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PubMed1991

The effect of tryptophan on the phenobarbital-mediated induction of cytochrome P-450 in rat liver. The role of tryptophan 2,3-dioxygenase.

The effect of intraperitoneal administration of phenobarbital (80 mg kg-1 body weight) and tryptophan (200 mg kg-1 body weight), separately or in combination, on the microsomal content of cytochrome P-450 and the activity of tryptophan 2,3-dioxygenase (EC 1.13.11.11) in Wistar rat liver was determined at different time intervals after injection. There was an increase in the amount of cytochrome P-450 within 12 h of administration of a single dose of phenobarbital which was maintained over the next 12 h. Tryptophan had no effect on the amount of cytochrome P-450, but administration of tryptophan in combination with phenobarbital blocked the increase that was found after administration of phenobarbital alone. Both phenobarbital and tryptophan increased tryptophan 2,3-dioxygenase activity (total enzyme and holoenzyme) but had different effects on the rate of activation and the degree of saturation of the enzyme with haem. Administration of tryptophan and phenobarbital in combination invoked the same effect as tryptophan alone. Significant activation of the holoenzyme was found, when tryptophan was administered 2 h after phenobarbital administration. It is proposed that combined administration of phenobarbital and tryptophan leads to substrate stabilisation of tryptophan 2,3-dioxygenase, and that this is accompanied by the binding of the newly synthesised haem, thus making haem unavailable for formation of cytochrome P-450.

Animals↗

PubMed1981

Short-term and repetitive administration of oral tryptophan in normal men. Effects on blood tryptophan, serotonin, and kynurenine concentrations.

Single and repetitive tryptophan loads were consumed by normal, adult male volunteers, and blood concentrations of tryptophan, serotonin, and kynurenine, their time courses, and their distributions within blood were measured. Repeated measures of basal and tryptophan-induced changes in tryptophan and serotonin blood concentrations were characteristic for individual subjects. Tryptophan dose-responsive increases in measured substances returned to basal levels within 24 hours after single tryptophan loads. However, cumulative increases in serotonin concentration in early-morning, predose blood samples were seen following repetitive daily tryptophan administration. Extra-platelet serotonin could be detected in blood samples taken after tryptophan loading and after repetitive daily tryptophan consumption but not in baseline samples taken before short-term loading. Neither platelet number nor size was altered by the loading procedures. Tryptophan loading produced lethargy and drowsiness within 30 minutes of ingestion under all loading conditions. Subjects with the slowest kynurenine response to tryptophan were most behaviorally affected.

Administration, Oral↗

PubMed1991

Decrease in plasma tryptophan after a tryptophan-free amino acid solution. A comparison between cirrhotic and control subjects.

In healthy subjects the administration of an amino acid mixture devoid of tryptophan causes a marked decrease of plasma tryptophan. This is because amino acid mixtures induce protein synthesis and tryptophan in blood is incorporated into newly synthesized proteins. We hypothesized that a tryptophan-free mixture could differently affect plasma tryptophan levels in subjects with an impaired protein synthesis such as chronic liver patients. We studied tryptophan levels after a tryptophan-free amino acid solution in controls and cirrhotics fasting 12 hours. Plasma total tryptophan fell to 91% of the initial level 60 minutes after the administration of the diet, to 71% after 120, and to 50% after 210' in controls. In cirrhotics the solution caused a decrease of plasma tryptophan that began significantly later than in controls, the delay being proportional to the severity of the disease. Cirrhotics were subdivided into two groups in accordance to the Pugh modification of the Child-Turcotte criteria. Total plasma tryptophan was 100% of base line levels after 60', 88% after 120', and 65% after 210' in less severe clinical condition; total plasma tryptophan was 102% of base line levels after 60', 98% after 120', and 75% after 210' in more severe clinical condition.

Adult↗

PubMed2005

Protein source tryptophan versus pharmaceutical grade tryptophan as an efficacious treatment for chronic insomnia.

BACKGROUND: Intact protein rich in tryptophan was not seen as an alternative to pharmaceutical grade tryptophan since protein also contains large neutral amino acids (LNAAs) that compete for transport sites across the blood-brain barrier (BBB). Deoiled gourd seed (an extremely rich source of tryptophan-22 mg tryptophan/1 g protein) was combined with glucose, a carbohydrate that reduces serum levels of competing LNAAs which was then compared to pharmaceutical grade tryptophan with carbohydrate as well as carbohydrate alone. METHOD: Objective and subjective measures of sleep were employed to measure changes in sleep as part of a double blind placebo controlled study where subjects were randomly assigned to one of three conditions: (1) Protein source tryptophan (deoiled gourd seed) in combination with carbohydrate; (2) pharmaceutical grade tryptophan in combination with carbohydrate; (3) carbohydrate alone. SUBJECTS: Out of 57 subjects 49 of those who began the study completed the three week protocol. RESULTS: Protein source tryptophan with carbohydrate and pharmaceutical grade tryptophan, but not carbohydrate alone, resulted in significant improvement on subjective and objective measures of insomnia. Protein source tryptophan with carbohydrate alone proved effective in significantly reducing time awake during the night. CONCLUSION: Protein source tryptophan is comparable to pharmaceutical grade tryptophan for the treatment of insomnia.

Avena↗

PubMed1980

Inversion of D-tryptophan to L-tryptophan and excretory patterns in the rat and chick.

The behavior of D-tryptophan in the blood plasma and the pattern of tryptophan excretion in the urine were studied in the rat and the chick. When D-tryptophan was administered orally to rats and chicks, both showed D-tryptophan in the plasma. Conversion of D-tryptophan to the L-isomer in the rat was found by an examination of plasma from the posterior vena cava and the portal vein, following stomach intubation of 100 micromoles D-tryptophan/100 g of body weight. The peak in the increase of L-tryptophan was approximately 150 nmoles/ml plasma when measured at 30 minutes after administration and the peak was 200 nmoles when measured 2 hours after administration. No conversion of D-tryptophan to the L-isomer was found in chicks. Under similar conditions, D-tryptophan was measured in the urine of rats and chicks. In rats the D-tryptophan excreted was at most 1% of the amount administered; while in chicks most of the D-tryptophan was excreted.

Animals↗

PubMed1990

Effect of dietary tryptophan on plasma and brain tryptophan, brain serotonin, and brain 5-hydroxyindoleacetic acid in rainbow trout.

In order to determine the effect of dietary tryptophan level on plasma and brain tryptophan, brain serotonin, and brain 5-hydroxyindoleacetic acid levels, juvenile rainbow trout (Salmo gairdneri) were raised for 16 weeks on semipurified diets containing 0.06%, 0.16%, 0.21%, 0.26%, 0.39%, or 0.59% tryptophan. After 14 weeks, feed intake was depressed in fish fed the diets containing 0.06% or 0.16% tryptophan. No further differences in feed intake were noted between the remaining treatments. In addition, body weight was lower in fish fed diets containing 0.06%, 0.16%, or 0.21% tryptophan compared with fish fed higher levels. After 16 weeks of feeding the test diets, plasma tryptophan levels were found to be directly related to dietary tryptophan levels. Similarly, increased dietary levels of tryptophan resulted in increased brain levels of tryptophan, serotonin, and 5-hydroxyindoleacetic acid. These results demonstrate that in rainbow trout, as in mammals, altered dietary levels of tryptophan result in alterations in plasma and brain tryptophan, brain serotonin, and brain 5-hydroxyindoleacetic acid.

Journal Article↗

PubMed2003

Inhibition of tryptophan - pyrrolase activity and elevation of brain tryptophan concentration by fluoxetine in rats.

OBJECTIVE: To investigate in-vitro as well as in-vivo effects of various doses of fluoxetine (SSRI) on tryptophan metabolism in rats. DESIGN: A pre-clinical study. PLACE AND DURATION OF STUDY: Clinical Biochemistry Research Laboratory, Department of Biochemistry, University of Karachi. The investigation was carried out during 2000 to 2001. SUBJECTS AND METHODS: Male Wistar rats (150-200 g body wt) were selected and divided into control and test groups (n = 5) for comparison. RESULTS: In in-vitro (10 - 1000mM) as well in-vivo (0.5-30 mg/kg body wt.) studies, fluoxetine showed a statistically significant inhibition of rat liver tryptophan pyrrolase (tryptophan-2,3-dioxygenase; EC 1.13.11.11) activity. Significant increases were noted at 10 and 30 mg/kg doses in brain, serum (total and free) and liver L-tryptophan concentrations. Similarly, serum non-estrified free fatty acids showed a significant increase at both doses. There was no effect on serum glucose and albumin concentrations. CONCLUSION: It is suggested that major mechanism of action of fluoxetine is that of elevating brain tryptophan concentration and hence 5-HT synthesis by increasing the availability of circulating tryptophan to the brain secondarily to inhibition of major tryptophan degrading enzyme, hepatic tryptophan pyrrolase. It is assumed that fluoxetine inhibits the binding of apoenzyme form of tryptophan pyrrolase with its cofactor haem. The results are discussed in relation to possible involvement of disturbed hepatic tryptophan metabolism in depressive illness.

Animals↗

PubMed1983

Tryptophan and tyrosine ratios to neutral amino acids in endogenous depression. Relation to antidepressant response to amitriptyline and lithium + L-tryptophan.

The plasma ratios of tryptophan and tyrosine to those amino acids that compete with them during transport across the blood-brain barrier have been determined in depressed patients before and after treatment for four weeks with amitriptyline or lithium + L-tryptophan. There was no relation between the absolute plasma concentrations of free or total tryptophan or tyrosine and the clinical response to amitriptyline. There was also no relation between pre-treatment ratio of plasma tyrosine to competing amino acids and response to amitriptyline, but depressives with subnormal tryptophan ratio improved significantly more than patients with supernormal tryptophan ratio with comparable serum drug levels. The therapeutic response to lithium + L-tryptophan was predicted neither by the absolute plasma concentrations of free or total tryptophan or tyrosine nor by the tyrosine ratio, but there was also a trend towards greater improvement in patients with subnormal compared with supernormal tryptophan ratio. The results suggest that the pre-treatment plasma ratio of tryptophan to competing amino acids is a useful predictor of clinical response to amitriptyline. The possible mode of action of amitriptyline and lithium + L-tryptophan is briefly discussed.

Amino Acids↗

PubMed1995

The mechanism of Escherichia coli tryptophan indole-lyase: substituent effects on steady-state and pre-steady-state kinetic parameters for aryl-substituted tryptophan derivatives.

We have examined the reaction of Escherichia coli tryptophan indole-lyase with fluoro, chloro, methyl and hydroxytryptophans using steady-state kinetics, rapid-scanning and single wavelength stopped-flow spectrophotometry, and rapid chemical quench methods. All of the 16 tryptophan derivatives examined are substrates for alpha, beta-elimination catalyzed by tryptophan indole-lyase. The steady-state kinetic parameter, kcat/Km, did not show a consistent trend with the steric bulk of the substituent, but Km increased for larger substituents. Rapid-scanning stopped-flow spectra show that all tryptophan analogues undergo covalent reaction with the pyridoxal-5'-phosphate cofactor to give equilibrating mixtures of external aldimine and quinonoid intermediates, but the relative amounts of each intermediate are strongly dependent on the nature and position of the substituent. The dissociation constants for external aldimine formation, Kd, obtained from single-wavelength stopped-flow experiments decreased for most substituted tryptophans, which suggests that part of the binding energy is derived from hydrophobic interactions between the enzyme and the indole ring of tryptophan. In contrast, the rate constants of quinonoid intermediate formation and reprotonation and of indole elimination were quite variable, depending on the position and the nature of the substituent. Overall, 6-substituted tryptophans have the most consistent reactivity, which indicates that there may be space in the enzyme active site near the 6-position. There is a good linear correlation between log (kcat/Km) and log (kf/Kd) (apparent second order rate constant for quinonoid intermediate formation), with a slope of 0.66. This suggests that quinonoid intermediate formation contributes only about 66% of the activation energy for the reaction, and thus a later step in the reaction must be partially rate-limiting. Rapid chemical quench experiments demonstrate a 'burst' of indole in the reaction of L-tryptophan under single turnover conditions, confirming that a step subsequent to the elimination is partially rate-determining. In contrast, 5-methyl-L-tryptophan does not exhibit a significant 'burst', suggesting that 5-methylindole elimination is nearly completely rate-determining. These results support the proposed mechanism and demonstrate that there are significant effects of aryl substituents on the distribution of covalent intermediates and on the rate-determining step in the alpha, beta-elimination reaction catalyzed by E. coli tryptophan indole-lyase.

Binding Sites↗

PubMed1996

Effects of feeding tryptophan-limiting diets on the conversion ratio of tryptophan to niacin in rats.

We investigated the effects of feeding various types of nicotinic acid-free, tryptophan-limiting diets on the conversion ratio of tryptophan to niacin in rats. Various tryptophan-limiting diets were made by adding zein, gelatin, glycine, threonine, methionine, or glycine + threonine + methionine to a nicotinic acid-free, 9% casein diet. When the rats were fed with the tryptophan-limiting diets, the conversion ratio of tryptophan to niacin was markedly decreased. However, the ratio recovered after the addition of tryptophan to the tryptophan-limiting diets. These results clearly prove that the conversion was lowest when the rats were fed with the tryptophan-limiting diets. Therefore, we think that the pellagragenic factor of corn is simply due to a low content of tryptophan, but the adverse effect is due to a low conversion ratio of tryptophan to niacin.

Amino Acids↗

PubMed1993

Depletion of patients' plasma tryptophan using tryptophan side-chain oxidase columns.

The use of the enzyme tryptophan side-chain oxidase, isolated from Pseudomonas XA, was explored in 3 patients with refractory acute lymphocytic leukemia. Patients were given either a low-tryptophan diet or tryptophan-free hyperalimentation, prior to and during therapy. Their plasma, separated by pheresis, was continuously passed through a tryptophan depletion column containing the immobilized tryptophan side-chain oxidase. Up to 4 plasma volumes were passed through the column daily, 5 days per week for 2-3 weeks, and plasma tryptophan levels, both free and total, were measured by high-performance liquid chromatography. Pre- and postcolumn plasma samples were collected throughout the pheresis procedure. All postcolumn plasma samples had unmeasurable tryptophan levels throughout the treatment period, whereas precolumn samples were always measurable. Generally, tryptophan levels of plasma isolated from peripheral blood decreased after therapy, but rebounded by the next day. The enzyme depletion column reduces circulating plasma tryptophan levels, and its use is well tolerated by patients. However, further development of this method will require study of the effects of diet and of the duration, interval, and frequency of use of this column on therapeutic efficacy. Problems include difficulties with extended diet compliance and apparently intensive mobilization of tryptophan from body stores, which may preclude the clinical application of this enzyme depletion column.

Chromatography, High Pressure Liquid↗

PubMed1978

Selective ion monitoring of tryptophan, N-acetyltryptophan and kynurenine in human serum. Application to the in vivo measurement of tryptophan pyrrolase activity.

A specific method is described for the determination of deuterated and non-deuterated N-acetyltryptophan, tryptophan and kynurenine in human serum and urine using gas chromatography-mass fragmentography. N-Acetyltryptophan was analysed as the N-trimethylsilyl methyl ester derivative; tryptophan and kynurenine were converted into their N-pentafluoropropionyl methyl esters. N-Acetyl-DL-tryptophan-d11, tryptophan-d8 and kynurenine-d2 were used as internal standards. The coefficients of variation were found to be about 8% (n = 9) for tryptophan and N-acetyltryptophan and about 2.4% (n = 9) for kynurenine. Using this method, an in vivo determination of the tryptophan pyrrolase activity [L-tryptophan oxygen 2,3-oxidoreductase (decyclizing), E.C. 1.13.11.11] is possible by loading the subjects with deuterated L-tryptophan-d5 and subsequently measuring the deuterated L-kynurenine-d4 formed and the residual L-tryptophan-d5.

Acetylation↗

PubMed1980

Inhibition of rat brain tryptophan metabolism by ethanol withdrawal and possible involvement of the enhanced liver tryptophan pyrrolase activity.

1. Chronic ethanol administration to rats was previously shown to enhance brain 5-hydroxytryptamine synthesis by increasing the availability of circulating tryptophan to the brain secondarily to the NAD(P)H-mediated inhibition of liver tryptophan pyrrolase activity. 2. At 24h after ethanol withdrawal, all the above effects were observed because liver [NAD(P)H] was still increased. By contrast, all aspects of liver and brain tryptophan metabolism were normal at 12 days after withdrawal. 3. At 7--9 days after withdrawal, brain 5-hydroxytryptamine synthesis was decreased, as was tryptophan availability to the brain. Liver tryptophan pyrrolase activity at these time-intervals was maximally enhanced. 4. Administration of nicotinamide during the withdrawal phase not only abolished the withdrawal-induced enhancement of tryptophan pyrrolase activity on day 8, but also maintained the inhibition previously caused by ethanol. Under these conditions, the withdrawal-induced decreases in brain 5-hydroxytryptamine synthesis and tryptophan availability to the brain were abolished, and both functions were enhanced. Nicotinamide alone exerted similar effects in control rats. 5. It is suggested that ethanol withdrawal inhibits brain 5-hydroxytryptamine synthesis by decreasing tryptophan availability to the brain secondarily to the enhanced liver tryptophan pyrrolase activity. 6. The results are discussed in relation to the possible involvement of 5-hydroxytryptamine in dependence on ethanol and other drugs.

Animals↗

PubMed1980

Dietary tryptophan level and the enzymes of tryptophan NAD pathway.

1. Dietary tryptophan was found to regulate the activities of tryptophan oxygenase (EC 1.13.1.12) and quinolinate phosphoribosyltransferase (EC 2.4.2a) in liver. 2. With increasing tryptophan concentration in the diet containing 100 g protein/kg, tryptophan oxygenase activity increased while that of quinolinate phosphoribosyltransferase decreased. The response of these enzymes to dietary tryptophan at lower dietary protein level (25 g/kg) was not significant. 3. Liver nicotinate phosphoribosyltransferase (EC 2.4.2.11) activity and kidney picolinate carboxylase (EC 4.1.1.45) activity were unaltered with different tryptophan concentrations in the diet. 4. The response of various biochemical measurements was dependent on the tryptophan intake and the changes were marked below and above the requirement level of tryptophan. 5. It is suggested that the urinary excretion of quinolinic acid and N'-methylnicotinamide may be useful in assessing the tryptophan nutritional status and its requirement.

Animals↗

PubMed2005

Enhanced enzymatic degradation of tryptophan by indoleamine 2,3-dioxygenase contributes to the tryptophan-deficient state seen after major trauma.

Decreased lymphocyte proliferation, lymphopenia, immunodepression, and opportunistic infections are common after major trauma. Early alimentation in these patients corrects lymphopenia, enhances immunity, and reduces the incidence of infections, but the underlying mechanisms are poorly understood. Tryptophan is essential for the production and function of rapidly proliferating cells such as lymphocytes. Tryptophan is enzymatically degraded by indoleamine 2,3-dioxygenase (IDO), whose activity is solely dependent on expression of interferon-gamma (IFN-gamma). Because increased expression of IFN-gamma has been reported in trauma patients, we investigated whether enhanced IDO-mediated tryptophan degradation is associated with lymphopenia and poor outcomes after major trauma. The incidence of bacteremic sepsis (BS), adult respiratory distress syndrome (ARDS), multiple organ dysfunction/failure syndromes (MODS/MOF), and death was prospectively documented in 22 trauma patients with a mean ISS of 24.9 +/- 2.2. Sequential blood samples were obtained from admission through postinjury day 10. Five patients developed BS, three of whom developed ARDS; two of the three ARDS patients developed MOF and died on day 10. Trauma patients had significantly lower tryptophan levels (days 1-10), higher kynurenine:tryptophan ratios (days 1-2), and fewer lymphocytes (days 1-4) than healthy volunteers (P < 0.05). Although patients with poor outcomes (i.e., BS, ARDS, MOF, and death) had significantly lower tryptophan levels and greater lymphopenia on several days after injury, the sample size was too small to draw any definitive conclusions. These data indicate that decreased plasma tryptophan levels and lymphopenia typically occur after major trauma. A concomitant increase in kynurenine suggests that the observed tryptophan deficiency is caused, in part, by IDO-mediated tryptophan degradation.

Adolescent↗

PubMed1990

Enzymatic production of L-tryptophan from DL-serine and indole by a coupled reaction of tryptophan synthase and amino acid racemase.

Enzymatic production of L-tryptophan from DL-serine and indole by a coupled reaction of tryptophan synthase and amino acid racemase was studied. The tryptophan synthase (EC 4.2.1.20) of Escherichia coli catalyzed beta-substitution reaction of L-serine into L-tryptophan and the amino acid racemase (EC 5.1.1.10) of Pseudomonas putida catalyzed the racemization of D-serine simultaneously in one reactor. Under optimal conditions established for L-tryptophan production, a large-scale production of L-tryptophan was carried out in a 200-liter reactor using intact cells of E. coli and P. putida. After 24 h of incubation with intermittent indole feeding, 110 g liter-1 of L-tryptophan was formed in molar yields of 91 and 100% for added DL-serine and indole, respectively. Continuous production of L-tryptophan was also carried out using immobilized cells of E. coli and P. putida. The maximum concentration of L-tryptophan formed was 5.2 g liter-1 (99% molar yield for indole), and the concentration decreased to 4.2 g liter-1 after continuous operation for 20 days.

Amino Acid Isomerases↗

PubMed1981

The respective roles of tryptophan uptake and tryptophan hydroxylase in the regulation of serotonin synthesis in the central nervous system.

1. The rate limiting enzyme for the synthesis of serotonin (5-HT) in brain, tryptophan hydroxylase, is not saturated under normal physiological conditions. 2. Therefore, any decrease or increase in brain tryptophan levels results in a reduction or a stimulation of 5-HT synthesis respectively. Thus, mechanisms controlling brain tryptophan levels, i.e. the concentration of free tryptophan in serum and the intrinsic activity of the tryptophan carrier in neuronal membranes, exert in fact a tonic regulation of 5-HT synthesis in central serotoninergic neurons. 3. Changes in the rate of 5-HT synthesis can also involve modifications in the intrinsic activity of tryptophan hydroxylase. This occurs in vivo following the intrastriatal injection of kainic acid and in vitro during the depolarization of brain slices. In both cases, an activation of tryptophan hydroxylase due to an increase in its apparent Vmax is detected in soluble extracts. 4. The depolarization-induced activation of tryptophan hydroxylase in brain slices very likely involves a Ca2+-dependent phosphorylation process. 5. Rapid changes in tryptophan hydroxylase activity produced by a phosphorylation-dephosphorylation process may be involved in the phasic regulation of 5-HT synthesis in serotoninergic neurons.

Animals↗

PubMed2004

Nitration and nitrosation of N-acetyl-L-tryptophan and tryptophan residues in proteins by various reactive nitrogen species.

Proteins are targets of reactive nitrogen species such as peroxynitrite and nitrogen dioxide. Among the various amino acids in proteins, tryptophan residues are especially susceptible to attack by reactive nitrogen species. We carried out experiments on the reactions of peroxynitrite and other reactive nitrogen species with N-acetyl-L-tryptophan under various conditions. Four major products were identified as 1-nitroso-N-acetyl-L-tryptophan, 1-nitro-N-acetyl-L-tryptophan, 6-nitro-N-acetyl-L-tryptophan, and N-acetyl-N'-formyl-L-kynurenine on the basis of their mass and UV spectra. The reactions with SIN-1 (a peroxynitrite generator), Angeli's salt (a nitroxyl donor), and spermine NONOate (a nitric oxide donor) generated the nitroso derivative but not the nitro derivatives. A myeloperoxidase-H(2)O(2)-NO(2)(-) system generated the nitro derivatives but not the nitroso derivative. Under physiological conditions 6-nitro-N-acetyl-L-tryptophan was stable, whereas the 1-nitroso and 1-nitro derivatives decomposed with half-lives of 1.5 and 18 h, respectively. After treatment with various reactive nitrogen species, bovine serum albumin was enzymatically hydrolyzed and analyzed for 6-nitro-L-tryptophan and 3-nitro-L-tyrosine by HPLC with electrochemical detection. Levels of 6-nitro-L-tryptophan and 3-nitro-L-tyrosine were similar in the nitrated protein. 6-Nitro-L-tryptophan in proteins can be measured as an additional biomarker of protein nitration.

Chromatography, High Pressure Liquid↗