbits. There was no evidence for decarboxylation of the 8-methyl ether of xanthurenic acid-carboxy-14C. However, rabbits O-demethylated nearly 20% of administered 8-methyl ether of xanthurenic acid-methoxy-14C, giving rise to 14CO2. This O-demethylation was accompanied by the presence of xanthurenic acid and its further metabolites, 8-hydroxyquinaldic acid and an 8-hydroxyquinaldic acid conjugate, in urine samples from rabbits receiving the 8-methyl ether of xanthurenic acid-carboxy-14C. The 8-methyl ether of xanthurenic acid-carboxy-14C and methoxy-14C were dehydroxylated in rabbits, as are xanthurenic acid and kynurenic acid, giving rise to a small amount of urinary 8-methoxyquinaldic acid. Thus, dehydroxylation represents a significant metabolic pathway for all 4-hydroxyquinoline-2-carboxylic acid derivatives studied to date. Pretreatment of rabbits with oral Neomycin sulfate in amounts sufficient to inhibit the multiplication of gastrointestinal microorganisms severely inhibited the O-demethylation and dehydroxylation of the 8-methyl ether of xanthurenic acid in rabbits. These results suggest that all further metabolism of the 8-methyl ether of xanthurenic acid in rabbits is mediated by or requires the presence of the gastrointestinal flora.

In a previous publication (1) the isolation of a green pigment from the urine of pyridoxine-deficient rats was described. The green pigment was shown to be the product of a reaction between ferric ammonium sulfate or other ferric salts and a compound whose nature was unknown. This compound has now been isolated in crystalline form. It is a yellow pigment and has been identified as xanthurenic acid.