2,3-ピリジンジカルボン酸

Crystals

Monoclinic crystals from water

Soluble in 180 parts water, in alkalies, slightly in alcohol. Almost insol in ether or benzene.

Slightly soluble in trifluoroacetic acid. Insoluble in ethanol.

In water, 1.1X10+4 mg/L at 25 °C

11.0 mg/mL

228.5 °C

190 °C

Dry Powder; Other Solid

Odorless solid; [Merck Index] White or light yellow powder; [MSDSonline]

Solid

2.43

pKa1 = 2.43 (conjugate acid)

130.03 Ų [M-H]- [CCS Type: DT; Method: stepped-field]

130.2 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

130.5 Ų [M+H-H2O]+ [CCS Type: DT; Method: single field calibrated with Agilent tune mix (Agilent)]

126.6 Ų [M-H]- [CCS Type: DT; Method: single field calibrated with ESI Low Concentration Tuning Mix (Agilent)]

134.9 Ų [M+H]+

Danger

H302 (12.8%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P264+P265, P270, P271, P280, P301+P317, P302+P352, P304+P340, P305+P351+P338, P305+P354+P338, P317, P319, P321, P330, P332+P317, P337+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 250 reports by companies from 13 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

2,3-Pyridinedicarboxylic acid is listed on the EPA's Chemical Data Reporting (CDR) system. Manufacturers and importers of 2,3-Pyridinedicarboxylic acid are required to report information about their production and use of this chemical to the EPA under the Toxic Substances Control Act (TSCA). (40 eCFR Part 711)

Status: Active Update: 22-04-2013 https://echa.europa.eu/registration-dossier/-/registered-dossier/7893

2,3-Pyridinedicarboxylic acid: Does not have an individual approval but may be used under an appropriate group standard

SRP: The most favorable course of action is to use an alternative chemical product with less inherent propensity for occupational exposure or environmental contamination. Recycle any unused portion of the material for its approved use or return it to the manufacturer or supplier. Ultimate disposal of the chemical must consider: the material's impact on air quality; potential migration in soil or water; effects on animal, aquatic, and plant life; and conformance with environmental and public health regulations.

...This work ... investigated the effect of a garlic-derived compound and well-characterized free radical scavenger, S-allylcysteine, on quinolinic acid-induced striatal neurotoxicity and oxidative damage. For this purpose, rats were administered S-allylcysteine (150, 300 or 450 mg/kg, i.p.) 30 min before a single striatal infusion of 1 uL of quinolinic acid (240 nmol). The lower dose (150 mg/kg) of S-allylcysteine resulted effective to prevent only the quinolinate-induced lipid peroxidation (P < 0.05), whereas the systemic administration of 300 mg/kg of this compound to rats decreased effectively the quinolinic acid-induced oxidative injury measured as striatal reactive oxygen species formation (P < 0.01) and lipid peroxidation (P < 0.05). S-Allylcysteine (300 mg/kg) also prevented the striatal decrease of copper/zinc-superoxide dismutase activity (P < 0.05) produced by quinolinate. In addition, S-allylcysteine, at the same dose tested, was able to reduce the quinolinic acid-induced neurotoxicity evaluated as circling behavior (P < 0.01) and striatal morphologic alterations. In summary, S-allylcysteine ameliorates the in vivo quinolinate striatal toxicity by a mechanism related to its ability to: (a) scavenge free radicals; (b) decrease oxidative stress; and (c) preserve the striatal activity of Cu,Zn-superoxide dismutase (Cu,Zn-SOD). This antioxidant effect seems to be responsible for the preservation of the morphological and functional integrity of the striatum.

... Oxidative damage to biomolecules was followed by measuring lipid peroxidation and protein carbonyl formation in rat brain tissue culture over a period of 24 hr of exposure to /quinolinic acid/ at a concentration of 0.5 millimeters. Quinolinic acid enhanced lipid peroxidation in an early stage of tissue culture, and protein carbonyl at a later stage. ... Melatonin, an antioxidant and neuroprotective agent with multiple actions as a radical scavenger and signaling molecule, completely prevented these prooxidant actions of quinolinic acid at a concentration of 1 millimeters. Morphological lesions and neurotoxicity induced by quinolinic acid were evaluated by light microscopy. Quinolinic acid produced extensive apoptosis/necrosis which was significantly attenuated by melatonin. Cotreatment with melatonin exerted a profound protective effect antagonizing the neurotoxicity induced by quinolinic acid. Glutathione reductase and catalase activities were increased by quinolinic acid and these effects were antagonized by melatonin. Furthermore, melatonin induced superoxide dismutase activity. Quinolinic acid and melatonin acted independently and by different mechanisms in modulating antioxidant enzyme activities.

The neuroprotective effect of melatonin against the quinolinic acid-induced degeneration of rat hippocampal neurons was investigated. Three groups of rats were given intrahippocampal injections of either; saline, quinolinic acid or ip injections of melatonin prior to and after being injected with quinolinic acid. On the fifth day after the intrahippocampal injections the brains were removed and the hippocampi either sectioned and stained for microscopic examination or used in glutamate receptor binding studies. The results show that melatonin protects hippocampal neurons from quinolinic acid-induced neurodegeneration and partially prevents the decrease in glutamate receptor numbers caused by quinolinic acid. Thus, melatonin has the potential to reduce hippocampal neuronal damage induced by neurotoxins such as quinolinic acid. PMID:9704893

To study the effects of the caspase-1 inhibitor Ac-YVAD-CHO on quinolinic acid (QA)-induced apoptosis ... rats were pre-treated with intrastriatal infusion of Ac-YVAD-CHO (2-8 ug) before intrastriatal injection of QA (60 nmol). Striatal total proteins, genomic DNA, and nuclear proteins were isolated. The effects of Ac-YVAD-CHO on QA-induced caspase-1 activity, internucleosomal DNA fragmentation, IkappaB-alpha degradation, NF-kappaB, and AP-1 activation, and increases in p53 protein levels were measured with enzyme assays, agarose gel electrophoresis, electrophoresis mobility shift assays, and Western blot analysis. ... Pretreatment with Ac-YVAD-CHO inhibited QA-induced internucleosomal DNA fragmentation. Ac-YVAD-CHO inhibited QA-induced increases in caspase-1 activity and p53 protein levels, but had no effect on QA-induced IkappaB-alpha degradation, NF-kappaB or AP-1 activation. /The authors concluded that/ caspase-1 is involved in QA-induced p53 upregulation but not IkappaB-alpha degradation. Inhibition of caspase-1 attenuates QA-induced apoptosis in rat striatum.

For more Interactions (Complete) data for QUINOLINIC ACID (31 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 26(SRC), determined from a water solubility of 1.1X10+4 mg/L(2) and a regression-derived equation(3), indicates that quinolinic acid is expected to have very high mobility in soil(SRC). A pKa1 of 2.43(4) and pKa2 of 5.48(5) indicate that this compound will primarily exist as a zwitterion in the environment and ions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(6). Quinolinic acid is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.1X10-6 mm Hg(SRC), determined from a fragment constant method(7). Quinolinic acid was 100% removed from soil after 8 days with 0.3% attributed to absorption and volatilization, respectively(8), suggesting that biodegradation is an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 26(SRC), determined from a water solubility of 1.10X10+4 mg/L(2) and a regression-derived equation(3), indicates that quinolinic acid is not expected to adsorb to suspended solids and sediment(SRC). A pKa1 of 2.43(4) and pKa2 of 5.48(5) indicate quinolinic acid will exist as a zwitterion at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(6). According to a classification scheme(7), an estimated BCF of 3(SRC), from its water solubility(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Quinolinic acid was 100% removed from soil after 8 days(8), suggesting that biodegradation is an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), quinolinic acid, which has an estimated vapor pressure of 6.1X10-6 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase quinolinic acid is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 15 days(SRC), calculated from its rate constant of 1.1X10-12 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Quinolinic acid contains chromophores that absorb at wavelengths >290 nm and therefore may be susceptible to direct photolysis by sunlight(4).

The Koc of quinolinic acid is estimated as 26(SRC), using a water solubility of 1.1X10+4 mg/L(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that quinolinic acid is expected to have very high mobility in soil. A pKa1 of 2.43(4) and a pka2 of 5.48(5) indicates that this compound will primarily exist as a zwitterion in the environment and ions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(6).

/SURVEILLANCE/ ... To evaluate the relationship between quinolinic acid, a neuroactive metabolite of L-tryptophan, and neuropsychiatric manifestations of systemic lupus erythematosus. ... 40 specimens of cerebrospinal fluid were obtained from 39 patients with systemic lupus erythematosus who were evaluated for 40 episodes of neuropsychiatric dysfunction. The diagnosis of the neuropsychiatric dysfunction was determined clinically. Cerebrospinal fluid and serum specimens were analyzed for levels of quinolinic acid without knowledge of the clinical diagnosis. ... Neuropsychiatric dysfunction attributed to systemic lupus erythematosus was confirmed in 30 patient-episodes (Group 1), whereas in the other 10 (Group 2) other etiologies were felt to explain their CNS dysfunction. The median levels of cerebrospinal fluid quinolinic acid for Group 1 (232.5 nmol/L) were significantly higher than those for Group 2 (median 38.2 nmol/L) (p < 0.014). Cerebrospinal fluid and serum quinolinic acid levels correlated significantly (p < 0.003) but there was no correlation between cerebrospinal fluid quinolinic acid and cerebrospinal fluid protein concentrations or white blood cell counts.

/SURVEILLANCE/ ... Quinolinic acid is a neurotoxic metabolite of the kynurenine pathway that accumulates within the central nervous system following immune activation. The present study determined whether the levels of quinolinic acid are increased in the cerebrospinal fluid of children with infections of the CNS, hydrocephalus, tumors or hemorrhage. Extremely high quinolinic acid concentrations were found in patients with bacterial infections or the CNS, despite treatment with antimicrobial agents. CSF quinolinic acid levels were also elevated to a lesser degree in patients with hydrocephalus or tumors. CSF L-kynurenine levels increased in parallel to the accumulations in quinolinic acid, which is consistent with increased activity of the first enzyme of the kynurenine pathway, indoleamine-2,3-dioxygenase. The CSF levels of neopterin, a marker of immune and macrophage activation, were also increase in patients with infections. The cytokines tumor necrosis factor-alpha and interleukin-6 were also detected in some patients' samples, and were highest in patients with infection. These results suggest that quinolinic acid is a sensitive marker of the presence of immune activation within the CNS. Further studies of quinolinic acid as a potential contributor to neurologic dysfunction and neurodegeneration in children with CNS inflammation are warranted.[Heyes MP et al; J Neurol Sci 133 (1-2): (1995)]

/ALTERNATIVE and IN VITRO TESTS/ Substantial increases in the tryptophan-kynurenine pathway metabolites, l-kynurenine and the neurotoxin quinolinic acid, occur in human brain, blood and systemic tissues during immune activation. Studies in vitro have shown that not all human cells are capable of synthesizing quinolinate. To investigate further the mechanisms that limit l-kynurenine and quinolinate production, the activities of kynurenine pathway enzymes and the ability of different human cells to convert pathway intermediates into quinolinate were compared. Stimulation with interferon gamma substantially increased indoleamine 2,3-dioxygenase activity and L-kynurenine production in primary peripheral blood macrophages and fetal brains (astrocytes and neurons), as well as cell lines derived from macrophage/monocytes (THP-1), U373MG astrocytoma, SKHEP1 liver and lung (MRC-9). High activities of kynurenine 3-hydroxylase, kynureninase or 3-hydroxyanthranilate 3,4-dioxygenase were found in interferon-gamma-stimulated macrophages, THP-1 cells and SKHEP1 cells, and these cells made large amounts of quinolinate when supplied with L-tryptophan, L-kynurenine, 3-hydroxykynurenine or 3-hydroxyanthranilate. Quinolinate production by human fetal brain cultures and U373MG cells was restricted by the low activities of kynurenine 3-hydroxylase, kynureninase and 3-hydroxyanthranilate 3,4-dioxygenase, and only small amounts of quinolinate were synthesized when cultures were supplied with L-tryptophan or 3-hydroxyanthranilate. In MRC-9 cells, quinolinate was produced only from 3-hydroxykynurenine and 3-hydroxyanthranilate, consistent with their low kynurenine 3-hydroxylase activity. The results are consistent with the notion that indoleamine 2,3-dioxygenase is an important regulatory enzyme in the production of L-kynurenine and quinolinate. Kynurenine 3-hydroxylase and, in some cells, kynureninase and 3-hydroxyanthranilate 3,4-dioxygenase are important determinants of whether a cell can make quinolinate.[Heyes MP et al; Biochem J 326 (Pt 2): 351-6 (1997)]

/ALTERNATIVE and IN VITRO TESTS/ ... Human fetal brain 14-16 weeks post-menses was cultured in medium with no detectable levels of quinolinic acid. After 4 weeks, 350 or 1200 nmol/L quinolinic acid was added to the feeding medium for a further 5 weeks. Neurotoxicity was evaluated using immunohistochemistry, transmission and scanning electron microscopy, and image analysis.... A total of 1200 nmol/L quinolinic acid caused altered cell associations, a decrease in cell density and decreased microtubule-associated protein (MAP)-2 immunoreactivity compared with cultures exposed to 350 nmol/L quinolinic acid or controls. Image analysis of neurons in randomly selected fields revealed significantly swollen cells (P < 0.0001) compared with those treated with 350 nmol/L quinolinic acid or controls. Dendritic varicosities and discontinuous microtubular arrays were present in neurons exposed to both quinolinic acid concentrations, but not in control cultures.... This study is the first to assess quinolinic acid levels in the experimental medium, and demonstrates that chronic exposure of human neurons to concentrations of quinolinic acid equivalent to those in the CSF of patients with AIDS dementia complex (ADC) leads to alterations in dendritic ultrastructure and MAP-2 immunoreactivity, which is consistent with ADC pathology.[Kerr SJ et al; Aids 12 (4): 355-63 (1998)]

For more Human Toxicity Excerpts (Complete) data for QUINOLINIC ACID (10 total), please visit the HSDB record page.

AEROBIC: Quinolinic acid, at a concn of 1 milli-Mole solution, underwent 100% biodegradation in 4 to 8 days when incubated in a 5 mL soil suspension consisting of 0.5% fertile garden soil, mineral salts, and maintained at pH 7(1). Quinolinic acid, starting concn of 54 ppm, was 100% degraded in 28 days using a soil inoculum at pH 7.0 and fortified with a basal salts medium(2). It was noted that 0.3% was sorbed by soil and less than 1% was lost due to volatilization(2). Using a Finecastle silt loam (Aeric Ochraqualfs) quinolinic acid, starting conc of 334 ppm, was 35.1, 96.2, 99.5 and 100% degraded after 1, 2, 4, and 8 days, respectively; samples were maintained at pH 6.7 and 25 °C with 11.3% loss from sterile control after 7 days due to volatilization noted(3).

ANAEROBIC: Quinolinic acid, at a concn of a 1 milli-Mole solution, underwent 100% biodegradation in 16 to 32 days when incubated in a 5 mL soil suspension consisting of 0.5% fertile garden soil, mineral salts, and maintained at pH 7(1).

An estimated BCF of 3 was calculated in fish for quinolinic acid(SRC), using a water solubility of 1.1X10+4 mg/L(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).

A pKa1 of 2.43(1) and a pKa2 of 5.48(2) indicate quinolinic acid will exist as a zwitterion at pH values of 5 to 9 and therefore volatilization from soil or water surfaces is not expected to be an important fate process. Quinolinic acid is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.1X10-6 mm Hg(SRC), determined from a fragment constant method(3).

/LABORATORY ANIMALS: Neurotoxicity/ Excitotoxin lesions induced by quinolinic acid were made unilaterally in the caudate nucleus and putamen of 12 rhesus monkeys. Both acute (2-3 weeks) and chronic (4-6 months) effects were evaluated. Excitotoxin striatal lesions were characterized by a central zone of intense astrogliosis and marked neuronal depletion, which was surrounded by a transition zone in which there was partial neuronal sparing throughout the entire lesioned side. Immunocytochemical and enzyme histochemical markers for both large and medium-sized aspiny- and spiny-striatal neurons clearly demonstrated a selective pattern of neuronal vulnerability to the excitotoxic effects of quinolinic acid within lesioned striata. Medium-sized spiny neurons containing calbindin Dk28, enkephalin, and substance P were disproportionately lost, while aspiny neuronal subpopulations containing NADPH diaphorase (NADPH-d) and choline acetyltransferase activity (ChAT) were relatively spared. Combined labeling by NADPH-d enzyme histochemistry and Nissl staining, as well as NADPH-d histochemistry and calbindin Dk28 immunocytochemistry, demonstrated significant increases in the ratio of aspiny to spiny neurons within the lesioned striata. Neurochemical measurements confirmed a loss of GABA and substance P-like immunoreactivity yet no significant depletion of somatostatin-like immunoreactivity, neuropeptide Y-like immunoreactivity, or ChAT were seen. The striatal patch-matrix pattern persisted, as demonstrated by acetylcholinesterase activity. The pattern was altered, however, in the chronic animals, such that the matrix zone was significantly reduced, while the total area of patches remained within normal limits. Ultrastructural analysis confirmed axon sparing lesions with neuronal loss and astrogliosis. Pretreatment of 3 monkeys with MK-801, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, blocked striatal quinolinic acid neurotoxicity. The present results provide an experimental primate model which closely resembles the neuropathologic and neurochemical features of Huntington's disease. These findings further strengthen the possibility that an NMDA receptor-mediated excitotoxic process plays a role in the pathogenesis of this disorder.[Ferrante RJ et al; Exp Neurol 119 (1): 46-71 (1993)]

/LABORATORY ANIMALS: Neurotoxicity/ Continuous infusion of quinolinic acid at low doses into the lateral ventricle has been previously shown to cause a reduction of the hippocampal and cortical ChAT activities in rats although GAD activities were unchanged. In the present study, we have studied behavioral changes in rats with continuous infusion of QA in an active avoidance task. Acquisition of active avoidance was significantly impaired in rats with QA infusion compared to control. These results suggest that continuous infusion of QA is a useful technique for the study of chronic neurodegenerative diseases associated with memory impairment.[Yamada K et al; J Pharmacobiodyn 14 (6): 351-5 (1991)]

/LABORATORY ANIMALS: Neurotoxicity/ ... In the present studies, cerebrospinal fluid quinolinic acid concentrations increased within 2 weeks following infection of 11 rhesus macaques (Macaca mulatta) with a neurotropic sooty mangabey isolate of the simian immunodeficiency virus (SIVsm) and were sustained to greater than 2 standard deviations above uninfected control macaques. Highest cerebrospinal fluid quinolinic acid concentrations (up to 400-fold above pre-inoculation levels) were observed in 6 SIVsm-infected macaques with motor and behavioral abnormalities during life, brain atrophy on MRI scan and inflammatory lesions within the brain and meninges. Four of the 6 neurologic macaques deteriorated rapidly within 12 weeks after inoculation and had substantially larger increases in cerebrospinal fluid quinolinic acid levels than 2 other neurologic macaques and 5 macaques without neurologic signs which survived for longer than 37 weeks. Increases in serum quinolinic acid and cerebrospinal fluid kynurenic acid also occurred but generally to a lesser degree than the increases in cerebrospinal fluid quinolinic acid. In some animals, increases in serum L-kynurenine concentrations and reductions in cerebrospinal fluid and serum L-tryptophan occurred and were consistent with activation of indoleamine-2, 3-dioxygenase, the first enzyme of the kynurenine pathway in extrahepatic tissues. cerebrospinal fluid quinolinic acid exceeded serum quinolinic acid in 8.8% of samples from macaques with neurologic signs, supporting increased quinolinic acid synthesis within the central nervous system. Production of [13C6]quinolinic acid was demonstrated in one SIVsm-infected macaque and one uninfected control macaque following an intracisternal injection of [13C6]L-tryptophan and suggests that L-tryptophan is a substrate for quinolinic acid synthesis within the nervous system or meninges, although the cellular localization of quinolinic acid synthesis remain to be determined.[Jordan EK et al; Brain Res 570 (1-2): 237-50 (1992)]

/LABORATORY ANIMALS: Neurotoxicity/ Huntington's disease is a hereditary neurodegenerative disorder presenting with chorea, dementia, and extensive striatal neuronal death. ... Transgenic Huntington's disease mice expressing exon 1 of a human Huntington's disease gene with an expanded number of CAG repeats (line R6/1) are strongly protected from acute striatal excitotoxic lesions. Intrastriatal infusions of the N-methyl-D-aspartate receptor agonist quinolinic acid caused massive striatal neuronal death in wild-type mice, but no damage in transgenic Huntington's disease littermates. The remarkable neuroprotection in transgenic Huntington's disease mice occurred at a stage when they had not developed any neurological symptoms caused by the mutant Huntington's disease gene. At this stage there was no change in the number of striatal neurons and astrocytes in untreated R6/1 mice, although the striatal volume was decreased by 17%. Moreover, transgenic Huntington's disease mice had normal striatal levels of N-methyl-D-aspartate receptors, calbindin D28k (calcium buffer), superoxide dismutase activity (antioxidant enzyme), Bcl-2 (anti-apoptotic protein), heat shock protein 70 (stress-induced anti-apoptotic protein), and citrate synthase activity (mitochondrial enzyme). /THe authors/ propose that the presence of exon 1 of the mutant Huntington's disease gene induces profound changes in striatal neurons that render these cells resistant to excessive N-methyl-D-aspartate receptor activation.[Hansson O et al; Proc Natl Acad Sci USA 96 (15): 8727-32 (1999)]

For more Non-Human Toxicity Excerpts (Complete) data for QUINOLINIC ACID (17 total), please visit the HSDB record page.

The rate constant for the vapor-phase reaction of quinolinic acid with photochemically-produced hydroxyl radicals has been estimated as 1.1X10-12 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 15 days at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Quinolinic acid is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Quinolinic acid does contain chromophores that absorb at wavelengths >290 nm and therefore may be susceptible to direct photolysis by sunlight(2).

Quinolinic acid's production and use in the production of the herbicide imazapyr and as an intermediate in the production of nicotinic acid may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 6.1X10-6 mm Hg at 25 °C indicates quinolinic acid will exist in both the vapor and particulate phases in the atmosphere. Vapor-phase quinolinic acid will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 15 days. Particulate-phase quinolinic acid will be removed from the atmosphere by wet or dry deposition. Quinolinic acid does contain chromophores that absorb at wavelengths >290 nm and therefore may be susceptible to direct photolysis by sunlight. If released to soil, quinolinic acid is expected to have very high mobility based upon an estimated Koc of 26. A pKa1 of 2.43 and pKa2 of 5.48 indicate that this compound will primarily exist as a zwitterion in the environment and ions generally do not adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts. Quinolinic acid was 100% removed from soil after 8 days with 0.3% attributed to absorption and volatilization, respectively, suggesting that biodegradation is an important environmental fate process in soil. If released into water, quinolinic acid is not expected to adsorb to suspended solids and sediment based upon the estimated Koc. The pKa1 and pKa2 values of 2.43 and 5.48, respectively, indicate quinolinic acid will exist almost entirely in the ion form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process. An estimated BCF of 3 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions. Occupational exposure to quinolinic acid may occur through inhalation and dermal contact with this compound at workplaces where quinolinic acid is produced or used. (SRC)

Huntington's disease is an autosomal dominant neurological disorder characterized by progressive chorea, cognitive impairment and emotional disturbance. The disease usually occurs in midlife and symptoms progress inexorably to mental and physical incapacitation. It has been postulated that an excitotoxin is involved in the pathogenesis of Huntington's disease. Schwarcz and colleagues have shown that quinolinic acid can produce axon-sparing lesions similar to those observed in Huntington's disease. The lesions result in a depletion of neurotransmitters contained within striatal spiny neurones, for example gamma-aminobutyric acid (GABA), while dopamine is unaffected. Recently, /several investigators/ ... demonstrated that in Huntington's disease striatum there is a paradoxical 3-5-fold increase in both somatostatin and neuropeptide Y which is attributable to selective preservation of a subclass of striatal aspiny neurones in which these peptides are co-localized. In the present study /the authors/ demonstrate that lesions due to quinolinic acid closely resemble those of Huntington's disease as they result in marked depletions of both GABA and substance P, with selective sparing of somatostatin/neuropeptide Y neurones. Lesions produced by kainic acid (KA), ibotenic acid (IA) and N-methyl-D-aspartate (MeAsp) were unlike those produced by quinolinic acid, as they affected all cell types without sparing somatostatin/neuropeptide Y neurones. These results suggest that quinolinic acid or a similar compound could be responsible for neuronal degeneration in Huntington's disease.

...To determine whether caspase cleavage of huntingtin is a key event in the neuronal dysfunction and selective neurodegeneration in Huntington's disease, /the authors/ generated YAC mice expressing caspase-3- and caspase-6-resistant mutant huntingtin. Mice expressing mutant huntingtin, resistant to cleavage by caspase-6 but not caspase-3, maintain normal neuronal function and do not develop striatal neurodegeneration. Furthermore, caspase-6-resistant mutant huntingtin mice are protected against neurotoxicity induced by multiple stressors including NMDA, quinolinic acid, and staurosporine. These results are consistent with proteolysis of huntingtin at the caspase-6 cleavage site being an important event in mediating neuronal dysfunction and neurodegeneration and highlight the significant role of huntingtin proteolysis and excitotoxicity in Huntington's disease.

... excitotoxic lesion of rat brain with the N-methyl-D-aspartate receptor agonist, quinolinic acid, induces expression of p53 messenger RNA and protein in brain regions showing delayed DNA fragmentation and that expression of p53 messenger RNA precedes DNA damage detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labelling. In addition, using in situ hybridization and immunocytochemistry we demonstrate increased expression of the p53-responsive gene Gadd-45 (preceding p53 expression) and re-expression of the p53-responsive gene Bax (following p53 expression), in these same areas. Bax has been shown to promote neuronal death by interacting with Bcl-2 family members while Gadd-45 expression has been associated with suppression of the cell-cycle and DNA repair. These results suggest that p53 protein may function as an active transcription factor in lesioned brain perhaps initiating the re-expression of Bax in injured brain regions. However, since Gadd-45 precedes p53 expression it appears unlikely that p53 is involved in regulating the early expression of Gadd-45. Taken together however, these results suggest that p53, Bax and Gadd-45 may play important roles in the response (damage/recovery) of the brain following excitotoxic injury.

The kynurenine pathway is a major route of L-tryptophan catabolism leading to production of a number of biologically active molecules. Among them, the neurotoxin quinolinic acid, is considered to be involved in the pathogenesis of a number of inflammatory neurological diseases. ... Most of the approaches to explain the pathogenesis of Alzheimer's disease focus on the accumulation of amyloid beta peptide (A beta), in the form of insoluble deposits leading to formation of senile plaques, and on the formation of neurofibrillary tangles composed of hyperphosphorylated Tau protein. Accumulation of A beta is believed to be an early and critical step in the neuropathogenesis of Alzheimer's disease. There is now evidence for the kynurenine pathway being associated with Alzheimer's disease. Disturbances of the kynurenine pathway have already been described in Alzheimer's disease. Recently, /the authors/ demonstrated that A beta 1-42, a cleavage product of amyloid precursor protein, induces production of quinolinic acid, in neurotoxic concentrations, by macrophages and, more importantly, microglia. Senile plaques in Alzheimer's disease are associated with evidence of chronic local inflammation (especially activated microglia) A major aspect of quinolinic acid toxicity is lipid peroxidation and markers of lipid peroxidation are found in Alzheimer's disease. Together, these data imply that quinolinic acid may be one of the critical factors in the pathogenesis of neuronal damage in Alzheimer's disease. This review describes the multiple correlations between the kynurenine pathway and the neuropathogenesis of Alzheimer's disease and highlights more particularly the aspects of quinolinic acid neurotoxicity, emphasizing its roles in lipid peroxidation and the amplification of the local inflammation.

For more Mechanism of Action (Complete) data for QUINOLINIC ACID (15 total), please visit the HSDB record page.

Kynurenine, a metabolite of tryptophan along the 'kynurenine pathway', is at a branch point of the pathway which can lead to the synthesis of both quinolinic acid and kynurenic acid. kynurenic acid is an antagonist of glutamate receptors; however, quinolinic acid is a selective agonist of NMDA receptors, and has been shown to act as an excitotoxic agent. A high quinolinic acid/kynurenic acid ratio has been implicated in a variety of neurological diseases in which excitotoxic neuronal cell death is found, e.g. AIDS-related dementia, stroke, etc. Inhibiting the key enzymes of this pathway (i.e. kynureninase and kynurenine 3-hydroxylase) would lower the quinolinic acid/kynurenic acid ratio, which may potentially have neuroprotective effects.

The incorporation of tritium-label into quinolinic acid, kynurenic acid, and other kynurenine pathway metabolites was studied in normal and quinolinic acid-lesioned rat striata after a focal injection of [5-3H]kynurenine in vivo. The time course of metabolite accumulation was examined 15 min to 4 hr after injection of [5-3H]kynurenine, and the concentration dependence of kynurenine metabolism was studied in rats killed 2 hr after injection of 1.5-1,500 uM [5-3H]kynurenine. Labeled quinolinic acid, kynurenic acid, 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid, and xanthurenic acid were recovered from the striatum in every experiment. Following injection of 15 uM [5-3H]kynurenine, a lesion-induced increase in kynurenine metabolism was noted. Thus, the proportional recoveries of [3H]kynurenic acid (5.0 vs. 1.8%), [3H]3-HK (20.9 vs. 4.5%), [3H]xanthurenic acid (1.5 vs. 0.4%), and [3H]quinolinic acid (3.6 vs. 0.6%) were markedly elevated in the lesioned striatum. Increases in kynurenine metabolism in lesioned tissue were evident at all time points and kynurenine 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 kynurenine pathway in the normal rat brain and for a substantial increase in flux after neuronal ablation.

Kynurenine is an intermediate in the pathway of the metabolism of tryptophan to nicotinic acid. Kynurenine is formed in the mammalian brain (40%) and is taken up from the periphery (60%), indicating that it can be transported across the blood-brain barrier. In the brain, kynurenine can be converted to two other components of the pathway: the neurotoxic quinolinic acid and the neuroprotective kynurenic acid. Quinolinic acid is probably the most widely studied metabolite of kynurenine, because it may cause excitotoxic neuronal cell loss and convulsions by interacting with the N-methyl-D-aspartate receptor complex, a type of glutamate receptor. Kynurenic acid is another metabolite of kynurenine; its synthesis is catalysed by kynurenine aminotransferases. This is the only known endogenous N-methyl-D-aspartate receptor inhibitor, which can act at the glycine site on the receptor complex. Furthermore, kynurenic acid non-competitively inhibits alpha7 nicotinic acetylcholine presynaptic receptors (nAChRs), inhibiting glutamate release, and regulates the expression of alpha4beta2 nAChR. It is well-known that the activation of excitatory amino acid receptors can play a role in a number of neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, stroke and epilepsy. Various studies have been made of whether the excitatory amino acid receptor antagonist kynurenic acid can exert a therapeutic effect in these neurological disorders. It has been established that kynurenic acid has only a very limited ability to cross the blood-brain barrier.

The kynurenine pathway is the main pathway of tryptophan metabolism. L-kynurenine is a central compound of this pathway since it can change to the neuroprotective agent kynurenic acid or to the neurotoxic agent quinolinic acid. The break-up of these endogenous compounds' balance can be observable in many disorders. It can occur in neurodegenerative disorders, such as Parkinson's disease, Huntington's and Alzheimer's disease, in stroke, in epilepsy, in multiple sclerosis, in amyotrophic lateral sclerosis, and in mental failures, such as schizophrenia and depression. The increase of quinolinic acid concentration or decrease of kynurenic acid concentration could enhance the symptoms of several diseases. According to numerous studies, lowered kynurenic acid level was found in patients with Parkinson's disease. It can be also noticeable that kynurenic acid-treatment prevents against the quinolinic acid-induced lesion of rat striatum in animal experiments.

For more Metabolism/Metabolites (Complete) data for QUINOLINIC ACID (6 total), please visit the HSDB record page.

A metabolite of tryptophan; Used to make Assert (herbicide) and nicotinic acid; [HSDB]

Quinolinic acid (QUIN), a pyridine dicarboxylic acid and metabolite of tryptophan, which has been detected in the central nervous system (CNS), behaves as an excitotoxin /and is being used as a research tool to examine the role of excitotoxicity in neuronal degeneration associated with a number of neurological diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease) which involve selective neurotransmitter deficits./

Quinolinic acid levels in CSF (a surrogate marker of neuronal cell damage) / are used to evaluate HIV disease progression in research settings./

Used to manufacture the herbicide Assert (imazapyr) ... and as an intermediate in the production of nicotinic acid

Preparation: S. Hoogewerff, W. A. van Dorp, Ber. 12, 747 (1879); W. Koenigs, ibid. 983; O. fischer, E. Renouf, ibid. 17, 755 (1884); E. Sucharda, ibid. 58B, 1727(1925); v. Yu. Stiks, S. A. Bulgach, ibid. 65B, 11 (1932); A.F. Lindenstruth, C.A. VanderWerf, J. Am. Chem. Soc. 71, 3020 (1949).

Not Known or Reasonably Ascertainable

2,3-Pyridinedicarboxylic acid: ACTIVE