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1.  The tryptophan utilization concept in pregnancy 
Obstetrics & Gynecology Science  2014;57(4):249-259.
The decrease in maternal plasma total (free + albumin-bound) tryptophan (Trp) during the third pregnancy trimester is attributed to induction of indoleamine 2,3-dioxygenase (IDO). When measured, free [Trp] is increased because of albumin depletion and non-esterified fatty acid elevation. The Trp depletion concept in pregnancy is therefore not supported because of incorrect interpretation of changes in Trp disposition and also for not addressing mouse strain differences in Trp-related responses and potential inhibition of Trp transport by the IDO inhibitor 1-methyl tryptophan. Application of the Trp utilization concept in pregnancy offers several physiological advantages favoring fetal development and successful outcome, namely provision of Trp for fetal protein synthesis and growth, serotonin for signaling pathways, kynurenic acid for neuroprotection, quinolinic acid for NAD+ synthesis, and other kynurenines for suppression of T cell responses. An excessive increase in Trp availability could compromise pregnancy by undermining T cell suppression, e.g., in pre-eclampsia.
doi:10.5468/ogs.2014.57.4.249
PMCID: PMC4124085  PMID: 25105097
Albumin; Free tryptophan; Non-esterified fatty acids; Pregnancy; Tryptophan
2.  Mechanisms of the Pellagragenic Effect of Leucine: Stimulation of Hepatic Tryptophan Oxidation by Administration of Branched-Chain Amino Acids to Healthy Human Volunteers and the Role of Plasma Free Tryptophan and Total Kynurenines 
The pellagragenic effect of leucine (Leu) has been proposed to involve modulation of L-tryptophan (Trp) metabolism along the hepatic kynurenine pathway. Here, we discuss some of the mechanisms suggested and report the effects in healthy volunteers of single doses of Leu (4.05–6.75 g) administered in a 16-amino acid mixture on concentrations of plasma Trp and its kynurenine metabolites. Flux of Trp through Trp 2,3-dioxygenase (TDO) is dose-dependently enhanced most probably by Leu and can be attributed to TDO activation. Trp oxidation is better expressed using plasma total kynure-nines, rather than kynurenine, and free, rather than total, Trp. Increased hepatic Trp oxidation may be an additional mechanism of action of branched-chain amino acids in the acute Trp depletion test. Inhibition of intestinal absorption or hepatic uptake of Trp by Leu can be excluded. Potential mechanisms of the aggravation of pellagra symptoms by Leu are discussed.
doi:10.4137/IJTR.S18231
PMCID: PMC4259507  PMID: 25520560
branched-chain amino acids; kynurenine pathway; leucine; pellagra; plasma free tryptophan; tryptophan 2; 3-dioxygenase
3.  Tryptophan in Alcoholism Treatment I:  Kynurenine Metabolites Inhibit the Rat Liver Mitochondrial Low Km Aldehyde Dehydrogenase Activity, Elevate Blood Acetaldehyde Concentration and Induce Aversion to Alcohol 
Aims: The aims were to provide proofs of mechanism and principle by establishing the ability of kynurenine metabolites to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) activity after administration and in vivo, and to induce aversion to alcohol. Methods: Kynurenic acid (KA), 3-hydroxykynurenine (3-HK) and 3-hydroxyanthranilic acid (3-HAA) were administered to normal male Wistar rats and ALDH activity was determined both in vitro in liver homogenates and in vivo (by measuring blood acetaldehyde following ethanol administration). Alcohol consumption was studied in an aversion model in rats and in alcohol-preferring C57 mice. Results: ALDH activity was significantly inhibited by all three metabolites by doses as small as 1 mg/kg body wt. Blood acetaldehyde accumulation after ethanol administration was strongly elevated by KA and 3-HK and to a lesser extent by 3-HAA. All three metabolites induced aversion to alcohol in rats and decreased alcohol preference in mice. Conclusions: The above kynurenine metabolites of tryptophan induce aversion to alcohol by inhibiting ALDH activity. An intellectual property covering the use of 3-HK and 3-HAA and derivatives thereof in the treatment of alcoholism by aversion awaits further development.
doi:10.1093/alcalc/agr134
PMCID: PMC3196366  PMID: 21896552
4.  Tryptophan in Alcoholism Treatment II:  Inhibition of the Rat Liver Mitochondrial Low Km Aldehyde Dehydrogenase Activity, Elevation of Blood Acetaldehyde Concentration and Induction of Aversion to Alcohol by Combined Administration of Tryptophan and Benserazide 
Aims: The aims were to provide proofs of mechanism and principle by establishing the ability of the amino acid L-tryptophan (Trp) combined with the kynureninase inhibitor benserazide (BSZ) to inhibit the liver mitochondrial low Km aldehyde dehydrogenase (ALDH) activity after administration and in vivo and to induce aversion to alcohol. Methods: Trp, BSZ or both were administered to male Wistar rats and ALDH activity was determined both in vitro in liver homogenates and in vivo (by measuring acetaldehyde accumulation in blood after ethanol administration). Alcohol consumption was studied in an aversion model in rats and in alcohol-preferring C57 mice. Results: Combined administration of Trp + BSZ, but neither compound alone, produced a strong inhibition of ALDH activity and an increase in blood acetaldehyde concentration after ethanol, and induced aversion to alcohol in rats and decreased preference in mice. Another kynureninase inhibitor, carbidopa, induced aversion to alcohol by itself, which was reversed by Trp co-administration. Conclusions: The present results establish a prior art for the use of a combination of Trp plus BSZ in the treatment of alcoholism by aversion, which merits rapid clinical development.
doi:10.1093/alcalc/agr135
PMCID: PMC3196367  PMID: 21896551
5.  Rapid Isocratic Liquid Chromatographic Separation and Quantification of Tryptophan and Six kynurenine Metabolites in Biological Samples with Ultraviolet and Fluorimetric Detection 
A simple, rapid isocratic liquid chromatographic procedure with ultraviolet and fluorimetric detection is described for the separation and quantification of L-tryptophan (Trp) and six of its kynurenine metabolites (kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic, kynurenic, xanthurenic and anthranilic acids). Using the Perkin Elmer LC 200 system, a reverse phase Synergi 4 μ fusion-RP80 A column (250 × 4.6 mm) (Phenomenex), and a mobile phase of 10 mM sodium dihydrogen phosphate: methanol (73:27, by vol) at pH 2.8 and a flow rate of 1.0–1.2 ml/min at 37 °C, a run took ∼13 min. The run took <7 min at 40 °C and a 1.4 ml/min flow rate. Limits of detection of all 7 analytes were 5–72 nM and their recoveries from human plasma and rat serum and liver varied between 62% and 111%. This simple method is suitable for high throughput work and can be further developed to include quinolinic acid and other Trp metabolites.
doi:10.4137/IJTR.S6225
PMCID: PMC3195243  PMID: 22084598
anthranilic acid; high-performance liquid chromatography; 3-hydroxyanthranilic acid; 3-hydroxykynurenine; kynurenic acid; kynurenine; quinolinic acid; tryptophan; xanthurenic acid
6.  Specificity of the Acute Tryptophan and Tyrosine Plus Phenylalanine Depletion and Loading Tests Part II: Normalisation of the Tryptophan and the Tyrosine Plus Phenylalanine to Competing Amino Acid Ratios in a New Control Formulation 
Current formulations for acute tryptophan (Trp) or tyrosine (Tyr) plus phenylalanine (Phe) depletion and loading cause undesirable decreases in ratios of Trp or Tyr + Phe to competing amino acids (CAA), thus undermining the specificities of these tests. Branched-chain amino acids (BCAA) cause these unintended decreases, and lowering their content in a new balanced control formulation in the present study led to normalization of all ratios. Four groups (n = 12 each) of adults each received one of four 50 g control formulations, with 0% (traditional), 20%, 30%, or 40% less of the BCAA. The free and total [Trp]/[CAA] and [Phe + Tyr]/[BCAA + Trp] ratios all decreased significantly during the first 5 h following the traditional formulation, but were fully normalized by the formulation containing 40% less of the BCAA. We recommend the latter as a balanced control formulation and propose adjustments in the depletion and loading formulations to enhance their specificities for 5-HT and the catecholamines.
PMCID: PMC2923411  PMID: 20725610
acute tryptophan depletion and loading; acute tyrosine depletion test; amino acid formulations; branched-chain amino acids; catecholamines; competing amino acids; dopamine; isoleucine; leucine; noradrenaline; phenylalanine; tryptophan; tyrosine; valine
7.  Specificity of the Acute Tryptophan and Tyrosine Plus Phenylalanine Depletion and Loading Tests I. Review of Biochemical Aspects and Poor Specificity of Current Amino Acid Formulations 
The acute tryptophan or tyrosine plus phenylalanine depletion and loading tests are powerful tools for studying the roles of serotonin, dopamine and noradrenaline in normal subjects and those with behavioural disorders. The current amino acid formulations for these tests, however, are associated with undesirable decreases in ratios of tryptophan or tyrosine plus phenylalanine to competing amino acids resulting in loss of specificity. This could confound biochemical and behavioural findings. Compositions of current formulations are reviewed, the biochemical principles underpinning the tests are revisited and examples of unintended changes in the above ratios and their impact on monoamine function and behaviour will be demonstrated from data in the literature. The presence of excessive amounts of the 3 branched-chain amino acids Leu, Ile and Val is responsible for these unintended decreases and the consequent loss of specificity. Strategies for enhancing the specificity of the different formulations are proposed.
PMCID: PMC2911801  PMID: 20676231
acute tryptophan depletion and loading; acute tyrosine depletion test; amino acid formulations; branched-chain amino acids; catecholamines; competing amino acids; dopamine; isoleucine; leucine; noradrenaline; phenylalanine; tryptophan; tyrosine; valine
8.  Specificity of the Acute Tryptophan and Tyrosine Plus Phenylalanine Depletion and Loading Tests Part II: Normalisation of the Tryptophan and the Tyrosine Plus Phenylalanine to Competing Amino Acid Ratios in a New Control Formulation 
Current formulations for acute tryptophan (Trp) or tyrosine (Tyr) plus phenylalanine (Phe) depletion and loading cause undesirable decreases in ratios of Trp or Tyr + Phe to competing amino acids (CAA), thus undermining the specificities of these tests. Branched-chain amino acids (BCAA) cause these unintended decreases, and lowering their content in a new balanced control formulation in the present study led to normalization of all ratios. Four groups (n = 12 each) of adults each received one of four 50 g control formulations, with 0% (traditional), 20%, 30%, or 40% less of the BCAA. The free and total [Trp]/[CAA] and [Phe + Tyr]/[BCAA + Trp] ratios all decreased significantly during the first 5 h following the traditional formulation, but were fully normalized by the formulation containing 40% less of the BCAA. We recommend the latter as a balanced control formulation and propose adjustments in the depletion and loading formulations to enhance their specificities for 5-HT and the catecholamines.
PMCID: PMC2923411  PMID: 20725610
acute tryptophan depletion and loading; acute tyrosine depletion test; amino acid formulations; branched-chain amino acids; catecholamines; competing amino acids; dopamine; isoleucine; leucine; noradrenaline; phenylalanine; tryptophan; tyrosine; valine
9.  Specificity of the Acute Tryptophan and Tyrosine Plus Phenylalanine Depletion and Loading Tests I. Review of Biochemical Aspects and Poor Specificity of Current Amino Acid Formulations 
The acute tryptophan or tyrosine plus phenylalanine depletion and loading tests are powerful tools for studying the roles of serotonin, dopamine and noradrenaline in normal subjects and those with behavioural disorders. The current amino acid formulations for these tests, however, are associated with undesirable decreases in ratios of tryptophan or tyrosine plus phenylalanine to competing amino acids resulting in loss of specificity. This could confound biochemical and behavioural findings. Compositions of current formulations are reviewed, the biochemical principles underpinning the tests are revisited and examples of unintended changes in the above ratios and their impact on monoamine function and behaviour will be demonstrated from data in the literature. The presence of excessive amounts of the 3 branched-chain amino acids Leu, Ile and Val is responsible for these unintended decreases and the consequent loss of specificity. Strategies for enhancing the specificity of the different formulations are proposed.
PMCID: PMC2911801  PMID: 20676231
acute tryptophan depletion and loading; acute tyrosine depletion test; amino acid formulations; branched-chain amino acids; catecholamines; competing amino acids; dopamine; isoleucine; leucine; noradrenaline; phenylalanine; tryptophan; tyrosine; valine
10.  Activation of Liver Tryptophan Pyrrolase Mediates the Decrease in Tryptophan Availability to the Brain after Acute Alcohol Consumption by Normal Subjects 
Aims: We have previously suggested that acute ethanol consumption by normal subjects decreases the availability of circulating tryptophan (Trp) to the brain by activating liver Trp pyrrolase, the first and rate-limiting enzyme of the (major) kynurenine pathway of Trp degradation. The aim of the present study was to examine this hypothesis further by measuring plasma levels of kynurenine metabolites following alcohol consumption. Methods: After an overnight fast and a light breakfast, each of 10 healthy subjects received one of five drinks (placebo and doses of ethanol of 0.2, 0.4, 0.6 and 0.8 g/kg body weight in tonic water) on five different occasions. Blood samples were withdrawn 2 h later and plasma was analysed for concentrations Trp, competing amino acids (CAA) and kynurenine metabolites. Results: Along with the depletion of plasma Trp and the decrease in its availability to the brain, as expressed by the ratio of [Trp]/[CAA], plasma kynurenine was elevated by doses of ethanol of 0.2–0.8 g/kg body weight. The ratio% of [kynurenine]/[Trp], an index of the expression of Trp pyrrolase activity, was also increased by all doses of ethanol. Conclusions: We conclude that activation of liver Trp pyrrolase mediates the depletion of plasma Trp and the decrease in its availability to the brain induced by acute ethanol consumption.
doi:10.1093/alcalc/agp005
PMCID: PMC2720730  PMID: 19201692
11.  Comparison of 50g and 100g L-tryptophan Depletion and Loading Formulations for Altering 5-HT Synthesis: Pharmacokinetics, Side Effects, and Mood States 
Psychopharmacology  2008;198(3):431.
Rationale
Differences in 5-HT function have been the subject of extensive research in psychiatric studies. Many studies have manipulated L-tryptophan (Trp) levels to temporarily decrease (depletion) or increase (loading) 5-HT synthesis. While most researchers have used a 100g formulation, there has been ongoing interest in using smaller-sized formulations.
Objectives
This study examined the time-course of multiple plasma indicators of brain 5-HT synthesis following 50g depletion and loading as a comparison to the typical 100g formulation.
Methods
Plasma was collected from 112 healthy adults at 7 hourly intervals following consumption of either a 50g or 100g depletion or loading. Self-ratings of mood and somatic symptoms were completed before and after Trp manipulations.
Results
The primary findings were that: (1) the 50g and 100g formulations produced the expected changes in plasma indicators following both depletion (−89% and −96%, respectively) and loading (+570% and +372%, respectively); (2) the 100g depletion showed more robust effects at the 4, 5, and 6 h measurements than the 50g depletion; (3) there was significant attrition following both the 100g depletion and loading, but not after either 50g formulation; and (4) both 50g and 100g depletions produced increases in negative self-ratings of mood and somatic symptoms, while loading significantly increased negative ratings following the 100g only.
Conclusions
There are important considerations when choosing among formulation sizes for use in Trp manipulation studies, and the complete 7-hr time-course data set of the typical plasma Trp measures presented here may help researchers decide which methodology best suits their needs.
doi:10.1007/s00213-008-1163-2
PMCID: PMC2818099  PMID: 18452034
L-tryptophan; depletion; serotonin; time course; human; competing amino acids; side effects; mood

Results 1-11 (11)