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PubMed1993

Characterization of human brain kynurenine aminotransferases using [3H]kynurenine as a substrate.

The brain metabolite kynurenic acid is an established broad-spectrum antagonist at ionotropic excitatory amino acid receptors. In the human brain, two distinct enzymes are capable of synthesizing kynurenic acid from its bioprecursor L-kynurenine. Using [3H]kynurenine as the substrate, the two kynurenine aminotransferases (kynurenine aminotransferase I and kynurenine aminotransferase II) are now characterized using partially purified enzyme preparations. When assayed at its pH optimum of 10.0, kynurenine aminotransferase I showed pronounced oxo acid specificity (pyruvate >> 2-oxoglutarate). This co-substrate selectivity was lost when assays were performed at pH 7.4. Kynurenine aminotransferase I activity was potently inhibited by 2 mM glutamine, tryptophan or phenylalanine, but not by 2 mM alpha-aminoadipate or glutamate. In contrast to kynurenine aminotransferase I, kynurenine aminotransferase II showed a shallow pH curve with an optimum of about 7.4, displayed virtually equal activity with all of the nine 2-oxo acids tested and was not susceptible to inhibition by any of 10 amino acids (2 mM) which are known to serve as substrates for enzymatic transamination. Kinetic analyses, performed at pH 7.4 (kynurenine aminotransferases I and II) and 10.0 (kynurenine aminotransferase I), and using various concentrations of kynurenine, pyruvate or 2-oxoglutarate, respectively, substantiated the differences between the two enzymes and further elucidated the pH dependence of kynurenine aminotransferase I activity [apparent Km values for kynurenine with 1 mM 2-oxoglutarate: 515 microM (pH 7.4) and 22 microM (pH 10.0)]. Taken together, these data suggest that under physiological conditions, human brain kynurenic acid may derive preferentially from kynurenine aminotransferase II.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed2005

Effect of arylformamidase (kynurenine formamidase) gene inactivation in mice on enzymatic activity, kynurenine pathway metabolites and phenotype.

The gene coding for arylformamidase (Afmid, also known as kynurenine formamidase) was inactivated in mice through the removal of a shared bidirectional promoter region regulating expression of the Afmid and thymidine kinase (Tk) genes. Afmid/Tk -deficient mice are known to develop sclerosis of glomeruli and to have an abnormal immune system. Afmid-catalyzed hydrolysis of N-formyl-kynurenine is a key step in tryptophan metabolism and biosynthesis of kynurenine-derived products including kynurenic acid, quinolinic acid, nicotinamide, NAD, and NADP. A disruption of these pathways is implicated in neurotoxicity and immunotoxicity. In wild-type (WT) mice, Afmid-specific activity (as measured by formyl-kynurenine hydrolysis) was 2-fold higher in the liver than in the kidney. Formyl-kynurenine hydrolysis was reduced by approximately 50% in mice heterozygous (HZ) for Afmid/Tk and almost completely eliminated in Afmid/Tk knockout (KO) mice. However, there was 13% residual formyl-kynurenine hydrolysis in the kidney of KO mice, suggesting the existence of a formamidase other than Afmid. Liver and kidney levels of nicotinamide plus NAD/NADP remained the same in WT, HZ and KO mice. Plasma concentrations of formyl-kynurenine, kynurenine, and kynurenic acid were elevated in KO mice (but not HZ mice) relative to WT mice, further suggesting that there must be enzymes other than Afmid (possibly in the kidney) capable of metabolizing formyl-kynurenine into kynurenine. Gradual kidney deterioration and subsequent failure in KO mice is consistent with high levels of tissue-specific Afmid expression in the kidney of WT but not KO mice. On this basis, the most significant function of the kynurenine pathway and Afmid in mice may be in eliminating toxic metabolites and to a lesser extent in providing intermediates for other processes.

Animals↗

PubMed1999

Labeled kynurenine pharmacokinetic modeling studies in gerbils. Nonequilibrium between infused and endogenous kynurenine.

In order to complete pharmacokinetic studies on the central vs. peripheral origin of several tryptophan metabolites, we infused gerbils with labelled kynurenine (2H4 or 15N2). Osmotic minipumps charged with kynurenine solutions were surgically implanted subcutaneously in adult female gerbils (50-60 g). After a variable number of hours, the gerbils were sacrificed and organs taken for determination of labelled/unlabelled kynurenine ratios using mass spectrometric assay of a pentafluorobenzyl derivative as described previously. Surprisingly high ratios of 2H to 1H-kynurenine were measured in the kidney (0.25-0.40) and urine (4.0-8.0), although the ratio of deuterium labelled to endogenous kynurenine remained below detection limits (< 0.05) in serum and other tissues. Infusion of greater quantities of 2H4-kynurenine confirmed these observations in gerbils in which ratios of 2H4-to-1H kynurenine were measurable in serum and tissues. Synthesis and infusion of 15N2-kynurenine demonstrated that these effects were not due to deuterium isotope substitution. The data demonstrate a non-equilibrium between infused and endogenous kynurenine, which is related to differential rates of protein binding and the rapid clearance of free, infused kynurenine by kidney.

Animals↗

PubMed2001

Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolites increase in the spinal cord of rats with experimental allergic encephalomyelitis.

Kynurenine 3-mono-oxygenase, one of the key enzymes of the "kynurenine pathway", catalyses the formation of 3-hydroxykynurenine and may direct the neo-synthesis of quinolinic and kynurenic acids. While 3-hydroxykynurenine and quinolinic acid have neurotoxic properties, kynurenic acid antagonizes excitotoxic neuronal death. Here we report that the expression and activity of kynurenine 3-mono-oxygenase significantly increased in the spinal cord of rats with experimental allergic encephalopathy, an experimental model of multiple sclerosis. As a consequence of this increase, the spinal cord content of 3-hydroxykynurenine and quinolinic acid reached neurotoxic levels. We also report that systemic administration of Ro 61-8048, a selective kynurenine 3-mono-oxygenase inhibitor, reduced the increase of both 3-hydroxykynurenine and quinolinic acid, and caused accumulation of kynurenic acid. In the brain and spinal cord of the controls, kynurenine 3-mono-oxygenase immunoreactivity was located in granules (probably mitochondria) present in the cytoplasm of both neurons and astroglial cells. In the spinal cord of rats with experimental allergic encephalopathy, however, cells with a very intense kynurenine 3-mono-oxygenase immunoreactivity, also able to express class II major histocompatibility complex and inducible nitric oxide synthase, were found in perivascular, subependymal and subpial locations. 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. 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. They also demonstrate that selective kynurenine 3-mono-oxygenase inhibitors reduce the neo-synthesis of these toxins.

Animals↗

PubMed1996

Kynurenine disposition in blood and brain of mice: effects of selective inhibitors of kynurenine hydroxylase and of kynureninase.

To study the regulation of the synthesis of quinolinic and kynurenic acids in vivo, we evaluated (a) the metabolism of administered kynurenine by measuring the content of its main metabolites 3-hydroxykynurenine, anthranilic acid, and 3-hydroxyanthranilic acid in blood and brain of mice; (b) the effects of (m-nitrobenzoyl)alanine, a selective inhibitor of kynurenine hydroxylase and of (o-methoxybenzoyl) alanine, a selective inhibitor of kynureninase, on this metabolism; and (c) the effects of (o-methoxybenzoyl)alanine on liver kynureninase and 3-hydroxykynureninase activity. The conclusions drawn from these experiments are (a) the disposition of administered kynurenine preferentially occurs through hydroxylation in brain and through hydrolysis in peripheral tissues; (b) (m-nitrobenzoyl)alanine, the inhibitor of kynurenine hydroxylase, causes the expected changes in brain kynurenine metabolism, such as a decrease of 3-hydroxykynurenine, and an increase of kynurenic acid; and (c) (o-methoxybenzoyl)alanine, the kynureninase inhibitor, increases brain concentration of the cytotoxic compound 3-hydroxykynurenine, and unexpectedly does not reduce brain concentration of 3-hydroxyanthranilic acid, the direct precursor of quinolinic acid. Taken together, the experiments suggest that the systemic administration of a kynurenine hydroxylase inhibitor is a rational approach to increase the brain content of kynurenate and to decrease that of cytotoxic kynurenine metabolites, such as 3-hydroxykynurenine and quinolinic acid.

Alanine↗

PubMed2003

Peripheral distribution of kynurenine metabolites and activity of kynurenine pathway enzymes in renal failure.

We investigated L-kynurenine distribution and metabolism in rats with experimental chronic renal failure of various severity, induced by unilateral nephrectomy and partial removal of contralateral kidney cortex. In animals with renal insufficiency the plasma concentration and the content of L-tryptophan in homogenates of kidney, liver, lung, intestine and spleen were significantly decreased. These changes were accompanied by increase activity of liver tryptophan 2,3-dioxygenase, the rate-limiting enzyme of kynurenine pathway in rats, while indoleamine 2,3-dioxygenase activity was unchanged. Conversely, the plasma concentration and tissue content of L-kynurenine, 3-hydroxykynurenine, and anthranilic, kynurenic, xanthurenic and quinolinic acids in the kidney, liver, lung, intestine, spleen and muscles were increased. The accumulation of L-kynurenine and the products of its degradation was proportional to the severity of renal failure and correlated with the concentration of renal insufficiency marker, creatinine. Kynurenine aminotransferase, kynureninase and 3-hydroxyanthranilate-3,4-dioxygenase activity was diminished or unchanged, while the activity of kynurenine 3-hydroxylase was significantly increased. We conclude that chronic renal failure is associated with the accumulation of L-kynurenine metabolites, which may be involved in the pathogenesis of certain uremic syndromes.

3-Hydroxyanthranilate 3,4-Dioxygenase↗

PubMedDate not supplied

[The intracerebral route of kynurenine administration is one of the reasons for the resistance of kynurenine-induced seizures to diazepam].

It has been shown many times that in experiments on mice systemic administration of anticonvulsive doses of diazepam caused a 15-20-fold higher effect against the endogenous convulsant kynurenine (injection into the brain ventricles) than against corasol (systemic injection). In the present work diazepam (0.5-2.0 mg/kg, intraperitoneal injection) prevented convulsions induced in nonbred and C57B1/6 mice by equally effective doses of corasol injected subcutaneously (80 mg/kg) better than in injection into the brain ventricles (500 micrograms). In injection of the three drugs into the ventricles diazepam (0.5-10 micrograms) relieved to a similar degree convulsions induced by equally effective doses of corasol (500 micrograms) and kynurenine (50 micrograms). It follows from this that the unique resistance the kynurenine convulsions to diazepam is due to the fact that only kynurenine is injected into the brain ventricles whereas all the other convulsants compared with it are administered systemically. It is suggested that besides the route of administration, the more significant dependence of kynurenine convulsions on GAMA(B) receptors and the activity of the brain dopaminergic system is responsible for the difference in the diazepam sensitivity of kynurenine and corasol convulsions.

Animals↗

PubMed1994

Modulation of the kynurenine pathway in search for new neuroprotective agents. Synthesis and preliminary evaluation of (m-nitrobenzoyl)alanine, a potent inhibitor of kynurenine-3-hydroxylase.

The synthesis of (o-nitrobenzoyl)-, (m-nitrobenzoyl)-, and (p-nitrobenzoyl)alanine (o-, m-, and p-NBA), three new kynurenine analogues, and their evaluation as inhibitors of kynureninase and kynurenine-3-hydroxylase are reported. The most potent of these compounds, m-NBA, has an IC50 of 0.9 +/- 0.1 microM as an inhibitor of kynurenine-3-hydroxylase and of 100 +/- 12 microM as an inhibitor of kynureninase. When administered to rats, m-NBA significantly increases the concentration of kynurenine and kynurenic acid in the brain as well as in blood and in the liver. m-NBA has also been shown to increase the concentration of kynurenic acid in hippocampal extracellular fluid. This increase is associated with sedative and anticonvulsant activities, thus confirming the possibility of antagonizing L-glutamate-mediated effects by modulating the kynurenine pathway of L-tryptophan metabolism.

Alanine↗

PubMed1978

In vitro studies of the effect of metal ions, EDTA and their mixtures on kynurenine aminotransferase and kynurenine hydrolase.

In the present study use was made of the chelating ability of EDTA and the activating property of some metal ions Ca(II), Mg(II) or Mn(II) to counteract the inhibitory effect of Cu(II), Co(II), Pb(II) or Zn(II) ions on the B6-dependent kynurenine hydrolase and on kynurenine aminotransferase. These may be of help in studying the therapeutic trials in the treatment of metal poisoning. EDTA was able to counteract the inhibitory effect of Cu(II) or Co(II) on kynurenine aminotransferase and partially counteract the inhibitory effect of Cu(II), Co(II) on kynurenine aminotransferase and partially counteract the inhibitory effect of Cu(II), Co(II), Pb(II) or Zn(II) ions on kynurenine hydrolase. The difference in the response of the two B6-dependent enzymes to EDTA is attributed to the difference in the functional groups involved in the active site(s) of the two apoenzymes. Moreover, Mn(II), Ca(II) and Mg(II) ions have the ability to counteract some of the inhibitory effect of these metal ions.

Animals↗

PubMed2005

Localisation of indoleamine 2,3-dioxygenase and kynurenine hydroxylase in the human placenta and decidua: implications for role of the kynurenine pathway in pregnancy.

Indoleamine 2,3-dioxygenase (IDO) has been implicated in contributing to immunotolerance in early pregnancy, but the presence in the term placenta of mRNAs for enzymes that produce other biologically active kynurenine end-products suggests other functions for kynurenine pathway metabolites. The aim of this study was to investigate the localisation of two key enzymes - IDO and kynurenine hydroxylase (KYN-OHase) - in first trimester decidua and in the human placenta across pregnancy. Using immunocytochemistry, it was shown that there was strong expression of IDO and KYN-OHase in stromal and glandular epithelial cells of first trimester decidua. In first and second trimester placenta, IDO and KYN-OHase were localised to the syncytiotrophoblast, stroma and macrophages. IDO and KYN-OHase mRNAs were also identified, and the enzymes appear to be functional because kynurenine and 3-hydroxy-anthranilic acid (respective products of the activity of these enzyme) were released into the medium when first trimester placental explants were maintained in culture for 48h. In term placenta, both IDO and KYN-OHase immunoreactivities were confined mainly to vascular endothelial cells of villous blood vessels, and to macrophages within the fetal villus, whereas syncytial staining was very weak or absent. The shift of expression of these enzymes away from the syncytiotrophoblast to fetal endothelial cells in terminal villi suggests that the function of the enzymes may change from a role in immunosuppression at the maternal-fetal interface in early pregnancy, to one associated with regulation of fetoplacental blood flow or placental metabolism in late gestation.

Cells, Cultured↗

PubMed1975

Relationship between pyridoxal phosphate and some synthetic oestrogens, gonadotropin and thyroxine in their effects on kynurenine hydrolase and kynurenine aminotransferase enzymes of normal mouse liver.

The interrelationship between pyridoxal phosphate and gonadotropin and thyroxine in their effects on kynurenine metabolism was studied in the whole liver homogenates from male mice. These in vitro studies were planned to investigate the effects of these hormones on the vitamin B6-dependent enzymes, kynurenine aminotransferase and kynurenine hydrolase. It was found that gonadotropin (from serum of pregnant mares) inhibits both enzymes, whereas thyroxine inhibits the kynurenine aminotransaminase enzymes only. There was evidence indicating that pyridoxal phosphate was not the factor directly responsible for the observed inhibition. Increasing concentrations of pyridoxal phosphate were unable to counteract the inhibitory effects of these hormones.

Animals↗

PubMed1995

Metabolism of [5-3H]kynurenine in the rat brain in vivo: evidence for the existence of a functional kynurenine pathway.

The incorporation of tritium-label into quinolinic acid (QUIN), kynurenic acid (KYNA), and other kynurenine (KYN) pathway metabolites was studied in normal and QUIN-lesioned rat striata after a focal injection of [5-3H]KYN in vivo. The time course of metabolite accumulation was examined 15 min to 4 h after injection of [5-3H]KYN, and the concentration dependence of KYN metabolism was studied in rats killed 2 h after injection of 1.5-1,500 microM [5-3H]KYN. Labeled QUIN, KYNA, 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid, and xanthurenic acid (XA) were recovered from the striatum in every experiment. Following injection of 15 microM [5-3H]KYN, a lesion-induced increase in KYN metabolism was noted. Thus, the proportional recoveries of [3H]KYNA (5.0 vs. 1.8%), [3H]3-HK (20.9 vs. 4.5%), [3H]XA (1.5 vs. 0.4%), and [3H]QUIN (3.6 vs. 0.6%) were markedly elevated in the lesioned striatum. Increases in KYN metabolism in lesioned tissue were evident at all time points and KYN concentrations used. Lesion-induced increases of the activities of kynurenine-3-hydroxylase (3.6-fold), kynureninase (7.6-fold), kynurenine aminotransferase (1.8-fold), and 3-hydroxyanthranilic acid oxygenase (4.2-fold) likely contributed to the enhanced flux through the pathway in the lesioned striatum. These data provide evidence for the existence of a functional KYN pathway in the normal rat brain and for a substantial increase in flux after neuronal ablation. This method should be of value for in vivo studies of cerebral KYN pathway function and dysfunction.

Animals↗

PubMed1983

Effect of some xenobiotics on kynurenine hydrolase and kynurenine aminotransferase of mouse liver.

The effects of some xenobiotics on the activity of the B6-dependent kynurenine hydrolase (KH) and kynurenine aminotransferase (KATE) in mouse liver, were investigated. Polychlorinated biphenyl (Aroclor 1254) (400mg/kg/day x4) markedly decreased the activity of both enzymes. Benzo(a)pyrene (BP) and 3-methylcholanthrene (3-MC) (40mg/Kg/day x1) as well as phenobarbital (PB) (75mg/kg/day x3) did not alter the activity of KH, while that of KATE was mildy reduced. The response of the two enzymes to treatment with chlorpromazine (CPZ) (5mg/Kg/day x5) were opposite with marked elevation of KH and inhibition of KATE activities. Treatment with B-naphthoflavone (B-NF) (80mg/Kg/day x2), Pyrazole (200mg/Kg/day x1) or indole (400mg/kg/day x1) produce no change in the activity of either enzyme. It, seems therefore, that Aroclor (1254) and chlorpromazine may cause disordered kynurenine metabolism through alterations in the activities of its metabolizing enzymes. This, in turn, might affect nicotinamide adenine dinucleotide biosynthesis and/or the accumulation of some tryptophan metabolites suspected of being carcinogenic or co-carcinogenic.

Animals↗

PubMed1992

A radiometric assay for kynurenine 3-hydroxylase based on the release of 3H2O during hydroxylation of L-[3,5-3H]kynurenine.

A rapid and sensitive assay for kynurenine 3-hydroxylase (KH) has been developed. This radiometric assay is based on the enzymatic synthesis of tritiated water from L-[3,5-3H]kynurenine during the hydroxylation reaction. Radiolabeled water is quantified following selective adsorption of the isotopic substrate and its metabolite with activated charcoal. The assay is suitable for detecting 0.1 pmol enzyme activity per minute per milligram protein in tissues displaying low levels of the enzyme. The amount of water produced in the reaction, as calculated from the tritium released, was stoichiometric with the 3-hydroxykynurenine product detected by HPLC. Rat liver KH was characterized by cofactor specificity and kinetic parameters. NADPH was preferred over NADH as coreductant in the reaction. Tetrahydrobiopterin was not a cofactor. The tissue distribution of KH activity in the rat suggested that the majority of active enzyme is located in liver and kidney. Detectable amounts were found in several other tissues, including brain which had low but significant levels of activity in every region assayed.

Animals↗

PubMed1991

Measurement of rat brain kynurenine aminotransferase at physiological kynurenine concentrations.

The production of the neuroinhibitory and neuroprotective metabolite kynurenic acid (KYNA) was investigated in rat brain by examining its biosynthetic enzyme, kynurenine aminotransferase (KAT). By using physiological (low micromolar) concentrations of the substrate L-kynurenine (KYN) and by determining the irreversible conversion of [3H]KYN to [3H]KYNA as a measure of KAT activity, a novel, simple, and sensitive assay was developed which permitted the detailed characterization of the enzyme. Only a single protein, which under routine assay conditions showed approximately equal activity with 2-oxoglutarate and pyruvate as the aminoacceptor, was found in rat brain. The enzyme was distributed heterogeneously between the nine brain regions studied, with the KAT-rich olfactory bulb displaying approximately five times higher activity than the cerebellum, the area with lowest KAT activity. In subcellular fractionation studies, the majority of KAT was recovered in mitochondria. In contrast to many known aminotransferases, partially purified KAT was shown to be highly substrate-specific. Thus, of the amino acids tested, only alpha-aminoadipate and tryptophan displayed moderate competition with KYN. Notably, 3-hydroxykynurenine, reportedly a very good substrate of KAT, competed rather poorly with KYN as well. Aminooxyacetic acid, a nonspecific transaminase inhibitor, blocked KAT activity with an apparent Ki of 5 microM. Kinetic analyses with partially purified rat brain KAT revealed a Km of 17 microM for KYN with 1 mM 2-oxoglutarate, but a much higher Km (910 microM) with 1 mM pyruvate. Km values for 2-oxoglutarate and pyruvate were 150 and 160 microM, respectively. The cellular localization of KAT was examined in striatal homogenates obtained from rats 7 days after an intrastriatal injection of quinolinate.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗

PubMed1987

Photoinduced electron transfer reaction from N-formyl-L-kynurenine and L-kynurenine to cytochrome C.

The reduction of cytochrome c was found in the presence of N-formyl-L-kynurenine (NFK) and L-kynurenine (KN) during irradiation, suggesting electron transfer to cytochrome c. The reaction occurred both under aerobic and anaerobic conditions. In the former case, oxygen molecules may act mainly as a quencher of excited NFK and KN, and superoxide anion produced by electron transfer may partially contribute to the reduction. The reaction proceeded via the excited triplet state of NFK and KN. The actual reductive chemical species might be an intermediate from excited state NFK or KN, which is assumed to be ketyl radical type species.

Aerobiosis↗

PubMed1977

Metabolism of 14C-labelled L-tryptophan, L-kynurenine and hydroxy-L-kynurenine in miners with scleroderma.

Six South African White miners were studied with the 2-g L-tryptophan load test and tracer doses of L-tryptophan-7a-14C, L-kynurenine-keto-14C and hydroxy-L-kynurenine-keto-14C. The breath 14CO2 and 14 urinary metabolities were measured. When they were compared with a previous study of American women with scleroderma, similar 14CO2 and tryptophan metabolite excretion patterns were observed in the data from the miners. The labelled quinolinic acid excretion was more significantly elevated in the South African miners' urine than in the urine of the American women. The data from both studies suggest that some patients with scleroderma have an altered step in the tryptophan metabolic pathway after hydroxy-anthranilic acid. What relationship exists between the induction of pulmonary silicosis and the subsequent development of scleroderma, requires additional human studies.

Carbon Dioxide↗

PubMed2003

Prognostic value of tryptophan load test followed by serum kynurenine determination. Its comparison with pyridoxal-5-phosphate, kynurenine, homocysteine and neopterin amounts.

Tryptophan load test followed by serum kynurenine determination at fasting state and after L-tryptophan loading, as well as serum pyridoxal-5-phosphate (P-5-P), homocysteine and neopterin concentrations at fasting state have been examined in 30 healthy individuals and 87 patients with coronary heart disease (CHD), verified by coronary angiography. Received results have shown that low serum P-5-P concentration as well as P-5-P deficiency identified by tryptophan load test have been found in 78% of CHD patients, while increased homocysteine concentration above 15 micromol/L in 31.8%, and elevated neopterin concentration above 8.7 nmol/L in 32.1% of cases. It allows to conclude that a lot of CHD patients have P-5-P deficiency. Moreover P-5-P deficiency is an earlier indicator of CHD than increased homocysteine level above 15 micromol/L. Elevated serum neopterin concentration above 8.7 nmol/L may be a marker of coronary disease activity rather than a marker of the presence of CHD.

Biomarkers↗