The Action of Pyridoxine in Primary Hyperoxaluria

1970 ◽  
Vol 38 (2) ◽  
pp. 277-286 ◽  
Author(s):  
Dorothy A. Gibbs ◽  
R. W. E. Watts
Keyword(s):  
Kynurenic Acid ◽  
Enzyme System ◽  
Primary Hyperoxaluria ◽  
Xanthurenic Acid ◽  
Normal Range ◽  
Before And After ◽  
Tryptophan Metabolite ◽  
Pre Treatment ◽  
Hydroxyanthranilic Acid ◽  
Urinary Oxalate Excretion

1. Evidence of deficiency of, antagonism to, or abnormal dependency upon pyridoxine has been sought in four patients with primary hyperoxaluria. The urinary excretion of kynurenine, 3-hydroxykyurenine, 3-hydroxyanthranilic acid, kynurenic acid and xanthurenic acid, before and after a loading dose of l-tryptophan was used to assess pyridoxine nutrition. 2. Three of the four patients studied had abnormal l-tryptophan metabolite excretion patterns, but these were not of the type which is associated with abnormalities of pyridoxine nutrition. 3. The changes which were observed are compatible with impaired conversion of kynurenine to 3-hydroxykynurenine by the NADH2 dependent kynurenine 3-hydroxylase (EC 1.99.1.5) enzyme system. 4. Large doses of pyridoxine hydrochloride reduced the urinary oxalate excretion by two of the patients to levels which were intermediate between the normal range and the pre-treatment values. This effect was maintained for 6 months, which was the longest period of observation. 5. It is concluded that this action of pyridoxine is mediated by a mechanism which does not involve the correction of an abnormality of pyridoxine metabolism.

Relationship between Serum Tryptophan and Tryptophan Metabolite Levels after Tryptophan Ingestion in Normal Subjects and Age-Related Cataract Patients

1995 ◽  
Vol 89 (6) ◽  
pp. 591-599 ◽  
Author(s):  
Roger J. W. Truscott ◽  
Anthony J. Elderfield
Keyword(s):  
Anthranilic Acid ◽  
Kynurenic Acid ◽  
Normal Subjects ◽  
Serum Levels ◽  
Xanthurenic Acid ◽  
Control Subjects ◽  
Age Related ◽  
Hydroxyanthranilic Acid ◽  
And Control ◽  
Cataract Patients

1. Cataract is the single major cause of blindness worldwide; however, the reasons for the development of this condition remain unknown. It has been suggested that the essential amino acid tryptophan may be implicated in the aetiology but definitive evidence has been lacking. 2. The serum levels of tryptophan and seven of its metabolites have been measured in both cataract patients and control subjects, after administration of tryptophan, in order to determine the typical response profile and to discover whether differences could be found in tryptophan metabolism in the two groups. 3. Tryptophan, kynurenine, kynurenic acid, xanthurenic acid, 3-hydroxyanthranilic acid, 5-hydroxyanthranilic acid, 5-hydroxytryptophan and anthranilic acid were measured by HPLC with dual electrochemical and programmable wavelength fluorescence detection. Fasting cataract patients (n = 42) and control subjects (n = 37) were given an oral dose of l-tryptophan and sera were sampled at 0, 1, 2, 4 and 6 h. 4. Statistically significant differences in the distribution of data between the two groups were observed. The responses of kynurenine and 5-hydroxyanthranilic acid were higher in cataract patients, but those of kynurenic acid and total tryptophan were lower than in control subjects. No statistically significant differences in free tryptophan, anthranilic acid, 3-hydroxyanthranilic acid, xanthurenic acid or 5-hydroxytryptophan levels were noted. 5. We conclude that there is a major subgroup of age-related cataract patients with a dysfunction in the metabolism of tryptophan. This may be related to the onset of cataract. The mechanism remains to be established but may operate via the action of tryptophan metabolites, such as 5-hydroxyanthranilic acid, which become reactive towards protein upon oxidation.

scholarly journals Organ Correlation with Tryptophan Metabolism Obtained by Analyses of TDO-KO and QPRT-KO Mice

2016 ◽  
Vol 9 ◽  
pp. IJTR.S37984 ◽  
Author(s):  
Katsumi Shibata ◽  
Tsutomu Fukuwatari
Keyword(s):  
Quinolinic Acid ◽  
Kynurenic Acid ◽  
Conversion Ratio ◽  
Tryptophan Metabolism ◽  
Limiting Factors ◽  
Xanthurenic Acid ◽  
Wild Type ◽  
Organ Specific ◽  
Hydroxyanthranilic Acid ◽  
Rate Limiting

The aim of this article is to report the organ-specific correlation with tryptophan (Trp) metabolism obtained by analyses of tryptophan 2,3-dioxygenase knockout (TDO-KO) and quinolinic acid phosphoribosyltransferase knockout (QPRT-KO) mice models. We found that TDO-KO mice could biosynthesize the necessary amount of nicotinamide (Nam) from Trp, resulting in the production of key intermediate, 3-hydroxyanthranilic acid. Upstream metabolites, such as kynurenic acid and xanthurenic acid, in the urine were originated from nonhepatic tissues, and not from the liver. In QPRT-KO mice, the Trp to quinolinic acid conversion ratio was 6%; this value was higher than expected. Furthermore, we found that QPRT activity in hetero mice was half of that in wild-type (WT) mice. Urine quinolinic acid levels remain unchanged in both hetero and WT mice, and the conversion ratio of Trp to Nam was also unaffected. Collectively, these findings show that QPRT was not the rate-limiting enzyme in the conversion. In conclusion, the limiting factors in the conversion of Trp to Nam are the substrate amounts of 3-hydroxyanthranilic acid and activity of 3-hydroxyanthranilic acid 3,4-dioxygenase in the liver.

scholarly journals An Investigation into the Temporal Reproducibility of Tryptophan Metabolite Networks Among Healthy Adolescents

2021 ◽  
Vol 14 ◽  
pp. 117864692110413
Author(s):  
Kolade Oluwagbemigun ◽  
Andrea Anesi ◽  
Gerard Clarke ◽  
Matthias Schmid ◽  
Fulvio Mattivi ◽  
...  
Keyword(s):  
Kynurenic Acid ◽  
Graphical Model ◽  
Bioactive Metabolites ◽  
Xanthurenic Acid ◽  
Dynamic Interactions ◽  
Healthy Adolescent ◽  
Time Points ◽  
Stable Pattern ◽  
Hydroxyanthranilic Acid ◽  
Network Approaches

Tryptophan and its bioactive metabolites are associated with health conditions such as systemic inflammation, cardiometabolic diseases, and neurodegenerative disorders. There are dynamic interactions among metabolites of tryptophan. The interactions between metabolites, particularly those that are strong and temporally reproducible could be of pathophysiological relevance. Using a targeted metabolomics approach, the concentration levels of tryptophan and 18 of its metabolites across multiple pathways was quantified in 24-hours urine samples at 2 time-points, age 17 years (baseline) and 18 years (follow-up) from 132 (52% female) apparently healthy adolescent participants of the DOrtmund Nutritional and Anthropometric Longitudinally Designed (DONALD) Study. In sex-specific analyses, we applied 2 network approaches, the Gaussian graphical model and Bayesian network to (1) explore the network structure for both time-points, (2) retrieve strongly related metabolites, and (3) determine whether the strongly related metabolites were temporally reproducible. Independent of selected covariates, the 2 network approaches revealed 5 associations that were strong and temporally reproducible. These were novel relationships, between kynurenic acid and indole-3-acetic acid in females and between kynurenic acid and xanthurenic acid in males, as well as known relationships between kynurenine and 3-hydroxykynurenine, and between 3-hydroxykynurenine and 3-hydroxyanthranilic acid in females and between tryptophan and kynurenine in males. Overall, this epidemiological study using network-based approaches shed new light into tryptophan metabolism, particularly the interaction of host and microbial metabolites. The 5 observed relationships suggested the existence of a temporally stable pattern of tryptophan and 6 metabolites in healthy adolescent, which could be further investigated in search of fingerprints of specific physiological states. The metabolites in these relationships may represent a multi-biomarker panel that could be informative for health outcomes.

URINARY EXCRETION OF TRYPTOPHAN METABOLITES IN THE HEALTHY INFANT

PEDIATRICS ◽  
1962 ◽  
Vol 30 (4) ◽  
pp. 585-591
Author(s):  
Franco Vassella ◽  
Bo Hellström ◽  
Bo Wengle
Keyword(s):  
Body Weight ◽  
Urinary Excretion ◽  
Paper Chromatography ◽  
Kynurenic Acid ◽  
Healthy Infant ◽  
Xanthurenic Acid ◽  
Two Dimensional ◽  
Healthy Infants ◽  
Tryptophan Metabolites ◽  
Hydroxyanthranilic Acid

Urinary excretion of tryptophan metabolites was studied qualitatively by two-dimensional paper chromatography in a group of 50 healthy infants with no tryptophan supplementation. Twenty-two infants of this group were given 100 mg of L-tryptophan per kilogram of body-weight, and the 24-hour urinary excretions of kynurenine, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and xanthurenic acid were estimated by quantitative paper chromatography. A high excretion of kynurenine was found to be a distinguishing feature. Various possibilities to explain this difference as compared to adults are discussed.

scholarly journals Relationship between tryptophan intake and urinary excretion of 3-hydroxy-kynurenine, 3-hydroxyanthranilic acid, xanthurenic acid and kynurenic acid.

1979 ◽  
Vol 25 (2) ◽  
pp. 115-122 ◽  
Author(s):  
Mitsuo WATANABE ◽  
Tetsuzo TAKAHASHI ◽  
Mieko YOSHIDA ◽  
Masatoshi SUZUKI ◽  
Shigeji MURAMATSU
Keyword(s):  
Urinary Excretion ◽  
Kynurenic Acid ◽  
Xanthurenic Acid ◽  
Hydroxyanthranilic Acid

Effect of Nicotinamide Administration on the Tryptophan-Nicotinamide Pathway in Humans

2007 ◽  
Vol 77 (4) ◽  
pp. 255-262 ◽  
Author(s):  
Fukuwatari ◽  
Shibata
Keyword(s):  
Urinary Excretion ◽  
Young Women ◽  
Quinolinic Acid ◽  
Kynurenic Acid ◽  
De Novo ◽  
Conversion Ratio ◽  
Xanthurenic Acid ◽  
Dependent Manner ◽  
Hydroxyanthranilic Acid ◽  
Dose Dependent

The vitamin nicotinamide is synthesized in the liver from tryptophan, and distributed to non-hepatic tissues. Although it is generally accepted that 60 mg tryptophan is equivalent to 1 mg nicotinamide in humans, the conversion ratio of tryptophan to nicotinamide is changeable. To determine if de novo nicotinamide synthesis from tryptophan is influenced by nicotinamide intake itself, six young women consumed controlled diets containing 30.4 or 24.8 mg niacin-equivalent nicotinamide supplements with 0, 89, 310, or 562 μmol/day (0, 10.9, 37.8, or 68.6 mg/day, respectively), and urinary excretion of intermediates and metabolites of the tryptophan-nicotinamide pathway were measured. Urinary excretion of nicotinamide metabolites increased linearly in a dose-dependent manner. None of the intermediates, including anthranilic acid, kynurenic acid, xanthurenic acid, 3-hydroxyanthranilic acid, and quinolinic acid, changed at all, even when up to 562 μmol/day nicotinamide was given. That is, exogenous nicotinamide did not affect de novo nicotinamide synthesis. Therefore, when niacin equivalent is calculated, the intake of nicotinamide itself need not be considered as a factor that changes the tryptophan-nicotinamide conversion ratio.

Cytoprotective Effect of Tocotrienol-Rich Fraction and α-Tocopherol Vitamin E Isoforms Against Glutamate-Induced Cell Death in Neuronal Cells

2014 ◽  
Vol 84 (3-4) ◽  
pp. 0140-0151 ◽  
Author(s):  
Thilaga Rati Selvaraju ◽  
Huzwah Khaza’ai ◽  
Sharmili Vidyadaran ◽  
Mohd Sokhini Abd Mutalib ◽  
Vasudevan Ramachandran ◽  
...  
Keyword(s):  
Vitamin E ◽  
Cell Viability ◽  
Neuronal Cells ◽  
Positive Control ◽  
Post Treatment ◽  
Mitochondrial Activity ◽  
Before And After ◽  
Pre Treatment ◽  
Tocotrienol Rich Fraction ◽  
Major Mediator

Glutamate is the major mediator of excitatory signals in the mammalian central nervous system. Extreme amounts of glutamate in the extracellular spaces can lead to numerous neurodegenerative diseases. We aimed to clarify the potential of the following vitamin E isomers, tocotrienol-rich fraction (TRF) and α-tocopherol (α-TCP), as potent neuroprotective agents against glutamate-induced injury in neuronal SK-N-SH cells. Cells were treated before and after glutamate injury (pre- and post-treatment, respectively) with 100 - 300 ng/ml TRF/α-TCP. Exposure to 120 mM glutamate significantly reduced cell viability to 76 % and 79 % in the pre- and post-treatment studies, respectively; however, pre- and post-treatment with TRF/α-TCP attenuated the cytotoxic effect of glutamate. Compared to the positive control (glutamate-injured cells not treated with TRF/α-TCP), pre-treatment with 100, 200, and 300 ng/ml TRF significantly improved cell viability following glutamate injury to 95.2 %, 95.0 %, and 95.6 %, respectively (p < 0.05).The isomers not only conferred neuroprotection by enhancing mitochondrial activity and depleting free radical production, but also increased cell viability and recovery upon glutamate insult. Our results suggest that vitamin E has potent antioxidant potential for protecting against glutamate injury and recovering glutamate-injured neuronal cells. Our findings also indicate that both TRF and α-TCP could play key roles as anti-apoptotic agents with neuroprotective properties.

Metabolism of Oxalate in Humans: A Potential Role Kynurenine Aminotransferase/Glutamine Transaminase/Cysteine Conjugate Betalyase Plays in Hyperoxaluria

2019 ◽  
Vol 26 (26) ◽  
pp. 4944-4963 ◽  
Author(s):  
Qian Han ◽  
Cihan Yang ◽  
Jun Lu ◽  
Yinai Zhang ◽  
Jianyong Li
Keyword(s):  
Cellular Localization ◽  
Structural Characteristics ◽  
Gene Mutations ◽  
Primary Hyperoxaluria ◽  
Glycolate Oxidase ◽  
Kynurenine Aminotransferase ◽  
Underlying Mechanisms ◽  
Urinary Oxalate Excretion ◽  
Glyoxylate Aminotransferase ◽  
Oxalate Metabolism

Hyperoxaluria, excessive urinary oxalate excretion, is a significant health problem worldwide. Disrupted oxalate metabolism has been implicated in hyperoxaluria and accordingly, an enzymatic disturbance in oxalate biosynthesis can result in the primary hyperoxaluria. Alanine-glyoxylate aminotransferase-1 and glyoxylate reductase, the enzymes involving glyoxylate (precursor for oxalate) metabolism, have been related to primary hyperoxalurias. Some studies suggest that other enzymes such as glycolate oxidase and alanine-glyoxylate aminotransferase-2 might be associated with primary hyperoxaluria as well, but evidence of a definitive link is not strong between the clinical cases and gene mutations. There are still some idiopathic hyperoxalurias, which require a further study for the etiologies. Some aminotransferases, particularly kynurenine aminotransferases, can convert glyoxylate to glycine. Based on biochemical and structural characteristics, expression level, and subcellular localization of some aminotransferases, a number of them appear able to catalyze the transamination of glyoxylate to glycine more efficiently than alanine glyoxylate aminotransferase-1. The aim of this minireview is to explore other undermining causes of primary hyperoxaluria and stimulate research toward achieving a comprehensive understanding of underlying mechanisms leading to the disease. Herein, we reviewed all aminotransferases in the liver for their functions in glyoxylate metabolism. Particularly, kynurenine aminotransferase-I and III were carefully discussed regarding their biochemical and structural characteristics, cellular localization, and enzyme inhibition. Kynurenine aminotransferase-III is, so far, the most efficient putative mitochondrial enzyme to transaminate glyoxylate to glycine in mammalian livers, which might be an interesting enzyme to look for in hyperoxaluria etiology of primary hyperoxaluria and should be carefully investigated for its involvement in oxalate metabolism.

scholarly journals Transcriptomic analysis identifies differences in gene expression in actinic keratoses after treatment with imiquimod and between responders and non responders

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Megan H. Trager ◽  
Emanuelle Rizk ◽  
Sharon Rose ◽  
Kuixi Zhu ◽  
Branden Lau ◽  
...  
Keyword(s):  
Gene Expression ◽  
Squamous Cell Carcinoma ◽  
Distinct Pattern ◽  
Study Endpoint ◽  
Inflammatory Gene Expression ◽  
Immune Modulators ◽  
Actinic Keratoses ◽  
Before And After ◽  
Pre Treatment

AbstractThe presence of actinic keratoses (AKs) increases a patient’s risk of developing squamous cell carcinoma by greater than six-fold. We evaluated the effect of topical treatment with imiquimod on the tumor microenvironment by measuring transcriptomic differences in AKs before and after treatment with imiquimod 3.75%. Biopsies were collected prospectively from 21 patients and examined histologically. RNA was extracted and transcriptomic analyses of 788 genes were performed using the nanoString assay. Imiquimod decreased number of AKs by study endpoint at week 14 (p < 0.0001). Post-imiquimod therapy, levels of CDK1, CXCL13, IL1B, GADPH, TTK, ILF3, EWSR1, BIRC5, PLAUR, ISG20, and C1QBP were significantly lower (adjusted p < 0.05). Complete responders (CR) exhibited a distinct pattern of inflammatory gene expression pre-treatment relative to incomplete responders (IR), with alterations in 15 inflammatory pathways (p < 0.05) reflecting differential expression of 103 genes (p < 0.05). Presence of adverse effects was associated with improved treatment response. Differences in gene expression were found between pre-treatment samples in CR versus IR, suggesting that higher levels of inflammation pre-treament may play a part in regression of AKs. Further characterization of the immune micro-environment in AKs may help develop biomarkers predictive of response to topical immune modulators and may guide therapy.

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