Tryptophan Abstracts 1

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Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan.
            (Allen et al., 2011) Download
Eosinophilia-myalgia syndrome (EMS) is characterized by subacute onset of myalgias and peripheral eosinophilia, followed by chronic neuropathy and skin induration. An epidemic of EMS in 1989 was linked to consumption of L-tryptophan that had originated from a single source. Following the ban by the Food and Drug Administration (FDA) on the sale of L-tryptophan, the incidence of EMS declined rapidly. Moreover, no new cases have been described since the FDA ban was lifted in 2005. We report the clinical, histopathologic, and immunogenetic features of a new case of L-tryptophan-associated EMS, along with evidence of activated transforming growth factor beta and interleukin-4 signaling in the lesional skin.

A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM).
            (Blankfield, 2012) Download
Last century there was a short burst of interest in the tryptophan related disorders of pellagra and related abnormalities that are usually presented in infancy.1,2 Nutritional physiologists recognized that a severe human dietary deficiency of either tryptophan or the B group vitamins could result in central nervous system (CNS) sequelae such as ataxia, cognitive dysfunction and dysphoria, accompanied by skin hyperpigmentation.3,4 The current paper will focus on the emerging role of tryptophan in chronic fatigue syndrome (CFS) and fibromyalgia (FM).

L -5-Hydroxytryptophan treatment of sleep terrors in children.
            (Bruni et al., 2004) Download
To test the hypothesis that the administration of L -5-hydroxytryptophan (L -5-HTP) might exert beneficial effects on sleep terrors, we carried out an open pharmacological trial in a group of children with sleep terrors compared to a group of children with the same disorder but without L -5-HTP treatment. Participants in the trial were 45 children (34 males and 11 females; age range 3.2-10.6 years), referred to the Sleep Centre of the Department of Developmental Neurology and Psychiatry of the University of Rome "La Sapienza", affected by sleep terrors. All subjects underwent: (1) complete medical and sleep history; (2) complete neurological examination and EEG recording whilst awake and sleeping, (3) a structured sleep diary for 2 months, (4) after 1 month, all subjects were examined again from the clinical and EEG points of view and (5) after 6 months, a structured interview in order to evaluate the clinical outcome. After the first visit, L -5-HTP was administered (2 mg/kg per day) at bedtime to 31 randomly selected patients for a single period of 20 consecutive days. After 1 month of treatment, 29/31 (93.5%) of patients showed a positive response. In the comparison group without drug therapy, after 1 month, the episodes disappeared only in four children (28.6%) while ten children (71.4%) showed the persistence of episodes with the same frequency as before. After 6 months, 26/31 (83.9%) of children treated with L -5HTP were sleep terror-free, while in five children (16.1%) sleep terror episodes persisted. Of the children in the comparison group, ten (71.4%) continued to show sleep terrors at 6-month follow-up. CONCLUSION: to our knowledge, this is the first study demonstrating the efficacy of a new drug treatment for sleep terrors. These results confirm our initial hypothesis and represent evidence that treatment with L -5-hydroxytryptophan is able to modulate the arousal level in children and to induce a long-term improvement of sleep terrors.

The vitamin B6 requirement in oral contraceptive users. II. Assessment by tryptophan metabolites, vitamin B6, and pyridoxic acid levels in urine.
            (Donald and Bosse, 1979) Download

Effects and side effects associated with the non-nutritional use of tryptophan by humans.
            (Fernstrom, 2012) Download
The daily nutritional requirement for L-tryptophan (Trp) is modest (5 mg/kg). However, many adults choose to consume much more, up to 4-5 g/d (60-70 mg/kg), typically to improve mood or sleep. Ingesting L-Trp raises brain tryptophan levels and stimulates its conversion to serotonin in neurons, which is thought to mediate its actions. Are there side effects from Trp supplementation? Some consider drowsiness a side effect, but not those who use it to improve sleep. Though the literature is thin, occasional side effects, seen mainly at higher doses (70-200 mg/kg), include tremor, nausea, and dizziness, and may occur when Trp is taken alone or with a drug that enhances serotonin function (e.g., antidepressants). In rare cases, the "serotonin syndrome" occurs, the result of too much serotonin stimulation when Trp is combined with serotonin drugs. Symptoms include delirium, myoclonus, hyperthermia, and coma. In 1989 a new syndrome appeared, dubbed eosinophilia myalgia syndrome (EMS), and was quickly linked to supplemental Trp use. Key symptoms included debilitating myalgia (muscle pain) and a high peripheral eosinophil count. The cause was shown not to be Trp but a contaminant in certain production batches. This is not surprising, because side effects long associated with Trp use were not those associated with the EMS. Over 5 decades, Trp has been taken as a supplement and as an adjunct to medications with occasional modest, short-lived side effects. Still, the database is small and largely anecdotal. A thorough, dose-related assessment of side effects remains to be conducted.

Fate of dietary tryptophan in young Japanese women.
            (Hiratsuka et al., 2012) Download
The purpose of this study was to determine, using the high-performance liquid chromatographic methods recently modified by us, the fate of dietary tryptophan in 17 healthy female Japanese adults who ate self-selected food. The experimental period was 22 days. The habitual intake of tryptophan was 3328.4 mumol/day. 24-hour urine samples were collected at the beginning of the experiment and then once per week. Blood was collected at the beginning and end of the experiment. Levels of tryptophan and its metabolites were measured in blood and urine. Tryptophan, nicotinamide and 2-oxoadipic acid were the major compounds of the blood. The urinary excretion amounts of tryptophan, 5-hydroxyindole-3-acetic acid, kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, 3-hydroxyanthranilic acid and quinolinic acid were about 40, 20, 4, 1, 10, 4, 3, 5 and 20 mumol/day, respectively.

Supplementing healthy women with up to 5.0 g/d of L-tryptophan has no adverse effects.
            (Hiratsuka et al., 2013) Download
Because of the frequent use of L-tryptophan (L-Trp) in dietary supplements, determination of the no-observed-adverse-effect-level is desirable for public health purposes. We therefore assessed the no-observed-adverse-effect-level for L-Trp and attempted to identify a surrogate biomarker for excess L-Trp in healthy humans. A randomized, double-blind, placebo-controlled, crossover intervention study was performed in 17 apparently healthy Japanese women aged 18-26 y with a BMI of approximately 20 kg/m(2). The participants were randomly assigned to receive placebo (0 g/d) or 1.0, 2.0, 3.0, 4.0, or 5.0 g/d of L-Trp for 21 d each with a 5-wk washout period between trials. Food intake, body weight, general biomarkers in blood and urine, and amino acid composition in blood and urine were not affected by any dose of L-Trp. Administration of up to 5.0 g/d L-Trp had no effect on a profile of mood states category measurement. The urinary excretion of nicotinamide and its catabolites increased in proportion to the ingested amounts of L-Trp, indicating that participants could normally metabolize this amino acid. The urinary excretion of L-tryptophan metabolites, including kynurenine (Kyn), anthranilic acid, kynurenic acid, 3-hydroxykynurenine (3-HK), 3-hydroxyanthranilic acid, and quinolinic acid (QA), all of which are intermediates of the L-TRP-->Kyn-->QA pathway, was in proportion to L-Trp loading. The response of 3-HK was the most characteristic of these L-Trp metabolites. This finding suggests that the urinary excretion of 3-HK is a good surrogate biomarker for excess L-Trp ingestion.

Maternal tryptophan and kynurenine pathway metabolites and risk of preeclampsia.
            (Nilsen et al., 2012) Download
OBJECTIVE: To estimate the association of maternal plasma concentrations of tryptophan and six kynurenine pathway metabolites with the risk of preeclampsia. METHODS: The study was based on a subsample of 2,936 pregnant women who delivered singleton neonates in the Norwegian Mother and Child Cohort Study in 2002-2003. Maternal blood plasma was obtained at approximately gestational week 18 and was measured for tryptophan, kynurenine, kynurenic acid, anthranilic acid, 3-hydroxykynurenine, xanthurenic acid, and 3-hydroxyanthranilic acid. RESULTS: Of the 2,936 pregnant women included in this study, 116 (4.0%, 95% confidence interval [CI] 3.2-4.7) had preeclampsia subsequently diagnosed. The prevalence of preeclampsia was significantly higher among women with plasma kynurenic acid concentrations greater than the 95th percentile than among those with concentrations in the 25th-75th percentile (11.0% compared with 3.3%, P<.001; adjusted odds ratio 3.6, 95% CI 1.9-6.8). This association was significantly stronger in women with prepregnancy body mass index of 25 or more (P for interaction=.03; 20.4% compared with 4.2%; P<.001). No statistically significant associations of preeclampsia with other tryptophan metabolites were found. CONCLUSION: Elevated maternal plasma kynurenic acid concentrations in early pregnancy are associated with a substantial increased risk of preeclampsia in obese women. LEVEL OF EVIDENCE: II.

Immunogenetic risk and protective factors for the development of L-tryptophan-associated eosinophilia-myalgia syndrome and associated symptoms.
            (Okada et al., 2009) Download
OBJECTIVE: To assess L-tryptophan (LT) dose, age, sex, and immunogenetic markers as possible risk or protective factors for the development of LT-associated eosinophilia-myalgia syndrome (EMS) and related clinical findings. METHODS: HLA-DRB1 and DQA1 allele typing and Gm/Km phenotyping were performed on a cohort of 94 white subjects with documented LT ingestion and standardized evaluations. Multivariate analyses compared LT dose, age, sex, and alleles among groups of subjects who ingested LT and subsequently developed surveillance criteria for EMS, developed EMS or characteristic features of EMS (EMS spectrum disorder), or developed no features of EMS (unaffected). RESULTS: Considering all sources of LT, higher LT dose (odds ratio [OR] 1.4, 95% confidence interval [95% CI] 1.1-1.8), age >45 years (OR 3.0, 95% CI 1.0-8.8), and HLA-DRB1*03 (OR 3.9, 95% CI 1.2-15.2), DRB1*04 (OR 3.9, 95% CI 1.1-16.4), and DQA1*0601 (OR 13.7, 95% CI 1.3-1.8) were risk factors for the development of EMS, whereas DRB1*07 (OR 0.12, 95% CI 0.02-0.48) and DQA1*0501 (OR 0.23, 95% CI 0.05-0.85) were protective. Similar risk and protective factors were seen for developing EMS following ingestion of implicated LT, except that DRB1*03 was not a risk factor and DQA1*0201 was an additional protective factor. EMS spectrum disorder also showed similar findings, but with DRB1*04 being a risk factor and DRB1*07 and DQA1*0201 being protective. There were no differences in sex distribution, Gm/Km allotypes, or Gm/Km phenotypes among any groups. CONCLUSION: In addition to the xenobiotic dose and subject age, polymorphisms in immune response genes may underlie the development of certain xenobiotic-induced immune-mediated disorders, and these findings may have implications for future related epidemics.

Urinary excretory ratio of anthranilic acid/kynurenic acid as an index of the tolerable amount of tryptophan.
            (Okuno et al., 2008) Download
Some people may take excessive tryptophan as a supplement in the expectation that the tryptophan metabolite, melatonine, will help to induce sufficient sleep. We investigated the basis for a useful index to assess the risk of a tryptophan excess. Young rats were fed on a 20% casein diet with 0, 0.5, 1.0, 2.0 or 5.0% added tryptophan for 30 d the apparent toxicity and growth retardation was observed in the 5.0% tryptophan-added group. Metabolites of the Tryptophan-nicotinamide pathway and such intermediates as kynurenic acid (KA), anthranilic acid (AnA), xanthurenic acid, 3-hydroxyanthranilic acid and quinolinic acid in 24-h urine increased in a dose-dependent manner. Of those metabolites and intermediates, the urinary excretion of KA progressively increased, and that of AnA dramatically increased in the 2.0 and 5.0% tryptophan-added groups. The urinary excretory ratio of AnA/KA was a high value for both the groups. These results suggest that the urinary ratio of AnA/KA could be a useful index to monitoran excessive tryptophan intake.

Tryptophan metabolism in women using steroid hormones for ovulation control.
            (Price et al., 1967) Download


 

Aspects of tryptophan metabolism in health and disease: a review.
            (Rose, 1972) Download

A community-based study on determinants of circulating markers of cellular immune activation and kynurenines: the Hordaland Health Study.
            (Theofylaktopoulou et al., 2013) Download
Circulating neopterin and kynurenine/tryptophan ratio (KTR) increase during inflammation and serve as markers of cellular immune activation, but data are sparse on other determinants of these markers and metabolites of the kynurenine pathway. We measured neopterin, tryptophan, kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid in plasma in two age groups, 45-46 years (n = 3723) and 70-72 years (n = 3329). Differences across categories of the potential determinants, including age, gender, renal function, body mass index (BMI), smoking and physical activity, were tested by Mann-Whitney U-test and multiple linear regression including age group, gender, renal function and lifestyle factors. In this multivariate model, neopterin, KTR and most kynurenines were 20-30% higher in the older group, whereas tryptophan was 7% lower. Men had 6-19% higher concentrations of tryptophan and most kynurenines than women of the same age. Compared to the fourth age-specific estimated glomerular filtration rate (eGFR) quartile, the first quartile was associated with higher concentrations of neopterin (25%) and KTR (24%) and 18-36% higher concentrations of kynurenines, except 3-hydroxyanthranilic acid. Additionally, KTR, tryptophan and all kynurenines, except anthranilic acid, were 2-8% higher in overweight and 3-17% higher in obese, than in normal-weight individuals. Heavy smokers had 4-14% lower levels of tryptophan and most kynurenines than non-smokers. Age and renal function were the strongest determinants of plasma neopterin, KTR and most kynurenines. These findings are relevant for the design and interpretation of studies investigating the role of plasma neopterin, KTR and kynurenines in chronic diseases.

 


References

Allen, JA, et al. (2011), ‘Post-epidemic eosinophilia-myalgia syndrome associated with L-tryptophan.’, Arthritis Rheum, 63 (11), 3633-39. PubMedID: 21702023
Blankfield, A (2012), ‘A Brief Historic Overview of Clinical Disorders Associated with Tryptophan: The Relevance to Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM).’, Int J Tryptophan Res, 5 27-32. PubMedID: 23032646
Bruni, O, et al. (2004), ‘L -5-Hydroxytryptophan treatment of sleep terrors in children.’, Eur J Pediatr, 163 (7), 402-7. PubMedID: 15146330
Donald, EA and TR Bosse (1979), ‘The vitamin B6 requirement in oral contraceptive users. II. Assessment by tryptophan metabolites, vitamin B6, and pyridoxic acid levels in urine.’, Am J Clin Nutr, 32 (5), 1024-32. PubMedID: 433819
Fernstrom, JD (2012), ‘Effects and side effects associated with the non-nutritional use of tryptophan by humans.’, J Nutr, 142 (12), 2236S-44S. PubMedID: 23077193
Hiratsuka, C, T Fukuwatari, and K Shibata (2012), ‘Fate of dietary tryptophan in young Japanese women.’, Int J Tryptophan Res, 5 33-47. PubMedID: 23150724
Hiratsuka, C, et al. (2013), ‘Supplementing healthy women with up to 5.0 g/d of L-tryptophan has no adverse effects.’, J Nutr, 143 (6), 859-66. PubMedID: 23616514
Nilsen, RM, et al. (2012), ‘Maternal tryptophan and kynurenine pathway metabolites and risk of preeclampsia.’, Obstet Gynecol, 119 (6), 1243-50. PubMedID: 22617590
Okada, S, et al. (2009), ‘Immunogenetic risk and protective factors for the development of L-tryptophan-associated eosinophilia-myalgia syndrome and associated symptoms.’, Arthritis Rheum, 61 (10), 1305-11. PubMedID: 19790128
Okuno, A, T Fukuwatari, and K Shibata (2008), ‘Urinary excretory ratio of anthranilic acid/kynurenic acid as an index of the tolerable amount of tryptophan.’, Biosci Biotechnol Biochem, 72 (7), 1667-72. PubMedID: 18603814
Price, JM, MJ Thornton, and LM Mueller (1967), ‘Tryptophan metabolism in women using steroid hormones for ovulation control.’, Am J Clin Nutr, 20 (5), 452-56. PubMedID: 6023855
Rose, DP (1972), ‘Aspects of tryptophan metabolism in health and disease: a review.’, J Clin Pathol, 25 (1), 17-25. PubMedID: 4552476
Theofylaktopoulou, D, et al. (2013), ‘A community-based study on determinants of circulating markers of cellular immune activation and kynurenines: the Hordaland Health Study.’, Clin Exp Immunol, 173 (1), 121-30. PubMedID: 23607723