Presence of 3‐Hydroxyanthranilic Acid in Rat Tissues and Evidence for Its Production from Anthranilic Acid in the Brain

Abstract

As assessed by HPLC with electrochemical detection, 3-hydroxyanthranilic acid (3-HANA) was found to be present in the rat brain and peripheral organs. The highest concentrations were measured in the kidney (86 fmol/mg of tissue) and spleen (56 fmol/mg of tissue), whereas the adrenal gland, liver, heart, and several forebrain areas (hippocampus, striatum, parietal cortex, thalamus, amygdala/pyriform cortex, and frontal cortex) contained less 3-HANA (between 15 and 22 fmol/mg of tissue). Slightly lower concentrations of 3-HANA were found in the brainstem and the cerebellum. The metabolic disposition of 3-HANA was examined in tissue slices which were incubated in Krebs-Ringer buffer at 37 degrees C in vitro. Incubation for up to 2 h did not affect 3-HANA concentration in brain tissue. However, inhibition of 3-HANA degradation by the specific 3-hydroxyanthranilic acid oxygenase blocker 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HANA; 10 microM) resulted in a rapid (within 2.5 min) doubling of 3-HANA levels in slices from cerebral cortex. No further increases were observed after incubations of up to 120 min. Exposure of cortical slices to 3-HANA's putative bioprecursors, 3-hydroxykynurenine (3-HK) and anthranilic acid (ANA), in the absence of 4-Cl-3-HANA resulted in rapid, transient increases in 3-HANA production. Maximal 3-HANA synthesis from ANA exceeded the maximal effect of 3-HK by approximately 11-fold.2+ In the presence of 4-Cl-3-HANA, 1 mM ANA produced 9.0 +/- 0.3 and 89.0 +/- 9.3 (5 min) or 51.6 +/- 7.9 and 187.5 +/- 11.2 (120 min) fmol of newly synthesized 3-HANA/mg of brain tissue, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Targeted Deletion of Kynurenine 3-Monooxygenase in Mice

“…4, 5, and 7). Thus, in stark contrast to the periphery, anthranilic acid is far superior to 3-HK as a bioprecursor of 3-hydroxyanthranilic acid in the brain (48) and should therefore be much better suited to sustain cerebral QUIN levels when 3-HK formation is compromised. Our results also may indicate that the anthranilic acid branch of KP metabolism is the minor pathway for kynurenine catabolism in all tissues.…”

Kynurenines with Neuroactive and Redox Properties: Relevance to Aging and Brain Diseases

“…This metabolite (1.25–5 mM) has an effect, in a dose-dependent way, on the respiratory parameters: it dropped state III and respiratory control index using 5 mM glutamate/malate as respiratory substrates. On the other hand, no effect was seen in the presence of succinate or NADH as substrates [86, 135]. These contradictory effects found for ANA can be due to its capability to produce hydroxyl radicals to the 3-HA metabolite, considering that ANA is a substrate to produce it.…”

3-Hydroxyanthranilic Acid Is an Efficient, Cell-derived Co-antioxidant for α-Tocopherol, Inhibiting Human Low Density Lipoprotein and Plasma Lipid Peroxidation

“…In contrast, 3HAA is not present at significant levels under normal conditions. However, 3HAA and 3-hydroxykynurenine and other tryptophan metabolites along the kynurenine pathway are detected in experimental animals and humans under inflammatory conditions (40,(45)(46)(47). 3HAA is produced and released by human monocytes/macrophages, and IFN␥ is the principal inducer of tryptophan degradation along the kynurenine pathway via induction of indoleamine 2,3-dioxygenase (IDO).…”