[Studies of tryptophan metabolism of streptomycetes. IV. Studies of the inhibition of enzyme of tryptophan metabolism].
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Azides↗
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A defect in tryptophan metabolism.
Oral tryptophan loading tests were performed in a patient with photosensitive pellagra-like skin rash and cerebellar ataxia but without hyperaminoaciduria. Plasma tryptophan concentrations after loading were similar in the patient and control subjects. Average urinary excretion of tryptophan in the patient from 0 to 6 and 6 to 12 hr was 2.69 and 2.58 mumol/kg, respectively; that in the control subjects was 0.82 and 0.34 mumol/kg, respectively. However, the average renal clearance of tryptophan during the first 6 hr of the loading tests in the patient was 0.757 ml plasma/1.73 m2 and that in the control subjects was 0.706 ml plasma/1.73 m2. Renal excretion of kynurenine in the patient was markedly decreased. The average from 0 to 6 and 6 to 12 hr in the patient was 1.90 and 1.13 mumol/kg, respectively; that in the control subjects was 12.90 and 18.15 mumol/kg, respectively. Under ultraviolet light, paper chromatograms of urine from the patient showed a deficiency of xanthurenic acid, kynurenic acid, kynurenine, and formylkynurenine. The deficiency of formylkynurenine in the patient's urine was confirmed by staining the paper chromatograms with Ehrlich's reagent. The patient was "sensitive" to oral nicotinic acid treatment; however, oral nicotinamide was well tolerated with improvement in the photosensitive skin rash.
Cerebellar Ataxia↗
The acute effects of ethanol on liver and brain tryptophan metabolism.
1. The effects of acute ethanol administration of liver and brain tryptophan metabolism are reviewed. 2. Ethanol enhances the activity of rat liver tryptophan pyrrolase by increasing the availability of circulating free tryptophan to the liver by catecholamine-mediated lipolysis followed by displacement of protein-bound serum tryptophan. 3. The response of the mouse liver enzyme to ethanol is strain-dependent. Ethanol activates the enzyme in CBA/CA but not in C57/BL mice. 4. Ethanol exerts a biphasic effect on the concentrations of rat brain tryptophan, 5-hydroxytryptamine and 5-hydroxyindol-3-ylacetic acid. 5. Both aspects of this biphasic effect are associated with an altered availability of circulating free tryptophan. 6. The initial enhancement by ethanol of brain tryptophan metabolism may be due to the above-mentioned lipolytic mechanism, whereas the subsequent decrease in brain indoles may be caused by the enhanced tryptophan pyrrolase activity. 7. Brain tryptophan metabolism is decreased by ethanol in CBA/CA whereas no change is observed in that in C57/BL mice. 8. These results are discussed in relation to previous work on the acute effects of ethanol on rat and mouse brain 5-hydroxytryptamine metabolism.
Animals↗
[Tryptophan metabolism and oligophrenia (author's transl)].
After dealing with the biochemistry of tryptophan metabolism the most important results obtained in humans are presented. Special emphasis is given to the hereditary defects of tryptophan metabolism associated with mental retardation and convulsions due to lack of pyridoxine. The author's findings demonstrate the existence of a hereditary disturbance of the tryptophan metabolism via kynurenine in a certain part of oligophrenic patients. This metabolic defect can be controlled by high doses of vitamin B6. Furthermore investigations conducted with a view to interpreting these results are discussed, especially the determination of kynureninase activity, serotonin blood levels and pyridine nucleotide synthesis.
Amino Acid Metabolism, Inborn Errors↗
Studies of tryptophan metabolism in protein-energy malnutrition (PEM).
Studies on tryptophan metabolism in PEM were performed. In this respect, the basal excretion of tryptophan and some of its metabolites, namely, kynurenine, 3 OH-anthranilic, anthramilic, indol-3-acetic, 5 OH-indol acetic and xanthurenic acids were determined. The response of these metabolites to oral tryptophan load, singly and in combination, with pyridoxine, were performed in kwashiorkor cases compared to normal controls. The study revealed that kynurenine leads to niacine pathway is hindered, Indole-3-acetic acid levels are lower and respond poorly to tryptophan loading in PEM. Increased levels of 5 OH-indol acetic were found in kwashiorkor compared to marasmus, although lower response to tryptophan was noted. Xanthurenic acid excretion is much higher in PEM and poorly responds to tryptophan load either singly or in combination with pyridoxine. These errors of tryptophan metabolism in PEM are suggested to be due to defects in the enzyme systems involved rather than to vitamin B6 deficiency.
Child, Preschool↗
Tryptophan metabolism "via" nicotimic acid in patients with scleroderma.
The tryptophan metabolism "via" kynurenine was studied in five patients with scleroderma after aminoacid loading. Four of these patients had abnormal tryptophan metabolism, characterized by a large urinary excretion of kynurenine and kynurenic acid in two cases, of kynurenine, 3-hydroxykynurenine and kynurenic acid in one case and of 3-hydroxyanthranilic acid in another case and generally a reduced excretion of xanthurenic acid and its 8-methyl ether in comparison with a group of healthy controls. Only two of the four patients had a normal response to tryptophan loading after pyridoxine administration, while no one of these responded to nicotinamide supplementation. But the simultaneous administration of pyridoxine and nicotinamide to three of these patients normalized the excretory picture after tryptophan loading. This suggested the presence of a combined vitamin deficiency in seleroderma. As four out of five patients showed total excretory values of kynurenine, kynurenic acid and acetylkynurenine higher than that of the controls, the sum of these values might be considered as a characteristic index of scleroderma.
Adult↗
Enhancement of rat brain tryptophan metabolism by chronic ethanol administration and possible involvement of decreased liver tryptophan pyrrolase activity.
1. Chronic ethanol administration enhances rat brain 5-hydroxytryptamine synthesis by increasing the availability of circulating tryptophan to the brain. This increased availability is not insulin-mediated or lipolysis-dependent. 2. Under these conditions, tryptophan accumulates in the liver and apo-(tryptophan pyrrolase) activity is completely abolished, but could be restored by administration of regenerators of liver NAD+ and/or NADP+. 3. All four regenerators used (fructose, Methylene Blue, phenazine methosulphate and sodium pyruvate) prevented the ethanol-induced increase in liver tryptophan concentration and the increased availability of tryptophan to the brain. 4. It is suggested that the enhancement of brain tryptophan metabolism by chronic ethanol administration is caused by the decreased hepatic tryptophan pyrrolase activity. The results are briefly discussed in relation to previous work with ethanol. 5. Fructose enhances the conversion of tryptophan into 5-hydroxyindol-3-ylacetic acid in brains of ethanol-treated rats, whereas Methylene Blue inhibits this conversion in both control and ethanol-treated animals.
Animals↗
On the regulation of tryptophan metabolism "via" kynurenine.
The tryptophan leads to nicotinic acid pathway is inhibited in the nicotinic acid administered rats; in this case tryptophan chiefly metabolizes "via" serotonin. The serotonin pathway is inhibited in the excess phenylalanine administered rats, especially due to the inhibition of the tryptophan-5-hydroxylase reaction. Xanthurenic acid inhibits kynurenine-3-hydroxylase in vitro, which is a very important regulatory enzyme for xanthurenic acid and nicotinic acid production.
Animals↗
Tryptophan metabolism in bladder cancer patients from Copenhagen.
Urinary excretion before and after a loading dose of tryptophan, plasma pyridoxal phosphate concentration and urinary excretion of 4-pyridoxic acid was studied in 44 male bladder cancer patients from Copenhagen. Six patients (14%) had abnormal tryptophan metabolism, decreased plasma pyridoxal phosphate concentration and in most cases low urinary excretion of 4-pyridoxic acid indicating decreased availability of vitamin B6 or decreased formation of pyridoxal phosphate from vitamin B6. It is concluded that abnormal tryptophan metabolism only plays a minor role for bladder cancer carcinogenesis in Copenhagen. It is, however, stressed that such studies do not rule out the possibility that the aromatic degradation products of tryptophan may be cocarcinogens or promotors as other studies have indicated.
Denmark↗
Effects of portocaval anastomosis on behaviour and brain tryptophan metabolism.
The rat with portocaval anastomosis represents a convenient took for the investigation of (a) factors determining the availability of tryptophan to the brain and (b) the role, if any, that altered tryptophan metabolism may have in the development of hepatic encephalopathy. It was found that increases in brain tryptophan following anastomosis paralleled plasma free tryptophan rather than plasma total tryptophan regardless of whether or not correction for inhibition from amino acids competing with tryptophan for uptake into brain was applied. Nevertheless, while plasma free tryptophan exerts a major influence on brain tryptophan in both sham-operated and anastomosed rats, in the latter group brain tryptophan is raised further by some other mechanism. The anastomosed rat was also found to be behaviourally abnormal in a number of test situations. Thus, they were hypoactive during chronic exposure to an open-field and were less responsive to electric shock. Following the administration of tryptophan, sham-operated rats were also less active in an open-field and less responsive to electric shock when compared with saline-treated rats. Thus, anastomosed rats have behavioural abnormalities for which altered tryptophan metabolism might, to some extent, be responsible.
Animals↗
Tryptophan metabolism in animals with dermatitis. I) In Rats.
Tryptophan metabolism "via kynurenine" after load of amino-acid has been studied in urine of 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. After six days of dermatitis, when the skin damage was in repair, the excretory values after tryptophan load in rats are only slightly increased indicating that the metabolic disturbance is correlated with the skin damage.
Animals↗
Disturbance of tryptophan metabolism and its correction during oestrogen treatment in postmenopausal women.
A relative pyridoxine deficiency was found in all of 12 women using conjugated oestrogens unopposed by progestagsns. This was due to disturbed tryptophan metabolism, expressed in increased xanthurenic acid (XA) excretion (greater than or equal to 60 mumol/8 h) during 8 h following oral administration of 2 g L-tryptophan. The intake of synthetic oestrogens such as ethinyl oestradiol has already been found to lead to a disturbance of tryptophan metabolism and to a deficiency of vitamin B6. Now we have evidence that this is the case not only in women taking oestrogens in oral contraceptives but also as replacement therapy during the postmenopause. This disturbance is clear after 1 yr of oestrogen treatment. Xanthurenic acid excretion was only slightly increased in 3 women who used progestagens in high dosages at the same time. The biochemical changes induced could easily be corrected by administration of vitamin B6. Our cyclic treatment regimen now consists of 25 days of oestrogens per month. In the remaining days a 250 mg tablet per day of vitamin B6 is prescribed.
Adult↗
Tryptophan metabolism in animals with dermatitis. II) In guinea pigs.
Tryptophan load in guinea pigs after induction of a photodermatitis from psoralen caused marked increase of urinary excretion of total metabolites "via kynurenine" in comparison with that obtained before dermatitis. Xanthurenic acid is the metabolite which showed the most increased levels in urine during dermatitis. This dermatitis from furocoumarin caused an alteration of tryptophan metabolism in guinea pigs as well as rats, but species differences in the excretion of metabolites after amino acid load are observed.
Animals↗
The effect of environment on tryptophan metabolism "via kynurenine" in oral contraceptives users.
We have studied tryptophan metabolism "via kynurenine" in women who were oral contraceptives users, living in two different egyptian environments: in the city of Alexandria or in a rural area near Tanta and, in comparison, in control groups of women living in the same environments but who were not contraceptives users. In the non contraceptives users of Tanta we have registered a higher elimination of some metabolites (anthranilic acid, kynurenic acid, xanthurenic acid and 3-OH-anthranilic acid) which might be related to the way of life and environment. The pattern of the kynurenine pathway metabolites of the contraceptives users (studied 1, 3 and 12 months after contraceptives administration) shows some differences with respect to the controls, both in the spontaneous elimination and in that after tryptophan load. These differences are especially evident for anthranilic acid glucuronide, kynurenine and kynurenic, anthranilic and xanthurenic acids. Some differences may be observed after 1 month of contraceptives administration. The effect of tryptophan oral load is superimposed on those of environment and contraceptives use; in the spontaneous elimination of tryptophan metabolites an accomodation to the contraceptives administration is evident. The discrepancies between some of our results and those of the literature might be related to the influence of environmental factors and of the way of life.
Aminohippuric Acids↗
Isolation, crystallization, and properties of indolyl-3-alkane alpha-hydroxylase. A novel tryptophan-metabolizing enzyme.
Indolyl-3-alkane alpha-hydroxylase, a novel tryptophan-metabolizing enzyme, was prepared in crystalline form from soil isolate organism Pseudomonas XA. Emission spectroscopy and atomic absorption analyses of purified enzyme revealed the presence of iron (0.8 mol/mol of protein), and a number of observations supported the presence of heme prosthetic group (1.1 mol/mol of protein). The S20,w value of indolyl-3-alkane alpha-hydroxylase is 10.2 S, and the molecular weight by sedimentation equilibrium ultracentrifugation is 250,000. The E1%280 of the enzyme is 21, and the isoelectric point by isoelectric focusing on ampholine polyacrylamide gel plates is 4.8. The enzyme catalyzes hydroxylation on the side chain of a variety of 3-substituted indole compounds, including certain tryptophan-containing oligopeptides. The reaction product from tryptamine was identified by proton nuclear magnetic resonance and gas chromatography/mass spectroscopy analyses. While the indole ring remained intact, hydroxylation occurred at the side chain carbon adjacent to the ring. Nuclear magnetic resonance studies indicated that hydroxylation always took place at the same position when the substrate was tryptophan methyl ester, tryptophol, indole-3-propionate, or indole-3-butyrate. No other chemical change occurred when these substrates were incubated with the enzyme. The Km value of indolyl-3-alkane alpha-hydroxylase for L-tryptophan is 2.4 X 10(-6) M, at pH 7.2. The enzyme is inhibited by potassium cyanide (0.1 mM) or hydroxylamine (1mM), but not by NaBH4 (25 mM), aminooxyacetic acid (7mM), quinacrine (1 mM), chlortetracycline (1 mM), p-mercuribenzoate (0.1 mM), or ethylenediaminetetraacetate (1 mM). The plasma half-life (t1/2) of indolyl-3-alkane alpha-hydroxylase in tumor-bearing mice is approximately 25 h.
Amino Acids↗
Relationship between tryptophan metabolism and vitamin B6 and nicotinamide in aged subjects.
The urinary excretion of tryptophan metabolites was studied in 20 aged subjects (over 70 years) after oral tryptophan loading (100 mg/kg body weight). All the subjects considered showed an abnormal excretion of metabolites with mean values of 24.67% in men and 25.83% in women in comparison to 6.77% in young controls. Among the metabolites the highest excretion was from kynurenine; moreover kynurenic acid and N-alpha-acetylkynurenine were also excreted in signficantly high amounts. The other metabolites too showed increased values. As the abnormal tryptophan metabolism in aging seemed to be in connection with vitamin B6 and nicotinamide, in a group of 7 aged sugjects the urinary excretion of tryptophan metabolites was studied after aminoacid loading with or without simultaneous administration of these two vitamins. The results show that the abnormal excretory pattern is normalized after vitamin administration (from 16.49% to 7.42% total mean metabolite values).
Adult↗
[Effect of hypercapnia on tyrosine and tryptophan metabolism].
Experiments were conducted on albino rats; it was revealed that an increase in CO2 content in the inspired air (3.8%) caused disturbances in tyrosine and tryptophane metabolism. The activity of tyrosine-aminotranspherase and of tryptophane-oxygenase proved to increase in the liver; blood serum displayed a reduced concentration of free tyrosine and free total tryptophane, but the level of free tryptophane obtained by dialysis proved to rise. A possible significance of these deviations in endogenous blastomogenesis is discussed.
Animals↗
Studies on tryptophan metabolism in ethylism.
The urinary excretion of the metabolites "via kynurenine" was studied in a group of patients with chronic alcoholism after a L-tryptophan loading (100 mg/kg body-weight) with or without simultaneous administration of vitamin B6 or nicotinamide or both. In these subjects an abnormal tryptophan metabolism was obtained with excretion total mean values of 9 metabolites of 15.34% against 6.86% in healthy controls. The treatment with vitamin B6 or nicotinamide in 5 patients decreased the total average excretion from 14.41% to 9.47% and to 9.92% respectively without normalizing, however, the excretory pattern produced from the aminoacid loading. The simultaneous administration of these two vitamins in 9 chronic alcoholic men corrected completely the metabolic defect (from 15.34% to 6.55%).
Adult↗