Anthranilic acid conjugation

A note on the rapid conversion of fevo-kynurenine to anthranilic acid, and the conjugation of the latter with glucuronic acid by riboflavin-deficient rat-liver and rat-kidney slices, has recently appeared.148... 

Disposition in the Body. Readily absorbed after oral administration bioavailability about 60%. It is metabolised by hydroxyla-tion to V-(2-hydroxymethyl-3-chlorophenyl)anthranilic acid and V-(2-methyl-3-chloro-4-hydroxyphenyl)anthranilic acid, which are the major metabolites. About 50% of an oral dose is excreted in the urine in 48 hours mainly as glucuronide conjugates of the two hydroxylated metabolites. Less than 10% of a dose is excreted in the urine as unchanged drug or its glucuronide conjugate. Tolfenamic acid and its metabolites are excreted in the bile. 

Boyland and Williams (B18) loaded 10 normal controls with 10 g DL-tryptophan. In spite of the fact that it is essential to use L-tryptophan in studies of this type and although data on excretion of kynurenic and xanthurenic acids are lacking, at least 5% was recovered as increased kynurenine, 3-hydroxykynurenine, anthranilic acid, and 3-hydroxyan-thranilic acid, free and conjugated. It should be pointed out that in these studies only a low percentage of the ingested dose of tryptophan was found in the form of urinary metabolites. The remainder, approximately 93-94%, of the load could not be recovered. 

K18. Kotake, Y., and Nogami, K., Xanthurenic acid. XIII. EfiFect of 5-hydroxy-anthranilic acid on the formation and conjugating reaction of xanthurenic acid in albino rat. ]. Biochem. (Tokyo) 43, 437-443 (1956). 

Both anthranilic acid and hydroxyanthranilic acid can be formed from tryptophan in insect mutants, and both are conjugated with glycine to give substituted hippuric acids (796), whereas in plants or bacteria anthranilic acid tends to be conjugated as the /3-glucoside (848). 

In insects, glycine is the amino acid of choice for xenobiotic conjugation and glycine conjugates of a variety of substituted benzoic acids ( -aminobenzoic acid, -nitrobenzoic acid, salicylic acid and anthranilic acid) have been reported in the housefly (M-domestica), mosquito (Aedes sp.), locust (L. gregaria) and silkworm II. mori) (3,4,6,7,37). 

Fic. 1. Metabolism of tryptophan to serotonin (5-hydroxytryptamine) and niacin. Fyiidoxal phosphate (PLP) dependent reactions are indicated. Reactions not shown which may result in formation of products excreted in urine include the acetylation of liymuenine and 3-hydroxykynurenine, conjugation of anthranilic acid with glycine (to form o-aminohippuric acid) and with glucuronic acid, and the dehydroxylation of kynurenic acid and xanthurenic add to quinaldic add and 8-hydroxyquinaldic add, respectively. 

Nicotinic Add Metabolism. The sequence of reactions leading to the formation of pyridine compounds is of particular interest as a source of nicotinic acid. Nutritional, isotopic, and genetic experiments have all shown that tryptophan and its metabolic derivatives including 3-hydroxy-anthranilic acid are precursors of nicotinic acid in animals and in Neuro-spora. The terminal steps in this sequence are not known. Under certain physiological conditions an increase in picolinic carboxylase appears to reduce nicotinic acid synthesis. This implies a common pathway as far as the oxidation of 3-hydroxyanthranilic acid. Whether quinolinic acid is a precursor of nicotinic acid is still uncertain. The enzyme that forms the amide of nicotinic acid also has not been isolated. Subsequent reactions of nicotinamide include the formation of the riboside with nucleoside phosphorylase and methylation by nicotinamide methyl-kinase. In animals W-methylnicotinamide is oxidized to the corresponding 6-pyridone by a liver flavoprotein. Nicotinic acid also forms glycine and ornithine conjugates. Both aerobic and anaerobic bacteria have been found to oxidize nicotinic acid in the 6-position. ... 

The absorption spectra of the copolymers exhibit two major absorption bands at 312-321 nm and 640 nm. These are reported to be due to the n-n transition associated with the conjugation of phenyl rings, and the intrachain/interchain exciton transition, respectively (Figure 20.51). The latter band is blue shifted upon increasing the anthranilic acid content, from which it is inferred that steric effects due to the presence of pendent carboxylic acid perturbs the 7r-electron system and lowers the degree of conjugation. 

Role of Riboflavin. Riboflavin deficiency has been found to produce abnormaUties in the metabolism of tryptophan (307-311). The deficiency leads to an increased excretion in the urine of kynurenine, anthranilic acid, and kynurenic acid and its conjugates (308, 309). In liver and kidney slices riboflavin deficiency leads to a decrease in indolepyruvic acid accumulation and an increase in the production of kynurenic acid and anthranilic acid from L-kynurenine (310, 311). The deficiency was also found to... 

Mehler (69) has found that compound I can be decarboxylated to yield picolinic acid [reactions (Ilb) and (Illb), Fig. 2]. The formation of this pyridine derivative appears to take place in two steps with the formation of an open chain unsaturated aldehyde as an intermediate. Mehler s enzyme is specific with respect to the formation of picolinic acid and does not promote the conversion of compound I to nicotinic acid and does not decarboxylate quinolinic acid. Picolinic acid is not present in urine in large amounts following 3-hydroxyanthranilate injection (28). However, the glycine conjugate, picolinuric acid, appears to be excreted when the anthranilic acid is administered (70). 

The photochemical behavior of anthranils in acid solution is more complex. In general, mixtures of 3- and 5-substituted 2-aminoacylbenzenes are formed by conjugate addition of the acid to the initially formed resonance-stabilized nitrenium ion as outlined in Scheme 21 for 5-substitution (generally the major product).225,226... 

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