Disease relevance of Hydroxykynurenine

• 3-Hydroxykynurenine (3-HK) is a potential endogenous neurotoxin whose increased levels have been described in several neurodegenerative disorders [1].
• We have studied neurotoxicity induced by pharmacological concentrations of 3-hydroxykynurenine (3-HK), an endogenous toxin implicated in certain neurodegenerative diseases, in cerebellar granule cells, PC12 pheochromocytoma cells, and GT1-7 hypothalamic neurosecretory cells [2].
• Such an amphiphilic nitrone protected human neuroblastoma cells at low micromolar concentrations against oxidative damage and death induced by exposure to the beta-amyloid peptide, hydrogen peroxide and 3-hydroxykynurenine [3].
• KAT catalyses the transamination of kynurenine and 3-hydroxykynurenine to kynurenic acid and xanthurenic acid respectively, and the enzyme activity can be easily detected in E. coli cells [4].
• The results show that cells of the immune system are responsible for the increased formation of 3-hydroxykynurenine and quinolinic acid, two neurotoxic metabolites that accumulate in the central nervous system of rats with experimental allergic encephalomyelitis [5].

Psychiatry related information on Hydroxykynurenine

• Increased brain 3-hydroxykynurenine in Huntington's disease [6].
• 3-Hydroxykynurenine was substantially and significantly increased in all three brain areas studied in Huntington's disease, but not significantly increased in the cortex in Alzheimer's disease, when compared to matched controls [7].
• Age-dependent memory loss, synaptic pathology and altered brain plasticity in the Drosophila mutant cardinal accumulating 3-hydroxykynurenine [8].

High impact information on Hydroxykynurenine

• Excretion of 3-hydroxykynurenine and 3-hydroxyanthranilic acid was elevated above control levels in capuchin monkeys infected experimentally with S. haematobium [9].
• Hydrogen peroxide-mediated neuronal cell death induced by an endogenous neurotoxin, 3-hydroxykynurenine [10].
• After 30 min, about 70% of the radioactive compounds in the pancreas was unmetabolized 3-hydroxykynurenine, whereas most of the radioactivity in the kidneys, liver, lung, and submaxillary glands was derived from the other compounds [11].
• Kynurenine and 3-hydroxykynurenine inhibit cysteine conjugate beta-lyase activity [12].
• Thus, 3-hydroxykynurenine promotes the oxidation and modification of crystallins and may contribute to oxidative stress in the human lens [13].

Chemical compound and disease context of Hydroxykynurenine

• 3-Hydroxykynurenine, a tryptophan metabolite, is known to be potential neurotoxic in some neurodegenerative disorders [14].
• The concentration of CSF kynurenic acid (KYA) and 3-hydroxykynurenine (3-OHKY) in infantile spasms was analyzed by high-performance liquid chromatography and compared with CSF KYA from 10 age-matched controls [15].
• Beside methylmercury-cysteine conjugate, amino acid-related neurotoxins such as beta-N-methylamino-L-alanine, S-(1,2-dichlorovinyl)-L-cysteine and 3-hydroxykynurenine are proposed to pass through system L transporters to exert their toxicity [16].
• Of these, five were derived from tryptophan; namely hydroxytryptophan, N-formylkynurenine, kynurenine, residues consistent with the dehydration of kynurenine, and hydroxykynurenine, while three were derived from tyrosine; namely dihydroxyphenylalanine, dityrosine, and a cross-linked residue consistent with a hydroxylated dityrosine residue [17].

Biological context of Hydroxykynurenine

• Neuronal apoptosis induced by pharmacological concentrations of 3-hydroxykynurenine: characterization and protection by dantrolene and Bcl-2 overexpression [2].
• Similar posttranslational modifications of lens proteins accompany cataract formation, and knowledge of the precise mode of reaction of 3-hydroxykynurenine with proteins will assist in determining if 3-hydroxykynurenine is involved in degenerative conditions in which oxidation of such aminophenols is implicated [18].
• In the late phase of acute PM, we found a significant transcriptional upregulation of kynurenine-3-hydroxylase and an accumulation of the neurotoxic metabolites 3-hydroxykynurenine (3-HKYN) and 3-hydroxyanthranilic acid in cortex and hippocampus [19].
• It is likely this novel UV filter is formed in the lens by nucleophilic attack of cysteine on the unsaturated ketone derived from deamination of 3-hydroxykynurenine O-beta-d-glucoside [20].
• This study describes the comparative analysis of two insect recombinant aminotransferases, Aedes aegypti 3-hydroxykynurenine (3-HK) transaminase/alanine glyoxylate aminotransferase (Ae-HKT/AGT) and Drosophila melanogaster serine pyruvate aminotransferase (Dm-Spat), which share 52% identity in their amino acid sequences [21].

Anatomical context of Hydroxykynurenine

• As a consequence of this increase, the spinal cord content of 3-hydroxykynurenine and quinolinic acid reached neurotoxic levels [5].
• However, the activity in the Malpighian tubules mostly depended on 3-hydroxykynurenine [22].
• Inhibition of creatine kinase activity from rat cerebral cortex by 3-hydroxykynurenine [14].
• Cytotoxicity of 3-hydroxykynurenine in a neuronal hybrid cell line [23].
• Uptake of 3-hydroxykynurenine measured in rat brain slices and in a neuronal cell line [24].

Associations of Hydroxykynurenine with other chemical compounds

• In plasma, L-tryptophan and kynurenic acid levels were reduced by pokeweed mitogen, while the concentrations of L-kynurenine, 3-hydroxykynurenine and quinolinic acid were increased [25].
• These cells (most probably macrophages) were responsible for the large increase in 3-hydroxykynurenine and quinolinic acid found in the spinal cords of affected animals [5].
• The kynurenine pathway metabolites kynurenine, 3-hydroxykynurenine and xanthurenic acid have been tested against 5-hydroxytryptamine (5-HT) and 5-hydroxytryptophan (5-HTP)-induced head twitches in the mouse in a dose-range of 0.5--5.0 mg/kg [26].
• This study investigated the in vitro effect of 3-hydroxykynurenine on creatine kinase activity in the brain cortex of rats [14].
• At 9 h and 24 h, increases in L-tryptophan metabolites in cerebral cortex were: L-tryptophan, 42% and 39%; 5-hydroxyindoleacetic acid, 38% and 67%; 3-hydroxykynurenine, 235% and 381%; and quinolinic acid, 76% and 306% [27].

Gene context of Hydroxykynurenine

• Mitogen-activated protein kinase/extracellular signal-regulated kinase attenuates 3-hydroxykynurenine-induced neuronal cell death [28].
• In MRC-9 cells, quinolinate was produced only from 3-hydroxykynurenine and 3-hydroxyanthranilate, consistent with their low kynurenine 3-hydroxylase activity [29].
• Finally, expression of a long terminal repeat of the human immunodeficiency virus (HIV-LTR)-driven luciferase reporter gene, controlled by NF-kappa B activation, was severely decreased by OH-AA or 3-hydroxykynurenine in J.Jhan5-1 cells [30].
• Here we demonstrate that the levels of two of these metabolites, the free radical generator 3-hydroxykynurenine (3HK) and the neuroprotectant kynurenate (KYNA), are increased in the neostriatum of stage 1 HD patients and in the brain of mice transgenic for full-length mutant huntingtin [31].
• 3-Hydroxykynurenine in the presence of tyrosinase at pH 6.0 leads to formation of xanthommatin, and at pH 8.0 hydroxanthommatin is formed in the first step of the reaction followed by formation of black-brown pigments [32].

Analytical, diagnostic and therapeutic context of Hydroxykynurenine

• Quantification of 3-hydroxykynurenine in brain by high-performance liquid chromatography and electrochemical detection [33].
• An investigation on the role of 3-hydroxykynurenine in pigment formation by matrix-assisted laser desorption/ionization mass spectrometry [32].
• The amount of water produced in the reaction, as calculated from the tritium released, was stoichiometric with the 3-hydroxykynurenine product detected by HPLC [34].
• The fluorescent substance formed from 3-hydroxykynurenine was characterized by thin-layer chromatography followed by reaction with ninhydrin, UV and fluorescence spectrum analysis, and atom bombardment for molecular mass determination [35].
• A pulse radiolysis study of the reactions of 3-hydroxykynurenine and kynurenine with oxidizing and reducing radicals [36].

References