Urinary Tryptophan Metabolites Research Articles

Altered urinary tryptophan metabolites in alcohol-associated liver disease.

Alcohol-associated liver disease (ALD) leads to millions of deaths worldwide annually. A few potential biomarkers of ALD have been discovered through metabolomic or proteomic analysis. Tryptophan (Trp), one of nine essential amino acids, has been extensively studied and shown to play significant roles in many mammalian physiological processes. However, Trp metabolism changes in ALD are not yet fully understood. Whereas urine is an abundant and non-invasive source for disease biomarker discovery the current study investigated whether the abundance of Trp metabolites in the urine of ALD patients differs from that of healthy subjects. We also examined whether, if present in ALD, changes in urinary Trp metabolites can serve as markers for differentiating between mild/moderate and severe ALD. We quantified the concentration of Trp and its metabolites in urine samples of healthy controls (n = 18), patients with mild or moderate alcohol-related liver injury (non-severe ALD; n = 21), and patients with severe alcohol-associated hepatitis (severe AH; n = 25) using both untargeted and targeted metabolomics. Eighteen Trp metabolites were identified and quantified from the untargeted metabolomics data. We developed a targeted metabolomics method to quantify the Trp and its metabolites and quantified 17 metabolites from the human urine samples. The data acquired in the untargeted and targeted platforms agreed and showed that the Trp concentration is not affected by the severity of ALD. However, the abundance of 10 Trp metabolites was correlated with the model for end-stage liver disease (MELD) score, with the abundance of nine metabolites significantly different between the healthy control and ALD patient groups. We found that Trp metabolism differs between ALD patients and healthy controls even though the concentration of Trp was not affected. Two Trp metabolites, quinolinic acid and indoxyl sulfate, correlate highly with the severity of ALD.

Vitamin B-6 Status of Women with a Constant Intake of Vitamin B-6 Changes with Three Levels of Dietary Protein

To determine the effect of varying levels of dietary protein with a constant intake of vitamin B-6 (B-6) on B-6 status, nine women were fed diets providing daily intakes of 1.25 mg B-6 and 0.5, 1.0 and 2.0 g protein/kg body weight. After an 8-d adjustment period, the women consumed each level of dietary protein for 14 d in a Latin-square design. Several direct and indirect B-6 status indicators were measured in blood and urine. Significant differences among protein levels were found for urinary 4-pyridoxic acid (4-PA) excretion (P < 0.01), plasma pyridoxal 5′-phosphate (PLP) concentration (P < 0.05), and urinary excretion of volatile amines (VA, kynurenine plus acetylkynurenine) after a 2-g L-tryptophan load (P < 0.05). Nitrogen intake was significantly negatively correlated with urinary 4-PA excretion (r = -0.619, P < 0.001) and plasma PLP concentration (r = -0.549, P < 0.01), and positively correlated with erythrocyte alanine aminotransferase percentage stimulation (r = 0.418, P < 0.05) and urinary post-tryptophan load excretion of xanthurenic acid (r = 0.535, P < 0.05), kynurenic acid (r = 0.563, P < 0.05) and VA (r = 0.626, P < 0.01). Compared with men consuming diets with similar B-6 to protein ratios in a previous study, the women excreted a greater percentage of the B-6 intake as 4-PA, had lower plasma PLP concentrations and excreted greater amounts of postload urinary tryptophan metabolites at all three protein levels. If the Recommended Dietary Allowance (RDA) of vitamin B-6 is to be based on the dietary B-6 to protein ratio, gender differences in response to varying protein intakes should be considered. For the levels of protein intake used in this study and a B-6 intake of 1.25 mg/d, a B-6 to protein ratio of greater than 0.020 mg/g is required for adequate vitamin B-6 status in women.

Feed your microbes to deal with stress: a psychobiotic diet impacts microbial stability and perceived stress in a healthy adult population

The impact of diet on the microbiota composition and the role of diet in supporting optimal mental health have received much attention in the last decade. However, whether whole dietary approaches can exert psychobiotic effects is largely understudied. Thus, we investigated the influence of a psychobiotic diet (high in prebiotic and fermented foods) on the microbial profile and function as well as on mental health outcomes in a healthy human population. Forty-five adults were randomized into either a psychobiotic (n = 24) or control (n = 21) diet for 4 weeks. Fecal microbiota composition and function was characterized using shotgun sequencing. Stress, overall health and diet were assessed using validated questionnaires. Metabolic profiling of plasma, urine and fecal samples was performed. Intervention with a psychobiotic diet resulted in reductions of perceived stress (32% in diet vs. 17% in control group), but not between groups. Similarly, biological marker of stress were not affected. Additionally, higher adherence to the diet resulted in stronger decreases in perceived stress. While the dietary intervention elicited only subtle changes in microbial composition and function, significant changes in the level of 40 specific fecal lipids and urinary tryptophan metabolites were observed. Lastly, microbial volatility was linked to greater changes in perceived stress scores in those on the psychobiotic diet. These results highlight that dietary approaches can be used to reduce perceived stress in a human cohort. Using microbiota-targeted diets to positively modulate gut-brain communication holds possibilities for the reduction of stress and stress-associated disorders, but additional research is warranted to investigate underlying mechanisms, including the role of the microbiota.

Tryptophan: Its Metabolism along the Kynurenine, Serotonin, and Indole Pathway in Malignant Melanoma.

(1) Background: Tryptophan metabolism is known to be one of the important mechanisms used by cancer to evade immune surveillance. Altered tryptophan metabolism was studied in patients with pigmented malignant melanoma confirmed histologically by the anatomic stage grouping for cutaneous melanoma using clinical staging on the basis of the Breslow thickness of the melanoma, the degree of spread to regional lymph nodes, and by the presence of distant metastasis. (2) Methods: Urinary tryptophan metabolites were detected by RP-HPLC method. (3) Results: In the present work, we provided evidence of altered metabolism of all tryptophan pathways in melanoma patients. (4) Conclusions: Knowledge of the shifted serotonin pathway toward DHICA formation and kynurenine pathway shifted toward NAD+ production could serve in the early detection of the disease and the initiation of early treatment of malignant melanoma.

The evaluation of therapeutic horticulture effects on urinary tryptophan metabolites by using the spectrofluorimetric analysis in a group of students

The evaluation of therapeutic horticulture effects on urinary tryptophan metabolites by using the spectrofluorimetric analysis in a group of students

Quantification of urinary tryptophan metabolites and evaluation of their potential use as urothelial cancer biomarkers

Quantification of urinary tryptophan metabolites and evaluation of their potential use as urothelial cancer biomarkers

A Case of Isoniazid-induced Psychosis in a 42-year-old Man with Schizophrenia

Introduction Cases of isoniazid-related psychiatric disordersreported in the literature include psychosis, obsessive–compulsive neurosisand mania. Tuberculosis is an endemic issue in our area; so much people receiveprophylactic treatment for tuberculosis. Pyridoxine deficiency may play a rolein the pathogenesis of isoniazid-induced psychosis. Such deficiency states maybe detected indirectly by measuring urinary metabolites of tryptophan. Methods We performeda retrospective analysis of those patients in the literature and we report acase of isoniazid-induced psychosis in a 42-year-old man with schizophrenia andalcohol dependence. He was abstinent during the last six months. Results A 42-year-old man with schizophrenia, in full remission for the last twoyears, presented psychotic symptoms (delusions and hallucinations) suspected tobe related to prophylactic treatment with isoniazid after his brother testedpositive to a tuberculin test. The psychotic symptoms resolved completely afterisoniazid was discontinued. We didn´t change his treatment during the episode(Clopixol 200mg/21 days). Conclusions Clinicians should be aware of this adverseeffect of isoniazid and that it may present with a broad clinical picture. As aresult of our findings we coordinated a clinical session with others HospitalDepartments. 1 Isoniazid-Induced Psychosis Ann Pharmacother September 1998 32: 889-891. 2 Vallejo Ruiloba J, Leal Cercos C. Tratado de Psiquiatria. 20. ed. Barcelona: Ars Medica; 2010

長期補助循環中の尿中トリプトファン代謝産物と炎症性ストレス反応の関係

補助循環中の症例から、連続する2週間に尿中に排泄された必須アミノ酸のトリプトファンの代謝産物のうち、キヌレニン経路からの代謝産物を測定した。比較対照として肝機能指標である総アルブミン、AST、肝臓で産生される腎機能指標BUNおよび炎症性ストレス反応物質であるCRP、プロカルシトニン、尿中コルチゾールを測定した。トリプトファン代謝は肝臓で行われるため、肝機能指標との関係が示された。また、トリプトファン代謝産物の経日的な動態から補助循環回路などに使われる可塑剤の影響が示唆された。更に、肝臓の重要な機能である栄養代謝のうち、エネルギー賦活源であるNADや解糖系への代謝障害が示唆され、栄養学的な観点からも重要な課題と考えられる。また、トリプトファン代謝産物と炎症性ストレス反応物質との間に高い相関係数が得られ、抗ストレス性、炎症反応との関連なども示された。

Recognizing purple bag syndrome at first look

Purple urine bag syndrome is a clinical entity first described in 1978. Its typical discoloration is worrying for clinicians. In the past, these patients sometimes reached the emergency unit only because of this exceptional worrying urinary sign and underwent invasive diagnostic examinations including cystoscopy, without any abnormal finding. It is now clear that this astonishing phenomenon of double discoloration of the urine, appearing purple in the bag and dark blue in the test tube, results from the formation of 2 different pigments (indirubin and indigo) in very alkaline urines due to enzymes produced by gram-negative bacteria, such as indoxyl phosphatase/sulfatase, which can convert urinary metabolites of dietary tryptophan. Practicing physicians should identify purple urine bag syndrome as a usually benign medical condition diagnosed in asymptomatic patients, which only requires treatment of bacteriuria with antibiotics, prevention of constipation, substitution of catheter and acidification of the urine. After these measures, urine typically returns to its normal color.

Melatonin and Elimination of Kynurenines in Children with Down's Syndrome

Heightened activity of superoxide dimutase is an effect derived from the gene dose in the trisomy of Down's syndrome (DS), and has been related to the increased production of hydrogen peroxide and with greater lipid peroxidation. Many of the degenerative changes observed in patients with DS have been associated with the pathological effects of free radicals, and for this reason it is of interest to determine the levels present in these patients of powerful antioxidant molecules such as melatonin, and of metabolites with important neuroprotector and neurotoxic consequences such as those derived from the kynurenine pathway. A study was made of 15 children with DS, together with a control group of 15 non-DS children, matched for age and sex, examined at the Hospital Costa del Sol, Marbella, Spain. Serum melatonin and serotonin were analyzed by RIA; urinary tryptophan metabolites (kynurenine pathway) were determined during periods of light and darkness (09.00-21.00 h and 21.00-9.00 h) by thin-layer chromatography. The mean values of serotonin and melatonin were found to be lower in the patients with DS, although the level of nocturnal secretion of melatonin was higher. Urinary excretion of kynurenine was lower in the patients with DS, although greater quantities of kynurenic acid and anthranilic acid were excreted. Patients with DS present levels of plasma melatonin and urinary kynurenine that are lower than the corresponding levels in the control population, together with higher values of kynurenic acid and anthranilic acid. These circumstances constitute an added risk to these patients of damage by free radicals.

Effect of high intake of leucine on urinary tryptophan and niacin metabolites in humans.

Journal Article Effect of High Intake of Leucine on Urinary Tryptophan and Niacin Metabolites in Humans Get access Nutrition Reviews, Volume 34, Issue 4, April 1976, Pages 105–107, https://doi.org/10.1111/j.1753-4887.1976.tb05720.x Published: 01 April 1976

Urinary tryptophan metabolites in diabetic and non-diabetic juveniles

Levels of urinary tryptophan metabolites anthranilic acid (AA), 5-hydroxyindoleacetic acid (5HIAA), and indoleacetic acid (IAA) were measured by HPLC for 24 diabetic (insulin dependent diabetes mellitus; IDDM) and 12 non-diabetic human juveniles. A single urine collection was used to examine tryptophan metabolism by ratio comparisons of AA:5HIAA and AA:IAA. Ratios were calculated from peak areas. Ratios of AA:5HIAA were significantly (p=0.0001) lower in diabetic juveniles (0.19) compared to juveniles without diabetes (1.18). Ratios of AA:IAA were also significantly (p=0.0001) lower in juveniles with diabetes (0.54) compared to juveniles without diabetes (4.29). Neither race nor gender had a significant effect on ratios. These data suggested altered activity in the kynurenine pathway in IDDM subjects. Within the experimental group, ratios of AA:5HIAA were significantly (p=0.0191) different between subjects with Finger Stick Blood Sugar (FSBS) values that were below 70 mg/dl compared to those with levels between 100–250 mg/dl. No other significant effects (Hemoglobin A 1C, insulin concentration or duration of disease) were found within the experimental group.

Pellagra with colitis due to a defect in tryptophan metabolism

A 9-year-old girl presented with a red scaly rash confined to sun-exposed areas which started at 2 years of age and had the appearance of pellagra. Investigation of urinary tryptophan metabolites following an oral tryptophan load, showed increased excretion of kynurenine and kynurenic acid but reduced excretion of 3-hydroxy-kynurenine, xanthurenic acid and N1-methyl nicotinamide. These results indicated a defect in the hydroxylation of kynurenine, an important reaction in the synthesis of the nicotinamide nucleotide coenzymes, NAD and NADP, from tryptophan. The patient went on to develop severe colitis and psychological changes. All her symptoms responded to treatment with nicotinamide.

Measurement of urinary tryptophan metabolites by reverse-phase high-pressure liquid chromatography

Rapid, sensitive separation and determination of tryptophan, N′-for-mylkynurenine, kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid, nicotinic acid, nicotinamide, trigonelline, kynurenic acid, and xanthurenic acid in untreated and extracted urine were achieved using reverse-phase high-pressure liquid chromatography. Accuracy of the measurements is 5% or better and 50 pmole of each compound can be reliably measured. Determination of quinolinic acid was not possible with the conditions used. The method was found to be suitable for the analysis of urinary metabolites in a normal human subject under basal conditions and after tryptophan loading.

Urinary metabolites of tryptophan, serotonin and norepinephrine in alcoholics.

Levels of tryptamine, 3-methoxy-4-hydroxy phenylethylene glycol, 3-methoxy-4-hydroxy mandelic acid and the tryptamine: 5-hydroxyindole-3-acetic acid ratio differed between alcoholics, healthy volunteers and patients with nonalcoholic liver disease. There was no correlation between amine metabolite levels and results of liver function tests.

Effect of Diet Restriction on Some Key Enzymes of Tryptophan-NAD Pathway in Rats

Dietary intake of rats was restricted by feeding varying amounts of a 20% protein diet. After 6 weeks of feeding, some key enzymes of the tryptophan and nicotinic acid-NAD pathway, liver nicotinamide nucleotide concentration, and urinary metabolites of tryptophan and nicotinic acid were studied. With an increase in diet restriction, liver tryptophan oxygenase (EC 1.13.1.12) activity increased. Quinolinate phosphoribosyltransferase (EC 2.4.2.a) activity, on the other hand, was found to decrease with moderate diet restriction up to 50% restriction, but increased again with more severe diet restriction in rats fed 25% of ad libitum intake. Liver nicotinate phosphoribosyltransferase (EC 2.4.2.11) activity was also observed to decrease with moderate diet restriction and did not further change when the restriction was severe while picolinate carboxylase (EC 4.1.1.45) activity increased significantly only in severe diet restriction. In rats fed 25% of ad libitum intake, urinary quinolinic acid excretion was low whereas N'-methylnicotinamide excretion was elevated. Alterations in the enzyme activities accompanied by changes in the levels of urinary metabolites, observed in the present study, suggest that the potential efficiency of conversion of tryptophan to nicotinamide nucleotides is not constant and is influenced by dietary intake.

Effect of dietary protein level on some key enzymes of the tryptophan-NAD pathway

1. Six groups of rats were given diets containing protein at three levels (50, 100 and 200 g/kg), with and without nicotinic acid. After 4 weeks on these diets some key enzymes of the tryptophan and nicotinic acid-NAD pathway, liver nicotinamide nucleotide concentration, and urinary metabolites of tryptophan and nicotinic acid were studied. 2. Liver nicotinamide nucleotide levels were lower in rats given the diet with 50 g protein/kg as compared to those in rats given diets with 100 and 200 g protein/kg. The addition of nicotinic acid to the diet resulted in a significant increase in the levels of nicotinamide nucleotides only in rats given 50 g protein/kg diet but not in those given either 100 or 200 g protein/kg diet. 3. Liver tryptophan oxygenase (EC 1.13.1.12) activity increased with increasing dietary protein level. Niconitic acid in the diet had no effect on its activity. 4. Quinolinate phosphoribosyltransferase (EC 2.4.2.a) activity in liver was inversely related to dietary protein level, and nicotinic acid in the diet had no effect on its activity. 5. Liver nicotinate phosphoribosyltransferase (EC 2.4.2.11) activity and kidney picolinate carboxylase (EC 4.1.1.45) activity were not altered either by dietary protein level or nicotinic acid in the diet. 6. The addition of nicotinic acid to the diet resulted in increased excretion of N'-methylnicotinamide at all dietary protein levels. 7. The inverse relationship between protein level in the diet and liver quinolinate phosphoribosyltransferase activity, the rate-limiting enzyme of the tryptophan-NAD pathway suggests that the efficiency of conversion of tryptophan to NAD is related to protein level in the diet, the efficiency decreasing with an increase in the level of dietary protein.

The role of L-tryptophan's promoting factor on tumorgenesis in the urinary bladder. 1. A study on the urinary tryptophan metabolites (author's transl)

To study the correlation between urinary tryptophan metabolites and etiology of bladder tumor, an excretion of urinary tryptophan metabolites (kynurenine and 3-hydroxy-kynurenine: abbreviated as kyn. comp.) before and after a 3gm load of L-tryptophan was measured among the male patients with spontaneous bladder tumor (28 cases), occupational bladder tumor (12 cases), dyestuff worker (9 cases), and for the control normal healthy subjects (41 cases: 22 males, 17 females).The results were:1) In 41 control subjects, pre-loading values were low in both sexes and sexual differences were negligible. However, since the post-loading values among the female subjects were high especially with those who were at the immediate post menstrual stage, only male subjects were used as controls.2) In those patients who had spontaneous bladder tumor, occupational bladder tumor, and dyestuff workers, both pre- and post-loading values were high compared to the control values. These values were statistically significant by Student t test, though their increased values (post-loading value minus per-loading value) were statistically insignificant.3) Post-loading plasma tryptophan values of spontaneous bladder tumor patients were slightly lower than that of control subjects. The values of plasma kyn. comp, were so low that exact measurement of this value was impossible in general.4) Differences in urinary levels of kyn. comp. following the diet containing 3gm of L-tryptophan compared to those following the diet containing 1gm of L-tryptophan were insignificant.

The effect of cycloserine on pyridoxine-dependent metabolism in tuberculosis.

Measurements were made of urinary tryptophan metabolites of 13 tuberculosis patients in order to reveal characteristics of pyridoxine-dependent metabolism before and during cycloserine treatment. The abnormally high level of xanthurenic acid excretion in untreated patients suggests a decreased availability of pyridoxal phosphate related to the disease process. Although plasma cycloserine levels were kept high once therapy began, xanthurenic acid excretion before and after tryptophan load became progressively more normal as symptoms diminished. This observation suggests that the convulsions which may sometimes accompany cycloserine administration are not due to a direct pyridoxine antagonism by the drug. Throughout the study, no significant changes in 5-hydroxyindoleacetic acid excretion were observed. Presumably, the metabolic pathway of serotonin is unaffected by tryptophan loading, cycloserine administration, or the apparent pyridoxine depletion associated with tuberculosis.

Metabolism of D- and L-Tryptophan in Dogs

The metabolism of D- and L-[benzene ring-U-14C]tryptophan by dogs was studied. The distribution of label from each isomer in urine, feces, CO2 and various tissues was determined. Thirteen different urinary tryptophan metabolites were isolated by ion exchange cellulose chromatography. D-[14C]Tryptophan was poorly converted to 14CO2 relative to the L-isomer, while giving rise to nearly three times as much urinary 14C as did the L-isomer. The major urinary metabolites of D-tryptophan were unchanged D-tryptophan via indolepyruvic acid appeared to be the major fate of ingested D-tryptophan, with renal excretion of the unchanged D-isomer the next most important fate. The dog apparently utilizes D-tryptophan more efficiently than does the human but much less efficiently than does the rat. The dog appears to be a reasonable animal model for the human in studies of D-tryptophan metabolism.