Tryptophan Abstracts 2

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Influence of oral contraceptives, pyridoxine (vitamin B6), and tryptophan on carbohydrate metabolism.
            (Adams et al., 1976) Download
Carbohydrate metabolism and vitamin-B6 status were assessed before and after pyridoxine administration in 46 women taking combined oestrogen-progestagen oral contraceptives (O.C.). 18 women had evidence of tissue depletion of vitamin B6, although all the women had abnormal tryptophan metabolism, including increased urinary xanthurenic acid (X.A.) excretion. In the women with vitamin B6 deficiency, administration of this vitamin caused elevation of fasting blood-pyruvate levels, and reduction in plasma glucose, insulin, and blood-pyruvate responses after an oral glucose load. These changes in carbohydrate metabolism were not found in the 28 non-vitamin-B6-deficient women. These results indicate that carbohydrate intolerance in women on O.C. is unlikely to be mediated by the formation of a complex of X.A. with insulin, as has formerly been proposed. Since the synthesis of the tryptophan metabolite quinolinic acid, an inhibitor of the heptaic enzyme phosphoenolpyruvate carboxykinase, may be enhanced by the administration of pyridoxine, it is suggested that this metabolite might be the important factor in the improvement of glucose tolerance in the vitamin-B6-deficient women. This conclusion is supported by the improvement in glucose tolerance observed in 6 women on O.C. and in 4 patients with glucocorticoid excess who were not vitamin-B6 deficient, when they were given tryptophan to augment the synthesis of quinolinic acid.

Metabolite profile analysis reveals functional effects of 28-day vitamin B-6 restriction on one-carbon metabolism and tryptophan catabolic pathways in healthy men and women.
            (da Silva et al., 2013) Download
Suboptimal vitamin B-6 status, as reflected by low plasma pyridoxal 5'-phosphate (PLP) concentration, is associated with increased risk of vascular disease. PLP plays many roles, including in one-carbon metabolism for the acquisition and transfer of carbon units and in the transsulfuration pathway. PLP also serves as a coenzyme in the catabolism of tryptophan. We hypothesize that the pattern of these metabolites can provide information reflecting the functional impact of marginal vitamin B-6 deficiency. We report here the concentration of major constituents of one-carbon metabolic processes and the tryptophan catabolic pathway in plasma from 23 healthy men and women before and after a 28-d controlled dietary vitamin B-6 restriction (<0.35 mg/d). liquid chromatography-tandem mass spectrometry analysis of the compounds relevant to one-carbon metabolism showed that vitamin B-6 restriction yielded increased cystathionine (53% pre- and 76% postprandial; P < 0.0001) and serine (12% preprandial; P < 0.05), and lower creatine (40% pre- and postprandial; P < 0.0001), creatinine (9% postprandial; P < 0.05), and dimethylglycine (16% postprandial; P < 0.05) relative to the vitamin B-6-adequate state. In the tryptophan pathway, vitamin B-6 restriction yielded lower kynurenic acid (22% pre- and 20% postprandial; P < 0.01) and higher 3-hydroxykynurenine (39% pre- and 34% postprandial; P < 0.01). Multivariate ANOVA analysis showed a significant global effect of vitamin B-6 restriction and multilevel partial least squares-discriminant analysis supported this conclusion. Thus, plasma concentrations of creatine, cystathionine, kynurenic acid, and 3-hydroxykynurenine jointly reveal effects of vitamin B-6 restriction on the profiles of one-carbon and tryptophan metabolites and serve as biomarkers of functional effects of marginal vitamin B-6 deficiency.

The physiological significance of the xanthurenic acid-insulin comples.
            (Kotake et al., 1975) Download
The xanthurenic acid-insulin complex was found to have similar immunological properties to native Zn-insulin. This complex showed less hormonal activity on glucose metabolism in adipose tissue than native An-insulin, but its activity was increased by addition of Zn2+ ions.

Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders.
            (Oxenkrug, 2011) Download
This review of literature and our data suggests that up-regulated production of interferon-gamma (IFNG) in periphery and brain triggers a merger of tryptophan (TRY)-kynurenine (KYN) and guanine-tetrahydrobiopterin (BH4) metabolic pathways into inflammation cascade involved in aging and aging-associated medical and psychiatric disorders (AAMPD) (metabolic syndrome, depression, vascular cognitive impairment). IFNG-inducible KYN/pteridines inflammation cascade is characterized by up-regulation of nitric oxide synthase (NOS) activity (induced by KYN) and decreased formation of NOS cofactor, BH4, that results in uncoupling of NOS that shifting arginine from NO to superoxide anion production. Superoxide anion and free radicals among KYN derivatives trigger phospholipase A2-arachidonic acid cascade associated with AAMPD. IFNG-induced up-regulation of indoleamine 2,3-dioxygenase (IDO), rate-limiting enzyme of TRY-KYN pathway, decreases TRY conversion into serotonin (substrate of antidepressant effect) and increases production of KYN associated with diabetes [xanthurenic acid (XA)], anxiety (KYN), psychoses and cognitive impairment (kynurenic acid). IFNG-inducible KYN/pteridines inflammation cascade is impacted by IFNG (+874) T/A genotypes, encoding cytokine production. In addition to literature data on KYN/TRY ratio (IDO activity index), we observe neopterin levels (index of activity of rate-limiting enzyme of guanine-BH4 pathway) to be higher in carriers of high (T) than of low (A) producers alleles; and to correlate with AAMPD markers (e.g., insulin resistance, body mass index, mortality risk), and with IFN-alpha-induced depression in hepatitis C patients. IFNG-inducible cascade is influenced by environmental factors (e.g., vitamin B6 deficiency increases XA formation) and by pharmacological agents; and might offer new approaches for anti-aging and anti-AAMPD interventions.

Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways.
            (Oxenkrug, 2013b) Download
Insulin resistance (IR) underlines aging and aging-associated medical (diabetes, obesity, dyslipidemia, hypertension) and psychiatric (depression, cognitive decline) disorders. Molecular mechanisms of IR in genetically or metabolically predisposed individuals remain uncertain. Current review of the literature and our data presents the evidences that dysregulation of tryptophan (TRP)-kynurenine (KYN) and KYN-nicotinamide adenine dinucleotide (NAD) metabolic pathways is one of the mechanisms of IR. The first and rate-limiting step of TRP-KYN pathway is regulated by enzymes inducible by pro-inflammatory factors and/or stress hormones. The key enzymes of KYN-NAD pathway require pyridoxal-5-phosphate (P5P), an active form of vitamin B6, as a cofactor. Deficiency of P5P diverts KYN-NAD metabolism from production of NAD to the excessive formation of xanthurenic acid (XA). Human and experimental studies suggested that XA and some other KYN metabolites might impair production, release, and biological activity of insulin. We propose that one of the mechanisms of IR is inflammation- and/or stress-induced upregulation of TRP-KYN metabolism in combination with P5P deficiency-induced diversion of KYN-NAD metabolism towards formation of XA and other KYN derivatives affecting insulin activity. Monitoring of KYN/P5P status and formation of XA might help to identify subjects at risk for IR. Pharmacological regulation of the TRP-KYN and KYN-NAD pathways and maintaining of adequate vitamin B6 status might contribute to prevention and treatment of IR in conditions associated with inflammation/stress-induced excessive production of KYN and deficiency of vitamin B6, e.g., type 2 diabetes, obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection.


 

Kynurenines and vitamin B6: link between diabetes and depression.
            (Oxenkrug et al., 2013) Download
The increased association between depression and diabetes mellitus is generally acknowledged. Recent studies suggest that depression leads to diabetes. However, the underlying molecular mechanisms for this association remain unclear. Literature and our data indicate that inflammatory and/or stress factors in depression up-regulate tryptophan (TRP) conversion into kynurenine (KYN), a substrate for nicotinamide adenine dinucleotide (NAD) biosynthesis. Deficiency of vitamin B6, a cofactor of the key enzymes of KYN - NAD pathway, shunts KYN metabolism from formation of NAD towards production of xanthurenic (XA) and kynurenic (KYNA) acids. Human and experimental studies reveal that XA, KYNA and their metabolites interfere with production, release and biological activity of insulin. We propose that inflammation- and/or stress-induced up-regulation of TRP - KYN metabolism in combination with vitamin B6 deficiency is one of the mechanisms mediating increased risk of diabetes in depression. Consequently, monitoring formation of diabetogenic KYN derivatives might help to identify subjects-at-risk for the development of diabetes. Pharmacological down-regulation of the TRP - KYN - NAD pathway and maintenance of adequate vitamin B6 status might help to prevent the development of diabetes in depression and other conditions associated with inflammation/stress- induced excessive production of KYN and vitamin B6 deficiency, e.g., obesity, cardiovascular diseases, aging, menopause, pregnancy, and hepatitis C virus infection.

Serotonin-kynurenine hypothesis of depression: historical overview and recent developments.
            (Oxenkrug, 2013a) Download
This mini-review focuses on the studies of late Prof. IP Lapin (1903 - 2012) and his research team on the role of methoxyindole and kynurenine (KYN) pathways of tryptophan (TRP) metabolism in the pathogenesis of depression and action mechanisms of antidepressant effect. In the late 60s of the last century Prof. IP Lapin suggested that "intensification of central serotoninergic processes is a determinant of the thymoleptic (mood elevating) component" while "activation of noradrenergic processes is responsible for psychoenergetic and motor-stimulating component of the clinical antidepressant effect". The cause of serotonin deficiency in depression was attributed to the shunt of TRP "metabolism away from serotonin production towards KYN production" due to cortisol-induced activation of liver enzyme, tryptophan 2,3- dioxygenase, the rate-limiting enzyme of TRP - KYN pathway. Prof. Lapin suggested and discovered that KYN and its metabolites affect brain functions, and proposed the role of neurokynurenines in pathogenesis of depression and action mechanisms of antidepressant effect (kynurenine hypothesis). Further research suggested the antidepressant and cognition- enhancing effects of post-serotonin metabolite, N-acetylserotonin (NAS), an agonist to tyrosine kinase B (TrkB) receptor; and link between depression and chronic inflammation-associated disorders (e.g., insulin resistance, hepatitis C virus) via inflammation-induced activation of indoleamine 2,3- dioxygenase, brain located rate-limiting enzyme of TRY - KYN metabolism. NAS and kynurenines might be the targets for prevention and treatment of depression and associated conditions.

Metabolite profile analysis reveals association of vitamin B-6 with metabolites related to one-carbon metabolism and tryptophan catabolism but not with biomarkers of inflammation in oral contraceptive users and reveals the effects of oral contraceptives on these processes.
            (Rios-Avila et al., 2015) Download
BACKGROUND: The use of oral contraceptives (OCs) has been associated with low plasma pyridoxal 5'-phosphate (PLP). The functional consequences are unclear. OBJECTIVES: To determine whether functional vitamin B-6 insufficiency occurs in OC users and is attributable to OCs, we investigated the associations of PLP with metabolites of one-carbon metabolism, tryptophan catabolism, and inflammation in OC users, and evaluated the effects of OCs on these metabolites. METHODS: Plasma metabolite concentrations were measured in 157 OC users (20-40 y of age). Associations between PLP and the metabolites were analyzed through use of generalized additive models and partial least squares-discriminant analysis (PLS-DA). Additionally, data from 111 of the 157 OC users were compared to previously reported data from 11 nonusers, at adequate and low vitamin B-6 status, with use of multivariate ANOVA. RESULTS: PLP showed significant (P < 0.05) negative nonlinear association with homocysteine, glutathione, and ratios of asymmetric dimethylarginine to arginine, 3-hydroxykynurenine to 3-hydroxyanthranilic acid, and 3-hydroxykynurenine to kynurenic acid. PLS-DA supported these conclusions and identified 3-hydroxykynurenine and the 3-hydroxykynurenine-to-kynurenine ratio as discriminating biomarkers in women with PLP </=30 nmol/L. Among the many differences, OC users had significantly higher plasma pyridoxal (157% at adequate and 195% at low vitamin B-6 status), 4-pyridoxic acid (154% at adequate and 300% at low vitamin B-6 status), xanthurenic acid (218% at low vitamin B-6 status), 3-hydroxyanthranilic acid (176% at adequate and 166% at low vitamin B-6 status), quinolinic acid (127% at low vitamin B-6 status), and nicotinamide (197% at low vitamin B-6 status). Biomarkers of inflammation were not associated with PLP, and no differences were found between the 2 groups. CONCLUSIONS: PLP is associated with biomarkers of one-carbon metabolism and tryptophan catabolism but not with biomarkers of inflammation in OC users. Independent of vitamin B-6 status, OCs have effects on metabolites and ratios of one-carbon metabolism and tryptophan catabolism but not on biomarkers of inflammation. This study was registered at clinicaltrials.gov as NCT01128244. The study from which data for nonusers was derived was registered as NCT00877812.

Effect of oral contraceptives and vitamin B6 deficiency on carbohydrate metabolism.
            (Rose et al., 1975) Download
Oral glucose tolerance, urinary xanthurenic acid excretion, and plasma pyridoxal phosphate concentrations were determined in nine women taking oral contraceptives and in four controls. The tests were repeated after 4 weeks ingestion of a vitamin B6-deficient diet, and again after pyridoxine supplementation. Vitamin B6 deficiency, as judged by an increased xanthurenic acid excretion and reduced plasma pyridoxal phosphate, was associated with a deterioration in the glucose tolerance of the contraceptive steroid-treated group despite normal or elevated plasma insulin levels. This abnormality was reversed by pyridoxine. There was no change in the glucose tolerance of the vitamin B6-deficient controls. The observed pyridoxine-responsive alteration in carbohydrate metabolism may involve the complexing of insulin with xanthurenic acid with a consequent loss of biological activity. In addition, oral contraceptives may enhance gluconeogensis.

Association of maternal diabetes with autism in offspring.
            (Xiang et al., 2015) Download
IMPORTANCE: Information about the association of maternal diabetes and autism spectrum disorders (ASDs) in offspring is limited, with no report on the importance of timing of exposure during gestation. OBJECTIVE: To assess ASD risk associated with intrauterine exposure to preexisting type 2 diabetes and gestational diabetes mellitus (GDM) by gestational age at GDM diagnosis. DESIGN, SETTING, AND PATIENTS: Retrospective longitudinal cohort study including 322 323 singleton children born in 1995-2009 at Kaiser Permanente Southern California (KPSC) hospitals. Children were tracked from birth until the first of the following: date of clinical diagnosis of ASD, last date of continuous KPSC health plan membership, death due to any cause, or December 31, 2012. Relative risks of ASD were estimated by hazard ratios (HRs) using Cox regression models adjusted for birth year. EXPOSURES: Maternal preexisting type 2 diabetes (n = 6496), GDM diagnosed at 26 weeks' gestation or earlier (n = 7456) or after 26 weeks' gestation (n = 17 579), or no diabetes (n = 290 792) during the index pregnancy. MAIN OUTCOMES AND MEASURES: Clinical diagnosis of ASD in offspring. RESULTS: During follow-up, 3388 children were diagnosed as having ASD (115 exposed to preexisting type 2 diabetes, 130 exposed to GDM at </=26 weeks, 180 exposed to GDM at >26 weeks, and 2963 unexposed). Unadjusted annual ASD incidences were 3.26, 3.02, 1.77, and 1.77 per 1000 among children of mothers with preexisting type 2 diabetes, GDM diagnosed at 26 weeks or earlier, GDM diagnosed after 26 weeks, and no diabetes, respectively. The birth year-adjusted HRs were 1.59 (95% CI, 1.29-1.95) for preexisting type 2 diabetes, 1.63 (95% CI, 1.35-1.97) for GDM diagnosed at 26 weeks or earlier, and 0.98 (95% CI, 0.84-1.15) for GDM diagnosed after 26 weeks relative to no exposure. After adjustment for maternal age, parity, education, household income, race/ethnicity, history of comorbidity, and sex of the child, maternal preexisting type 2 diabetes was not significantly associated with risk of ASD in offspring (HR, 1.21; 95% CI, 0.97-1.52), but GDM diagnosed at 26 weeks or earlier remained so (HR, 1.42; 95% CI, 1.15-1.74). Antidiabetic medication exposure was not independently associated with ASD risk. Adjustment for a mother or older sibling with ASD in the full cohort and for maternal smoking, prepregnancy body mass index, and gestational weight gain in the subset with available data (n = 68 512) did not affect the results. CONCLUSIONS AND RELEVANCE: In this large, multiethnic clinical cohort of singleton children born at 28 to 44 weeks' gestation, exposure to maternal GDM diagnosed by 26 weeks' gestation was associated with risk of ASD in offspring.

 


 

References

Adams, PW, et al. (1976), ‘Influence of oral contraceptives, pyridoxine (vitamin B6), and tryptophan on carbohydrate metabolism.’, Lancet, 1 (7963), 759-64. PubMedID: 56585
da Silva, VR, et al. (2013), ‘Metabolite profile analysis reveals functional effects of 28-day vitamin B-6 restriction on one-carbon metabolism and tryptophan catabolic pathways in healthy men and women.’, J Nutr, 143 (11), 1719-27. PubMedID: 23966327
Kotake, Y, et al. (1975), ‘The physiological significance of the xanthurenic acid-insulin comples.’, J Biochem, 77 (3), 685-87. PubMedID: 1150636
Oxenkrug, G (2013a), ‘Serotonin-kynurenine hypothesis of depression: historical overview and recent developments.’, Curr Drug Targets, 14 (5), 514-21. PubMedID: 23514379
——— (2013b), ‘Insulin resistance and dysregulation of tryptophan-kynurenine and kynurenine-nicotinamide adenine dinucleotide metabolic pathways.’, Mol Neurobiol, 48 (2), 294-301. PubMedID: 23813101
Oxenkrug, G, R Ratner, and P Summergrad (2013), ‘Kynurenines and vitamin B6: link between diabetes and depression.’, J Bioinform Diabetes, 1 (1), PubMedID: 25401165
Oxenkrug, GF (2011), ‘Interferon-gamma-inducible kynurenines/pteridines inflammation cascade: implications for aging and aging-associated psychiatric and medical disorders.’, J Neural Transm, 118 (1), 75-85. PubMedID: 20811799
Rios-Avila, L, et al. (2015), ‘Metabolite profile analysis reveals association of vitamin B-6 with metabolites related to one-carbon metabolism and tryptophan catabolism but not with biomarkers of inflammation in oral contraceptive users and reveals the effects of oral contraceptives on these processes.’, J Nutr, 145 (1), 87-95. PubMedID: 25527663
Rose, DP, et al. (1975), ‘Effect of oral contraceptives and vitamin B6 deficiency on carbohydrate metabolism.’, Am J Clin Nutr, 28 (8), 872-78. PubMedID: 1146747
Xiang, AH, et al. (2015), ‘Association of maternal diabetes with autism in offspring.’, JAMA, 313 (14), 1425-34. PubMedID: 25871668