Kynurenine metabolism in vitamin-B-6-deficient rat liver after tryptophan injection.
Ontology highlight
ABSTRACT:
SUBMITTER: Takeuchi F
PROVIDER: S-EPMC1153685 | biostudies-other | 1984 Jun
REPOSITORIES: biostudies-other
Similar Datasets
Project description:Regulatory and functional aspects of the kynurenine (K) pathway (KP) of tryptophan (Trp) degradation are reviewed. The KP accounts for ~95% of dietary Trp degradation, of which 90% is attributed to the hepatic KP. During immune activation, the minor extrahepatic KP plays a more active role. The KP is rate-limited by its first enzyme, Trp 2,3-dioxygenase (TDO), in liver and indoleamine 2,3-dioxygenase (IDO) elsewhere. TDO is regulated by glucocorticoid induction, substrate activation and stabilization by Trp, cofactor activation by heme, and end-product inhibition by reduced nicotinamide adenine dinucleotide (phosphate). IDO is regulated by IFN-γ and other cytokines and by nitric oxide. The KP disposes of excess Trp, controls hepatic heme synthesis and Trp availability for cerebral serotonin synthesis, and produces immunoregulatory and neuroactive metabolites, the B3 "vitamin" nicotinic acid, and oxidized nicotinamide adenine dinucleotide. Various KP enzymes are undermined in disease and are targeted for therapy of conditions ranging from immunological, neurological, and neurodegenerative conditions to cancer.
| S-EPMC5398323 | biostudies-literature
Project description:Vitamin B-6 deficiency is associated with impaired tryptophan metabolism because of the coenzyme role of pyridoxal 5'-phosphate (PLP) for kynureninase and kynurenine aminotransferase. To investigate the underlying mechanism, we developed a mathematical model of tryptophan metabolism via the kynurenine pathway. The model includes mammalian data on enzyme kinetics and tryptophan transport from the intestinal lumen to liver, muscle, and brain. Regulatory mechanisms and inhibition of relevant enzymes were included. We simulated the effects of graded reduction in cellular PLP concentration, tryptophan loads and induction of tryptophan 2,3-dioxygenase (TDO) on metabolite profiles and urinary excretion. The model predictions matched experimental data and provided clarification of the response of metabolites in various extents of vitamin B-6 deficiency. We found that moderate deficiency yielded increased 3-hydroxykynurenine and a decrease in kynurenic acid and anthranilic acid. More severe deficiency also yielded an increase in kynurenine and xanthurenic acid and more pronounced effects on the other metabolites. Tryptophan load simulations with and without vitamin B-6 deficiency showed altered metabolite concentrations consistent with published data. Induction of TDO caused an increase in all metabolites, and TDO induction together with a simulated vitamin B-6 deficiency, as has been reported in oral contraceptive users, yielded increases in kynurenine, 3-hydroxykynurenine, and xanthurenic acid and decreases in kynurenic acid and anthranilic acid. These results show that the model successfully simulated tryptophan metabolism via the kynurenine pathway and can be used to complement experimental investigations.
| S-EPMC3743279 | biostudies-literature
Project description:BackgroundThis study aims to explore the role of indoleamine-2,3-dioxygenase (IDO)/kynurenine (KYN) pathway of tryptophan (TRY) metabolism in behavioral alterations observed in hepatic encephalopathy (HE) rats.MethodsExpression levels of proinflammatory cytokines were tested by QT-PCR and ELISA, levels of IDOs were tested by QT-PCR and Western blot, and levels of 5-hydroxytryptamine (5-HT), KYN, TRY, 3-hydroxykynurenine (3-HK), and kynurenic acid (KA) in different brain regions were estimated using HPLC. Effects of the IDO direct inhibitor 1-methyl-L-tryptophan (1-MT) on cognitive, anxiety, and depressive-like behavior were evaluated in bile duct ligation (BDL) rats.ResultsIncreased serum TNF-α, IL-1β, and IL-6 levels were shown in rats 7 days after BDL, and these increases were observed earlier than those in the brain, indicating peripheral immune activation may result in central upregulation of proinflammatory cytokines. Moreover, BDL rats showed a progressive decline in memory formation, as well as anxiety and depressive-like behavior. Further study revealed that IDO expression increased after BDL, accompanied by a decrease of 5-HT and an increase of KYN, as well as abnormal expression of 3-HK and KA. The above results affected by BDL surgery were reversed by IDO inhibitor 1-MT treatment.ConclusionTaken together, these findings indicate that (1) behavioral impairment in BDL rats is correlated with proinflammatory cytokines; (2) TRY pathway of KYN metabolism, activated by inflammation, may play an important role in HE development; and (3) 1-MT may serve as a therapeutic agent for HE.
| S-EPMC5753541 | biostudies-literature
Project description:Obesity is associated with increased inflammation and insulin resistance. In conditions with chronic immune activation, low plasma vitamin B6-levels are described, as well as an increased kynurenine:tryptophan-ratio (KTR). We investigated circulating tryptophan, kynurenine and its metabolites, neopterin, B-vitamins, CRP, and HbA1c in individuals with obesity before and after bariatric surgery.This longitudinal study included 37 patients with severe obesity, scheduled for bariatric surgery. Blood samples were taken at inclusion and at three months and one year postoperatively.We observed significant positive correlations between HbA1c and both 3-hydroxy-kynurenine and 3-hydroxyanthranilic acid at inclusion. After surgery, fasting glucose, HbA1C and triglycerides decreased, whereas HDL-cholesterol increased. Tryptophan, kynurenine and its metabolites, except for anthranilic acid, decreased during weight loss. The KTR and CRP decreased while vitamin B6 increased during the year following operation, indicating reduced inflammation (all p<0.05).In patients with obesity subjected to bariatric surgery, levels of 3-hydroxykynurenine and 3-hydroxyanthranilic acid seemed to be positively correlated to impaired glucose tolerance. One year following surgery, plasma levels of the kynurenine metabolites were substantially decreased, along with a metabolic improvement. The relation of circulating kynurenine pathway metabolites with biomarkers of metabolic impairment in patients with obesity needs further evaluation.
| S-EPMC5798786 | biostudies-literature
Project description:Exhaustive exercise can cause a transient depression of immune function. Data indicate significant effects of immune activation cascades on the biochemistry of monoamines and amino acids such as tryptophan. Tryptophan can be metabolized through different pathways, a major route being the kynurenine pathway, which is often systemically up-regulated when the immune response is activated. The present study was undertaken to examine the effect of exhaustive aerobic exercise on biomarkers of immune activation and tryptophan metabolism in trained athletes. After a standardized breakfast 2 h prior to exercise, 33 trained athletes (17 women, 16 men) performed an incremental cycle ergometer exercise test at 60 rpm until exhaustion. After a 20 min rest phase, the participants performed a 20 min maximal time-trial on a cycle ergometer (RBM Cyclus 2, Germany). During the test, cyclists were strongly encouraged to choose a maximal pedalling rate that could be maintained for the respective test duration. Serum concentrations of amino acids tryptophan, kynurenine, phenylalanine, and tyrosine were determined by HPLC and immune system biomarker neopterin by ELISA at rest and immediately post exercise. Intense exercise was associated with a strong increase in neopterin concentrations (p<0.001), indicating increased immune activation following intense exercise. Exhaustive exercise significantly reduced tryptophan concentrations by 12% (p<0.001) and increased kynurenine levels by 6% (p = 0.022). Also phenylalanine to tyrosine ratios were lower after exercise as compared with baseline (p<0.001). The kynurenine to tryptophan ratio correlated with neopterin (r = 0.560, p<0.01). Thus, increased tryptophan catabolism by indoleamine 2,3-dioxygenase appears likely. Peak oxygen uptake correlated with baseline tryptophan and kynurenine concentrations (r = 0.562 and r = 0.511, respectively, both p<0.01). Findings demonstrate that exhaustive aerobic exercise is associated with increased immune activation and alterations in monoamine metabolism in trained athletes which may play a role in the regulation of mood and cognitive processes.
| S-EPMC4849644 | biostudies-literature
Project description:Under physiological conditions 95% of the ingested essential amino acid tryptophan is metabolized by the kynurenine pathway (KP) to yield the ubiquitous co-enzyme nicotinamide adenine dinucleotide, fulfilling cellular energy requirements. Importantly, the intermediaries of KP exert crucial effects throughout the body, including the central nervous system. Besides, KP metabolites are implicated in diverse disease processes such as inflammation/immune disorders, endocrine/metabolic conditions, cancers and neuropsychiatric diseases. A burgeoning body of research indicates that the KP plays a pathogenic role in major psychiatric diseases like mood disorders and schizophrenia. Triggered by inflammatory processes, the balance between neurotoxic and neuroprotective branches of the KP is disturbed. In preclinical models these discrepancies result in behaviors reminiscent of depression and psychosis. In clinical samples, recent studies are discovering key kynurenine pathway abnormalities which incriminate it in the pathogenesis of the main psychiatric disorders. Harnessing this knowledge has the potential to find disease biomarkers helpful in identifying and prognosticating neuropsychiatric disorders. Concurrently, earnest research efforts directed towards manipulating the KP hold the promise of discovering novel pharmacological agents that have therapeutic value. In this manuscript, an in-depth appraisal of the extant literature is done to understand the working of KP as this applies to neuropsychiatric disorders. It is concluded that this pathway plays an overarching role in the development of major psychiatric disorders, the KP metabolites have the potential to serve as disease markers and new medications based on KP modulation can bring lasting cures for patients suffering from these intractable conditions.
| S-EPMC7609208 | biostudies-literature
Project description:ObjectivesExtrahepatic tryptophan (Trp)-kynurenine (Kyn) metabolism via indoleamine 2,3-dioxygenase 1 (IDO1) induction was found to be associated with intrinsic immune regulation. However, the Trp-Kyn metabolism-associated immune regulation in dermatomyositis (DM) remains unknown. Therefore, we aimed to investigate the clinical relevance of the Trp-Kyn metabolism via IDO1 induction in DM.MethodsLiquid chromatography-mass spectrometry (HPLC-MS) was used to examine the serum Kyn and Trp concentrations in DM. In addition, we used X-tile software to determine the optimal cutoff value of the Kyn/Trp ratio, a surrogate marker for Trp-Kyn metabolism. Spearman analysis was performed to evaluate the association of Trp-Kyn metabolism with muscle enzymes and inflammatory markers.ResultsDM patients had significantly higher serum Kyn/Trp ratio (× 10-3) when compared with the healthy controls. The serum Kyn/Trp ratio was positively correlated with the levels of muscle enzymes and inflammatory markers. In addition, the serum Kyn/Trp ratio significantly decreased (36.89 (26.00-54.00) vs. 25.00 (18.00-37.00), P = 0.0006) after treatment. DM patients with high serum Kyn/Trp ratio had a significantly higher percentage of muscle weakness symptoms (62.5% vs. 20.0%, P = 0.019) and higher levels of LDH (316.0 (236.0-467.0) vs. 198.0 (144.0-256.0), P = 0.004) and AST (56.5 (35.0-92.2) vs. 23.0 (20.0-36.0), P = 0.002)) than those with low serum Kyn/Trp ratio. Multiple Cox regression analyses identified ln(Kyn/Trp) (HR 4.874, 95% CI 1.105-21.499, P = 0.036) as an independent prognostic predictor of mortality in DM.ConclusionsDM patients with enhanced Trp-Kyn metabolism at disease onset are characterized by more severe disease status and poor prognosis. Intrinsic immune regulation function via enhanced Trp-Kyn metabolism by IDO1 induction may be a potential therapeutic target in DM. Key Points • HPLC-MS identified increased serum Kyn/Trp ratio in DM patients, which positively correlated with levels of muscle enzymes and inflammatory markers and was downregulated upon treatment. • Cox regression analyses identified ln(Kyn/Trp) as an independent prognostic predictor of mortality in DM. • Monitoring intrinsic immune regulation function should be considered a potential therapeutic target in DM patients.
| S-EPMC9485101 | biostudies-literature
Project description:In vitamin B-12 (cobalamin) deficiency the metabolism of propionyl-CoA and methylmalonyl-CoA are inhibited secondarily to decreased L-methylmalonyl-CoA mutase activity. Production of acylcarnitines provides a mechanism for removing acyl groups and liberating CoA under conditions of impaired acyl-CoA utilization. Carnitine metabolism was studied in the vitamin B-12-deficient rat to define the relationship between alterations in acylcarnitine generation and the development of methylmalonic aciduria. Urinary excretion of methylmalonic acid was increased 200-fold in vitamin B-12-deficient rats as compared with controls. Urinary acylcarnitine excretion was increased in the vitamin B-12-deficient animals by 70%. This increase in urinary acylcarnitine excretion correlated with the degree of metabolic impairment as measured by the urinary methylmalonic acid elimination. Urinary propionylcarnitine excretion averaged 11 nmol/day in control rats and 120 nmol/day in the vitamin B-12-deficient group. The fraction of total carnitine present as short-chain acylcarnitines in the plasma and liver of vitamin B-12-deficient rats was increased as compared with controls. When the rats were fasted for 48 h, relative or absolute increases were seen in the urine, plasma, liver and skeletal-muscle acylcarnitine content of the vitamin B-12-deficient rats as compared with controls. Thus vitamin B-12 deficiency was associated with a redistribution of carnitine towards acylcarnitines. Propionylcarnitine was a significant constituent of the acylcarnitine pool in the vitamin B-12-deficient animals. The changes in carnitine metabolism were consistent with the changes in CoA metabolism known to occur with vitamin B-12 deficiency. The vitamin B-12-deficient rat provides a model system for studying carnitine metabolism in the methylmalonic acidurias.
| S-EPMC1135203 | biostudies-other
Project description:Tumors display increased uptake and processing of nutrients to fulfill the demands of rapidly proliferating cancer cells. Seminal studies have shown that the proto-oncogene MYC promotes metabolic reprogramming by altering glutamine uptake and metabolism in cancer cells. How MYC regulates the metabolism of other amino acids in cancer is not fully understood. Using high-performance liquid chromatography (HPLC)-tandem mass spectrometry (LC-MS/MS), we found that MYC increased intracellular levels of tryptophan and tryptophan metabolites in the kynurenine pathway. MYC induced the expression of the tryptophan transporters SLC7A5 and SLC1A5 and the enzyme arylformamidase (AFMID), involved in the conversion of tryptophan into kynurenine. SLC7A5, SLC1A5, and AFMID were elevated in colon cancer cells and tissues, and kynurenine was significantly greater in tumor samples than in the respective adjacent normal tissue from patients with colon cancer. Compared with normal human colonic epithelial cells, colon cancer cells were more sensitive to the depletion of tryptophan. Blocking enzymes in the kynurenine pathway caused preferential death of established colon cancer cells and transformed colonic organoids. We found that only kynurenine and no other tryptophan metabolite promotes the nuclear translocation of the transcription factor aryl hydrocarbon receptor (AHR). Blocking the interaction between AHR and kynurenine with CH223191 reduced the proliferation of colon cancer cells. Therefore, we propose that limiting cellular kynurenine or its downstream targets could present a new strategy to reduce the proliferation of MYC-dependent cancer cells.
| S-EPMC6719621 | biostudies-literature
Project description:Background and Aims:Mucosal appearance on endoscopy is an important indicator of inflammatory burden and determines prognosis in ulcerative colitis (UC). Inflammation induces tryptophan metabolism along the kynurenine pathway (KP) and yields immunologically relevant metabolites. We sought to examine whether changes in serum tryptophan metabolites and tissue expression of KP enzymes are associated with UC endoscopic and histologic disease severity. Methods:Serum and mucosal samples were prospectively obtained at colonoscopy in patients with UC. Mayo disease activity scores, demographics, smoking status, medications, and outcomes were collected. Serum tryptophan metabolites were analyzed using ultra-high performance liquid chromatography (uHPLC), and gas chromatography-mass spectrometry (GC-MS), and enzyme expression was determined by quantitative real-time polymerase chain reaction. Metabolite and enzyme levels were compared by endoscopic subscore, clinical disease activity, time to surgery, and hospitalization. Results:This study included 99 patients with Mayo endoscopic subscores 0-3. Kynurenic acid/tryptophan ratio (KYNA/T) and expression of indolamine 2,3-dioxygenase 1 (IDO1), tryptophan 2,3-dioxygenase, kynurinase, and kynurenine monooxygenase correlated positively with endoscopic subscore. Adjusting for age of diagnosis, smoking status, disease extent, and medications yielded significant odds of endoscopic inflammation with increasing KYNA/T (OR 1.0015, P = 0.0186) and IDO1 expression (OR 1.0635, P = 0.0215). The highest tertile ratio of KYNA/T had shorter time to surgery (P = 0.009) and hospitalization (P = 0.01) than the lowest. Conclusions:Increasing KYNA/T is closely associated with endoscopic inflammation and predictive of disease outcomes in patients with UC. These findings identify this novel metabolic association and further support the role of the KP in regulating mucosal inflammation in UC. 10.1093/ibd/izy103_video1izy103.video15788135676001.
| S-EPMC6196764 | biostudies-literature