Tryptophan Load Research Articles

Dietary tryptophan reversal of septal lesion and 5,7-DHT lesion elicited shock-induced fighting

Using two procedures known to enhance shock-induced defensive fighting (SIF) and mouse-killing—septal lesions and 5,7-DHT lesions—we determined if a 5% tryptophan-loaded diet could reverse the lesion effects. The results indicated that SIF, but not mouse-killing, could be maintained at normal levels following dietary tryptophan loading in both septally lesioned and 5,7-DHT lesioned rats. This behavioral reversal was independent of pain sensitivity, feeding, drinking and body weight levels. Regional brain analysis of monoamines and metabolites indicated that the lesions produced substantial depletions in 5-HT and 5-HIAA with minimal reduction or no change in catecholamines. Dietary tryptophan loading elevated 5-HT and 5-HIAA in unlesioned animals and partially restored 5-HT and 5-HIAA levels in lesioned animals. These patterns of depletion and repletion were confined to the hippocampus following septal lesions and distributed throughout the brain following 5,7-DHT lesions. The results are discussed in terms of a possible hippocampal mediation of the dietary tryptophan reversal in shock-induced defensive fighting following lesioning.

The influence of tryptophan loading on EEG in patients with endogenous psychosis : K. Ernst, I. Gorynia, K. Haase, and R. Uebelhack (Berlin, GDR)

The influence of tryptophan loading on EEG in patients with endogenous psychosis : K. Ernst, I. Gorynia, K. Haase, and R. Uebelhack (Berlin, GDR)

Tryptophan malabsorption in dementia. Improvement in certain cases after tryptophan therapy as indicated by mental behaviour and blood analysis.

Twenty-four senile dementia patients in the age range 65-85 years were subjected to a new sensitive tryptophan loading test: Dopa-Tryptophan loading ("Dop-Try loading") in order to determine whether Try malabsorption occurs in senile dementia and if so how frequent this is. For comparison the same loading test was performed on 23 subjects in the same age grouping but with normal metal function. The differences in Try absorption were statistically analyzed and this revealed that absorption was less effective in the senile dementia group. Four patients with Try malabsorption were treated with 3 G 1-Try + 50 Mg dl-5-hydroxytryptophan (5-HTP) per day orally for 20-30 days and four patients with normal absorption were treated in the same way. The Dop-Try loading test was repeated after this treatment. Two patients showed improved absorption and coincident mental improvement, while one showed decreased absorption and mental deterioration. One died during the course of the treatment. None of the four patients with normal absorption showed mental improvement after the treatment. This pilot study suggests that increase in Try absorption following the Try treatment is a necessary condition for improvement in the mental state. The study is being continued with larger numbers of patients.

Influence of unilateral ECT on tryptophan metabolism in endogenous depression.

Thirteen patients with endogenous depression received an oral load of L-tryptophan (100 mg/kg) before and after a series of unilateral ECT. Age-matched and sex-matched controls also received the tryptophan load twice, at intervals corresponding to those used in the patients. After the loads the level of tryptophan in serum was lower in patients than in control subjects. ECT failed to influence either baseline or postload tryptophan levels. The results are consistent with the notion of disturbances in tryptophan metabolism in patients with endogenous depression, but they fail to clarify the mechanism responsible for the antidepressant effect of ECT.

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.

Effect of tryptophan administration on tryptophan, 5-hydroxyindoleacetic acid and indoleacetic acid in human lumbar and cisternal cerebrospinal fluid.

Tryptophan 5-hydroxyindoleacetic acid and indoleacetic acid were measured in cerebrospinal fluid taken during pneumoencephalography from patients, some of whom took a 3 g or 6 g tryptophan load at various times before. Measurements were made on both lumbar and cisternal cerebrospinal fluid and the results showed similarities between indoleamine metabolism in human brain and spinal cord. Our data suggested that (1) the blood-brain barrier active transport system for tryptophan is not far from saturation with tryptophan and the rate-limiting enzyme in 5-hydroxytryptamine (5HT) synthesis, tryptophan hydroxylase, is about half saturated. Therefore, both 3 g and 6 g tryptophan loads produced the same maximum rise in 5HT synthesis of just under 100%, (2) tryptamine differs from 5HT in two respects. It is more sensitive to changes in tryptophan availability than 5HT and the 6 g load increased brain tryptamine metabolism more than the 3 g load; also some of the tryptamine in brain is derived from peripheral sources and diffuses from blood to brain, (3) although the brain tryptamine content is much lower than that of 5HT, its rate of metabolism as indicated by CSF metabolite levels is not. In controls the rate of tryptamine metabolism is 15% of the rate of 5HT metabolism and this can increase to 40% after a 6 g tryptophan load.

Inhibition of kynureninase (L-kynurenine hydrolase, EC 3 . 7. 1 . 3) by oestrone sulphate: an alternative explanation for abnormal results of tryptophan load tests in women receiving oestrogenic steroids.

1. A partial purification of kynureninase (L-kynurenine hydrolase, EC 3 . 7. 1 . 3) from rat liver and a total resolution of the apoenzyme have been achieved. The hypothesis that conjugates of oestrogenic steroids compete with pyridoxal phosphate for the cofactor binding site of the enzyme, and so disturb tryptophan metabolism, leading to apparent vitamin B6 deficiency, has been tested. 2. Kynureninase from rat liver was partially purified, and the cofactor-free apoenzyme was prepared. Oestrone sulphate inhibited the enzyme uncompetitively with respect to pyridoxal phosphate, and competitively with respect to kynurenine, with a mean (+/- SE) inhibitor constant (Ki) of 82 +/- 6 microM. 3. The addition of a saturating concentration of pyridoxal phosphate to unfractionated liver homogenates led to an approximately fivefold increase in kynureninase activity, indicating the presence of a relatively large amount of apo-kynureninase in the tissue. 4. It is suggested that the abnormal results of tryptophan load tests in women receiving oestrogens are the result of inhibition of kynureninase by oestrogen conjugates, and that there is no evidence for oestrogen-induced vitamin B deficiency in such cases.

Effect of psoralen-induced photodermatitis on tryptophan metabolism in rats

Tryptophan metabolism ‘via kynurenine’ has been studied in rats before and after induction of experimental light-conditioned dermatitis with psoralen. Tryptophan load in animals during the acute phase of dermatitis (one day after induction) causes a markedly increased urinary excretion of total metabolites in comparison with that obtained before dermatitis. During this phase of the skin disease tryptophan pyrrolase activity is significantly increased and kynureninase activity significantly decreased in liver in respect to the control animals. Kynurenine aminotransferase activity shows no significant variations in both liver and kidneys. After 6 days of dermatitis, when the skin damage is in repair, both the excretory values of the urinary metabolites after L-tryptophan load and the enzymic activities are similar to those before dermatitis.

Tryptophan availability and the control of 5-hydroxytryptamine and tryptamine synthesis in human CNS.

The data presented here suggest that control of human brain 5HT synthesis by precursor availability is similar to that in the rat. Plasma tryptophan controls the brain level, although the plasma-brain relationship is modified by other large neutral amino acids in plasma. In normal circumstances brain tryptophan is an important factor controlling the synthesis of 5HT and tryptamine in human brain. However, the elevated brain tryptophan in patients with chronic liver disease does not lead to an increase in the rate of 5HT metabolism. In human brain the rate of tryptamine synthesis is normally aobut 10-20% of the rate of 5HT synthesis. Tryptamine metabolism is more sensitive than 5HT metabolism to changes in brain tryptophan. This is especially apparent after a tryptophan load. Our results suggest that tryptophan administration increases indoleamine function, as well as indoleamine synthesis, in depressed patients. Whether physiological variations in brain tryptophan in normal people are responsible for variations in indoleamine function is an open question.

Low dose injectable contraceptive norethisterone enanthate 20mg monthly — II. Metabolic side effects

Metabolic effects of a long-acting low dose injectable contraceptive, norethisterone enanthate 20-mg, monthly injections (Neten-20), was tested in 13 women belonging to the low income groups over a period of 1 year. No change was observed in hemoglobin, hematocrit, glucose tolerance, plasma lipids, iron, calcium, or serum glutamate-oxaloacetate transaminase after treatment. Marginal rise in albumin and fall in some globulin fractions was observed. The slight fall seen in serum alkaline phosphatase could be attributed to a change in lactation status. Vitamin A, pyridoxine and riboflavin status were not altered. A peculiar aberration in the tryptophan-niacin pathway as indicated by rise in kynurenic acid excretion after tryptophan load was observed. This could be corrected by multivitamin therapy. These data suggest that the use of Neten-20 for one year does not lead to adverse metabolic effects analogous to those seen with combination type oral contraceptives.

Metabolism of an oral tryptophan load III: effect of a pyridoxine supplement [letter

British Journal of Clinical PharmacologyVolume 10, Issue 6 p. 617-619 Free Access Metabolism of an oral tryptophan load III: effect of a pyridoxine supplement [letter] AR Green, AR GreenSearch for more papers by this authorJK Aronson, JK AronsonSearch for more papers by this author AR Green, AR GreenSearch for more papers by this authorJK Aronson, JK AronsonSearch for more papers by this author First published: December 1980 https://doi.org/10.1111/j.1365-2125.1980.tb00518.xCitations: 6AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat References CHADWICK, D., TRIMBLE, M., JENNER, P., DRIVER, M.V. & REYNOLDS, E.H. (1978). Manipulation of cerebral monoamines in the treatment of human epilepsy: a pilot study. Epilepsia, 19, 3– 10. GAL, E.M. YOUNG, R.B. & SHERMAN, A.D. (1978) Tryptophan loading: consequent effects on the synthesis of kynurenine and 5-hydroxyindoles in rat brain. J. Neurochem., 31, 237– 244. GREEN, A.R., ARONSON, J.K., CURZON, G. & WOODS, H.F. (1980). Metabolism of an oral tryptophan load I: Effects of dose and pretreatment with tryptophan. Br. J. clin. Pharmac., 10, 603– 610. GREEN, A.R., BLOOMFIELD, M.R., WOODS, H.F. & SEED, M. (1978). Metabolism of an oral tryptophan load by women and evidence against the induction of tryptophan pyrrolase by oral contraceptives. Br. J. clin. Pharmac., 5, 233– 241. GREEN, A.R. & CURZON, G. (1970). The effect of tryptophan metabolites on brain 5-hydroxytryptamine metabolism. Biochem. Pharmac., 19, 2061– 2068. KIELY, M. & SOURKES, T.L. (1970). Transport of l-tryptophan into slices of rat cerebral cortex. J. Neurochem., 19, 2863– 2872. SINGLETON, L. & MARSDEN, C.A. (1979). Increased responsiveness to 5-methoxy, n, n-dimethyl tryptamine in mice on a high tryptophan diet. Neuropharmacology, 18, 569– 572. YOUNG, S.N. & SOURKES, T.L. (1977). Tryptophan in the central nervous system: regulation and significance, Adv. Neurochem., 2, 133– 191. Citing Literature Volume10, Issue6December 1980Pages 617-619 ReferencesRelatedInformation

The effect of drugs on vitamin B 6 function in the rat

Some commonly used drugs were tested for an effect on vitamin B 6 function in Lister Hooded rats. An increase in urinary xanthurenic acid excretion after a tryptophan load was used as an indicator of impaired vitamin B 6 function. dl-Penicillamine, hydrallazine and phenelzine produced increases in xanthurenic acid excretion, and these were reversed by concomitant treatment of the animals with pyridoxine hydrochloride. dl-Penicillamine was the only drug which lowered the liver pyridoxal-5'-phosphate (PLP) content of these rats. dl-Penicillamine did not inhibit kynurenine aminotransferase (KAT) in vitro, whilst hydrallazine and phenelzine both inhibited the enzyme non-competitively with respect to the substrate. Hydrallazine produced mixed inhibition of KAT with respect to PLP; inhibition by phenelzine increased as the PLP concentration increased, indicating that the hydrazone formed between phenelzine and PLP was a more potent inhibitor of KAT than phenelzine itself. Isonicotinic acid hydrazide and its metabolites did not increase the xanthurenic acid excretion of tryptophan-loaded rats, and they were weak inhibitors of tryptophan pyrrolase in vitro. It is suggested that drugs may impair the normal function of vitamin B 6 by reducing tissue PLP levels, either through chemical reaction between drug and PLP or by inhibition of PLP synthesis. Drugs may also inhibit PLP-dependent enzymes without affecting systemic PLP levels.

Tryptophan loading may reverse tolerance to opiate analgesics in humans: A preliminary report

Five patients on chronic opiate medication to treat low-back and leg pain were determined to have developed opiate tolerance on the basis of their failure to obtain significant relief (rated on a subjective pain scale and by the degree of straight leg-raising they were able to endure) after receiving 30 mg of morphine administered i.v. in divided doses over 35 min. After these patients' diets had been supplemented with 4 g/day of l-tryptophan for 2–9 weeks, they achieved significant relief from pain when the opiate tolerance test was re-administered, and were able to lead more active lives while reducing their daily opiate intake. Chronic opiate administration probably reduces the serotonin turnover rate in the central nervous system; it may be that this is reversed by loading with the serotonin precursor, l-tryptophan.

Dietary tryptophan modulation and aggressive behavior in mice

The effects of a tryptophan-free diet on isolation-induced fighting and predatory cricket killing in mice were examined. The results demonstrated that consumption of a tryptophan-free diet for 18–20 days decreased both the number of fighters and duration of isolation-induced fighting; increased the number of cricket-killing mice and decreased the latencies to attack and the latencies to kill crickets; reduced brain serotonin 27%; increased water intake 38%; and decreased body weight 27% without affecting food intake. To determine if these effects were due specifically to the lack of dietary tryptophan, other groups of mice were fed a 5% tryptophan load in the standard chow; a 0.15% tryptophan supplement in the tryptophan-free diet; or a 3 grams/day restricted chow diet. The lack of tryptophan in the diet produced the marked inhibition in isolation-induced fighting, the reduction in brain serotonin, and the large decrease in body weight. The other non-specific effects appeared to be related to general factors such as dietary need for the cricket killing or diet composition (other than the lack of tryptophan) for the water intake.

L-kynurenine: its synthesis and possible regulatory function in brain.

One pathway by which tryptophan is metabolized in the brain as well as in the periphery is through cleavage of the indole ring to formylkynurenine and then kynurenine. Indoleamine-2,3-dioxygenase, the enzyme that catalyzes this cleavage, and kynurenine are distributed all across the different anatomic regions of brain. Approximately 40% of the kynurenine in brain is synthesized there, the remainder having come from plasma. Tryptophan loading, which has been used both experimentally and therapeutically as a means of increasing tryptophan conversion to serotonin, also increases kynurenine formation in the brain and in the periphery. Because of the formation of kynurenine, which competes for cerebral transport and cellular uptake of L-tryptophan, and because of substrate inhibition on tryptophan hydroxylase, excessively high doses of tryptophan may actually decrease the production of cerebral serotonin and 5-hydroxyindoleacetic acid.

Indoleamine metabolism in rat brain studied through measurements of tryptophan, 5-hydroxyindoleacetic acid, and indoleacetic acid in cerebrospinal fluid.

Abstract:Tryptophan, 5‐hydroxyindoleacetic acid (5HIAA), and indoleacetic acid (IAA) were measured in rat cerebrospinal fluid (CSF) using high‐performance liquid chromatography with fluorometric detection in order to study brain indoleamine metabolism. Previously we have shown that IAA in CSF is derived from tryptamine in the CNS. In this study our results indicated that the synthesis of both 5‐hydroxytryptamine (5HT) and tryptamine varied with changes in brain tryptophan. After a tryptophan load, tryptamine synthesis increased much more than 5HT synthesis; under these circumstances, it can be of the same order of magnitude as 5HT synthesis. Studies with treatments that cause release of 5HT (reserpine and cold stress) indicated that tryptamine is not released with 5HT and is probably not stored in vesicles. Use of selective monoamine oxidase inhibitors suggested that results obtained in vitvo concerning the substrates for monoamine oxidase A and B apply in vivo. Thus, 5HT was acted on preferentially by the A enzyme, and tryptamine by the B enzyme. Measurement of IAA in brain, CSF, and plasma before and after probenecid indicated that there are active transport systems moving IAA from CSF and brain to blood, and from brain to CSF. Our data suggest that measurements of CSF IAA are a simple and convenient way of studying CNS tryptamine metabolism and should be applied clinically.

Biochemical Studies in Cases of Hartnup’s Disease Detected at Bangalore

During a biochemical screening of mentally retarded people, two cases of Hartnup’s disease were detected. Biochemical studies revealed indi-canuria, hyperindoluria and hyperaminoaciduria. Both patients had skin rashes and cerebellar symptoms. It was noticed during remission that indole excretion was increased after tryptophan loading. The generalized hyperaminoaciduria was especially due to increased excretion of mono-carboxyl monoamino acids.

Tryptophan and lysine metabolism in alpha-aminoadipic aciduria.

Two brothers previously diagnosed as having alpha-aminoadipic aciduria (alpha-AA) were subjected to a tryptophan loading test to determine if their condition resulted from a defect in the alpha-aminoadipate aminotransferase (kynurenine aminotransferase) system. Normal increases in kynurenic and xanthurenic acids eliminated this possibility. Further analyses of their urines revealed that both boys had measurable amounts of previously undetected alpha-ketoadipic acid (alpha-KA) before and after the loading test. A reexamination of speciments from a prelysine and postlysine loading test reconfirmed the existence of alpha-KA in their urines at the time the original observation of alpha-AA was made. The response to the lysine load was a predictable increase in both alpha-AA and alpha-KA. The boy who had been referred to this institution with a learning defect responded to the tryptophan load with a slight decrease in alpha-AA and an unpredicted decrease in alpha-KA and 3-hydroxykynurenine. His mentally normal brother showed a significant decrease in alpha-AA and major increases in all other measured metabolites including alpha-KA. The latter results were compatible with a defect in the oxidative decarobxylation of alpha-KA. A comparison of the urinary alpha-AA and alpha-KA concentrations in our subjects with comparable data in mentally normal and mentally retarded patients with this condition suggested that the retardation may result from other causes.

The kynurenine load test, an adjunct to the tryptophan load test.

The kynurenine load test was introduced to distinguish, in vivo, between abnormal tryptophan metabolism caused by induction of tryptophan oxygenase or by impaired kynureninase function. This test was carried out by giving a loading dose of 700 mumol L-kynurenine sulphate followed by determination of urinary metabolites of the tryptophan-nicotinic acid ribonucleotide pathway. The results of the kynurenine load test in a group of healthy post-menopausal female subjects show a consistant increase in urinary excretion of some metabolites of the tryptophan-nicotinic acid ribonucleotide pathway (kynurenine, 3-hydroxy-kynurenine, and 3-hydroxyanthranilic acid) of a magnitude comparable to the increase seen after a loading dose of 9800 mumol L-tryptophan (the tryptophan load test).

Enhancement of rat brain metabolism of a tryptophan load by chronic ethanol administration.

We have previously shown that chronic ethanol administration enhances brain 5-hydroxytryptamine synthesis by increasing the availability of circulating tryptophan to the brain secondary to the decreased liver tryptophan pyrrolase activity. We now find that ethanol enhances the brain metabolism of a tryptophan load by the same mechanism. The results are discussed in relation to ethanol preference and the need for further clinical work on the effects of alcoholism on tryptophan metabolism.