Induction Of Tryptophan Pyrrolase Research Articles

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 growth hormone on the metabolism of a tryptophan load in the liver and brain of hypophysectomized rats.

Growth hormone antagonizes the induction of tryptophan pyrrolase and tyrosine amino-transferase by cortisol. We have shown that contrary to previous reports, growth hormone is also capable of antagonizing the induction of these enzymes by tryptophan and alpha-methyl tryptophan. As alpha-methyl tryptophan is not metabolized appreciably in the rat, our data show that growth hormone does not act indirectly through changes in the liver tryptophan content as was suggested previously. Growth hormone decreases the rate of tryptophan catabolism in vivo after induction of tryptophan pyrrolase by tryptophan and alpha-methyl tryptophan. Because the rate of catabolism of a tryptophan is slower in animals treated with growth hormone, tissue tryptophan levels and the rate of synthesis of 5-hydroxyltryptamine in the brain are higher in these animals than in those receiving tryptophan alone. Thus, although tryptophan administration raises brain 5-hydroxytryptamine levels, induction of tryptophan pyrrolase in the liver, by the load, limits the extent and duration of the rise in brain 5-hydroxytryptamine synthesis. This has important implications for the clinical use of tryptophan in psychiatric disorders, where tryptophan is given to produce long-lasting elevations of brain 5-hydroxytryptamine.

Reactivity of the liver to glucocorticoids during chemical hepatocarcinogenesis

Liver cells during chemical carcinogenesis (3′-methyldimethylaminoazobenzene) and cells of primary hepatomas retain the property of reacting to partial hepatectomy by increased incorporation of3H-thymidine into DNA, just as under normal conditions this process is inhibited by dexamethasone. The inducibility of tyrosine aminotransferase (EC 2.6.1.5) likewise remained unchanged, whereas induction of tryptophan pyrrolase (EC 1.13.11.11) in primary hepatomas was abolished. The adequacy of a model of chemical carcinogenesis of an organ if the heterogeneity of its cell populations is disregarded is discussed.

Nature of the inhibition by noradrenaline of induction by cortisol of hepatic tryptophan pyrrolase

Administration of noradrenaline inhibited the induction of hepatic trytophan pyrrolase by Cortisol but not by tryptophan. The selective inhibition of pyrrolase was specific to noradrenaline, whereas adrenaline and rat growth hormone also inhibited tyrosine aminotransferase. None of those three hormones had any effect on the incorporation of [ 32P]-orthophosphate into RNA, stimulated by cortisol. Other biogenic amines, polypeptide hormones and steroid analogues were not inhibitory to the induction of tryptophan pyrrolase by cortisol. The α-adrenergic agonist, phenylephrine, potentiated the noradrenaline inhibition whereas DL-threo-3,4-dihydroxyphenylserine, its precursor, together with pargyline had no effect on the induction process of pyrrolase. These results support the view that noradrenaline exerts its inhibitory action at the cell membrane via the α-receptor, and is not mediated directly by an intracellular mechanism.

Metabolism of an oral tryptophan load by women and evidence against the induction of tryptophan pyrrolase by oral contraceptives.

Rates of tryptophan and kynurenine appearance and disappearance in plasma following an oral tryptophan load have been studied in female volunteers, aged 19-39 years, taking no drugs or taking oral contraceptives (OCs). Following a single oral L-tryptophan load (50 mg/kg), plasma tryptophan concentrations rose 5 fold reaching a peak after 1-2 hours. Plasma kynurenine concentrations also rose reaching a peak after 3 hours. Tryptophan changes were similar in both groups but kynurenine concentrations were lower in the OC group 1 hour (p .01), 2 hours (p .05), and 3 hours (p .05) after the load. In both groups there was little increase in urinary tryptophan or 5-hydroxyindoleacetic acid excretion in the 24 hours after the load and just over a doubling of indoleacetic acid excretion. The OC group excreted less kynurenine than the controls both during the 24 hours before the load and the 24 hours after, although the percentage increase following the load was much greater in the OC group. The OC group also excreted more 3-hydroxykynurenine, xanthurenic acid, and 3-hydroxyanthranilic acid following the tryptophan load. Both groups revealed similar values for volume of distribution, plasma clearance, and plasma 1/2-life of tryptophan. It is concluded that the excretion of certain tryptophan metabolites is raised in women in OCs. This change does not appear to be attributable to an increase in the activity of liver tryptophan pyrrolase; 1 possible reason may be a relative deficiency of vitamin B6.

Tryptophan catabolism by tryptophan pyrrolase in rat liver. The effect of tryptophan loads and changes in tryptophan pyrrolase activity.

We investigated how changes in tryptophan pyrrolase activity and tryptophan loads affect the breakdown of tryptophan was estimated by injecting rats with [ring-2-14-C]tryptophan and measuring respiratory 14-CO2. We concluded, contrary to previous reports, that induction of tryptophan pyrrolase definitely will increase the rate of tryptophan breakdown. Tryptophan loads also increase tryptophan breakdown even in circumstances where there is no increase in tryptophan pyrrolase activity, presumably by increasing the saturation of the enzyme. After a tryptophan load (50 mg per kg) the increase in liver tryptophan concentration lasts only 30 min. The rapid return of liver tryptophan to normal may be due partly to the high turnover rate of liver tryptophan. We estimate that tryptophan pyrrolase degrades tryptophan in vivo at a rate that is equivalent to the whole liver tryptophan concentration in 7.5 min or less.

Nature of induction of tryptophan pyrrolase in cold exposure.

The activity of hepatic tryptophan pyrrolase in rats exposed to cold increased rapidly and reached a maximum of three-fold at 8 h. On continued exposure up to 48 h stress, the activity partly decreased but remained at a level higher than the initial. Withdrawal from the cold stress reversed the change. Adrenalectomy or treatment with inhibitors of protein synthesis abolished the increase in the enzyme activity during cold stress indicating a possible involvement of corticosteroids and de novo protein synthesis. Treatment with drugs known to block autonomic nervous system failed to inhibit the cold-mediated increase in enzyme activity. The results suggest that the increase in enzyme activity obtained on cold exposure is mediated by corticosteroids and not by either indoleaklylamines or autonomic nervous system. The changes in the enzyme obtained under cold stress with respect to the overshoot phenomenon, relationship to the degree of stress and reversibility on withdrawal from the stress indicate the "adaptate" nature of the response.

Tryptophan pyrrolase in rat liver after phenobarbital administration

The administration of phenobarbital increases the activity of tryptophan pyrrolase in the particle-free fraction of rat liver homogenate administration of the drug. The activity of tryptophan pyrrolase remains unaltered after the second day of phenobarbital administration in drinking water given daily until the seventh day. The presence of hematin in the incubation medium increase the specific activity of tryptophan pyrrolase both in the experimental in the control group. The degree of saturation of the enzyme by the heme, however, is higher in the experimental group since its activation in the presence of hematin is lower than in the control group. The presence of phenobarbital in the incubation medium produces a slight inhibitory effect on the activity of tryptophan pyrrolase. Repeated administration of phenobarbital does not increase significantly the induction of tryptophan pyrrolase by hydrocortisone or L-tryptophan.

Antidepressants and liver tryptophan pyrrolase activity

Tricyclic antidepressants were found to diminish liver tryptophan pyrrolase activity in rats. Neuroleptics and anticholinergics, used for comparison, did not change the enzyme activity. No effects of imipramine were observed in vitro nor in adrenalectomized animals. Imipramine did not influence tryptophan or hydrocortisone induction of tryptophan pyrrolase. Antidepressants in doses which lower the enzyme activity also lowered blood plasma concentration of 11-hydroxycorticosteroids. This effect may be responsible for inhibition of tryptophan pyrrolase activity by antidepressants. Inhibitors of monoamine oxidase did not decrease liver tryptophan pyrrolase activity in rats and mice but suppressed tryptophan induction of this enzyme. The possible relations between reduction by antidepressants of liver tryptophan pyrrolase activity and enhanced serotonin synthesis in the central nervous system and the thymoanaleptic effect are discussed.

Influence of non-steroid anti-inflammatory and immunosuppressive drugs on hepatic tryptophan pyrrolase activity in rats

High oral doses of the anti-inflammatory drugs indomethacin, acetylsalicyclic acid, sodium salicylate, salicylamide, mefenamic acid, flufenamic acid, amidopyrine, phenylbutazone and benzydamine administered repeatedly, did not influence tryptophan pyrrolase activity in livers of intact rats. The nonresponsiveness of tryptophan pyrrolase was in contrast to a stimulation of tyrosine aminotransferase caused by flufenamic acid. Induction of tryptophan pyrrolase due to hydrocortisone was not inhibited generally by non-steroid drugs; exceptions were flufenamic acid and benzydamine which depressed hormonal induction. The authors' recent statement is confirmed that inhibition of protein synthesis due to induction is no essential property of non-steroid antiinflammatory drugs. The immunosuppressive drugs cyclophosphamide, triaziquone and azathioprine increased tryptophan pyrrolase activity, probably due to an inhibition of enzyme degradation; chloroquine, 6-mercaptopurin, 6-azauridin and amethopterin did not influence enzyme activity. Induction of tryptophan pyrrolase due to hydrocortisone was depressed by azathioprine, 6-mercaptopurin, 6-azauridin and amethopterin.

Effect of diet and tryptophan on hepatic polyribosomal disaggregation due to actinomycin D.

Abstract The effect of prefeeding a complete diet on polyribosomal disaggregation due to actinomycin D and the effect of trytophan on polyribosomal disaggregation after actinomycin D on the livers of rats were investigated. Fasted rats that were treated with actinomycin D showed moderate to marked disaggregation of hepatic polyribosomes after 6–12 hr. In contrast, fed rats, especially those tube-fed shortly prior to actinomycin treatment, showed much less, only minimal, disaggregation of hepatic polyribosomes. The effect of prefeeding could be observed with a protein-free diet and was not related to altered absorption of actinomycin or changes in actinomycin-induced inhibition of RNA synthesis or induction of tryptophan pyrrolase after cortisone. The disaggregation of hepatic polyribosomes in fasted rats after actinomycin could be returned toward normal, becoming reaggregated, by the administration of tryptophan but not by other single amino acids. Tryptophan did not influence the degree of inhibition of hepatic RNA synthesis due to actinomycin.

The effect of staphylococcal α-toxin on rat liver tryptophan pyrrolase and uridine kinase

The administration of crude staphylococcal α-toxin increased the tryptophan pyrrolase activity in the liver of intact rats. The elevation did not occur in adrenalectomized or hypophysectomized animals. The level of uridine kinase was also raised after toxin administration, both in adrenalectomized and hypophysectomized animals but with a different time-course. The enhancement of uridine kinase and its time-dependency was similar after hydrocortisone administration. Actinomycin d which inhibits induction of tryptophan pyrrolase did not substantially influence the enhancement of uridine kinase activity after hydrocortisone. Twenty-two and 46 hr after staphylotoxin administration the level of uridine kinase was still enhanced. The same effect was observed after the administration of inhibitors of protein synthesis.

Effect of radix ginseng extract on serum protein synthesis.

Intraperitoneal administration of ginseng extract (fraction 3 or 4) to rat was found to increase the rate of synthesis of serum proteins such as albumin and γ-globulin. The incorporation rate of 3H-leucine into serum proteins was significantly increased 4 hr after the injection of fraction 3. The increased rate of protein synthesis reached a maximum about 8-12 hr after the administration and 46-49% increase in the rate of serum protein synthesis was observed. It was confirmed by immunochemical precipitation reaction that the increase in serum protein synthesis was due to the stimulation of albumin and γ-globulin synthesis. The rate declined to the control level at 20 hr following ginseng extract treatment. These observations are similar to the effect of cortisone on the liver. Although the mechanism of this increase in the rate of serum protein synthesis by ginseng extract is not known, some differences were observed in effects between fraction 4 and cortisone as follows. Induction of tryptophan pyrrolase and tyrosine transaminase, which is observed with cortisone, did not occur by fraction 4 administration. These results suggest that the observed effect of ginseng extract would not be due to the elevated concentration of adrenocortical steroids. From this point of view, this stimulating factor, which we term prostisol(protein synthesis stimulating factor), is active to RNA and protein syntheses when administered in vivo.

Interference of beryllium with enzyme induction in rat liver

These studies were stimulated by an earlier observation: in regenerating rat liver, beryllium interferes with the induction of enzymes involved in DNA synthesis. The effects of beryllium upon hepatic enzyme induction in rats were therefore examined in a few more test systems: induction of tryptophan pyrrolase by hydrocortisone and substrate, induction of acetanilid hydroxylase by 3-methylcholanthrene, and induction of aminopyrine demethylase by phenobarbital. Intravenous injection of 50 μmoles Be/kg inhibited enzyme induction in all systems 24 hr after beryllium administration and 30 μmoles Be/kg inhibited enzyme induction 72 hr later in all systems except substrate induction of tryptophan pyrrolase. Dose-effect relationships were established for 2 of the systems tested (tryptophan pyrrolase and acetanilid hydroxylase). The data establish that beryllium inhibits enzyme induction not only in regenerating rat liver, but also in other systems.

Relative rates of tryptophan pyrrolase degradation following the administration of hydrocortisone and tryptophan to intact and adrenalectomized rats

Studies have performed in normal and adrenalectomized rats to examine the mechanisms underlying hormonal and substrate induction of liver tryptophan pyrrolase (tryptophan oxidoreductase, EC 1.13.1.12). Tryptophan pyrrolase was induced either by the intraperitoneal administration of hydrocortisone sodium succinate or l-tryptophan. In a number of experiments actinomycin D was given to inhibit mRNA synthesis, in others puromycin dihydrochloride was given to prevent protein synthesis. After tryptophan administration to intact rats depression of enzyme degradation occurred (the t 1 2 for tryptophan pyrrolase after puromycin administration is significantly increased). Such a depression in the degradation of tryptophan pyrrolase was not observed during hormonal induction of the enzyme (in animals receiving hydrocortisone the t 1 2 for tryptophan pyrrolase following puromycin administration remained relatively constant). Actinomycin D had no effect on substrate induction of tryptophan pyrrolase in adrenalectomized animals. However, in intact animals the induction of tryptophan pyrrolase by substrate was greater than that observed in adrenalectomized animals, and this induction was significantly diminished by actinomycin D. Thus, based on present work and work reported in the literature, it appears that (1) hormonal induction of tryptophan pyrrolase in normal and adrenalectomized animals is associated with increased tryptophan pyrrolase synthesis which is dependent on new mRNA synthesis; (2) substrate induction of tryptophan pyrrolase in adrenalectomized animals is associated with decreased enzyme degradation; and (3) substrate induction in intact animals depends both upon decreased degradation of tryptophan pyrrolase and on an increased synthesis of the enzyme, which is dependent on new mRNA synthesis.

Cytoplasmic changes during thioacetamide induced hepatocarcinogenesis in rats.

Cytoplasmic changes were investigated in livers of rats at various intervals up to 50 weeks during primary induction of hepatoma by thioacetamide feeding.Microsomal Glucose-6-phosphatase and ATPase activities were shown to decrease progressively with increased period of thioacetamide feeding the fall in activities being more pronounced during the first 15 weeks.Hormonal induction of tryptophan pyrrolase and tyrosine transaminase activities was shown to undergo a significant decrease of 65% and 55% respectively at the end of 50 weeks feeding.The substrate induced tryptophan pyrrolase activity was decreased to 50% during the 50 weeks period whereas the substrate induced tyrosine transaminase activity gradually increased to 200%. The latter is attributable to differences in the optimal induction dose of tyrosine in normal and carcinogen fed rats.The m-RNA template lifetime for tryptophan pyrrolase was shown to be exceeding 24 hours in normal rats as against that of 13 hours in rats fed with carcinogen for 30 weeks. On the other hand the m-RNA template lifetime for tyrosine transaminase was 3 hours in control rats while it was 7 hours in the carcinogen fed rats.The observed changes were shown to occur long before the onset of malignant transformation.The alterations in terms of decreased Glucose-6-phosphatase and substrate induced tryptophan pyrrolase activities were shown to be reversible when the carcinogen was withdrawn from the diet after 30 weeks of feeding.The significance of these observations is discussed in relation to damage to endoplasmic reticulum during hepatocarcinogenesis.

Action of Actinomycin D on Tryptophan Uptake in the Adrenalectomized Rat and Its Effect on Induction of Tryptophan Pyrrolase and Tyrosine Transaminase in Liver

Abstract Orally intubated 3H-labeled tryptophan was retained significantly in the stomach and intestine of rats treated with actinomycin D (43%) as compared to controls (13%) 4 hours after intubation. Likewise, smaller amounts of the isotope subsequently appeared in the liver and serum of the drug-treated animals. In contrast, actinomycin had no effect on movement of intraperitoneally injected 3H-tryptophan out of the peritoneal cavity or its subsequent accumulation in the liver. Induction of tryptophan pyrrolase by intraperitoneally or intravenously administered tryptophan was unaffected by concomitant actinomycin D treatment. On the other hand, similar induction of tyrosine transaminase was completely blocked by the drug. When l-tryptophan was administered orally over a range of 5 to 20 mg/100 g, the maximum induction of tyrosine transaminase was obtained at the 5-mg dose with no further enhancement at higher levels. However, with tryptophan pyrrolase, there was a gradual response: no induction after 5 mg, a 3-fold increase at 10 mg, and a 6-fold enhancement at 20 mg. These experiments show that in the rat actinomycin D affects the transport and absorption of dietary metabolites from the gastrointestinal tract. Therefore it is important to consider any conclusion drawn from orally administered substrate induction experiments in the light of this action of actinomycin D.

Some biochemical effects of triamcinolone acetonide on rat liver and muscle.

1. The powerful anti-inflammatory glucocorticoid triamcinolone acetonide, administered to rats at 20 and 2.5mg/kg, leads to a decrease in the incorporation in vivo of [(3)H]uridine and [(32)P]orthophosphate into hind-limb skeletal muscle. 2. At the higher dose, this decrease in the rate of incorporation of precursors into RNA precedes a decrease in the incorporating ability of muscle ribosomes, which commences about 4-5h after drug administration, but is unaccompanied by any changes in the concentration of tissue ATP or free amino acids. 3. The ribosomal dysfunction extends to polyribosomes, which can only be successfully isolated from the muscle of triamcinolone-treated animals after the addition of alpha-amylase to the tissue homogenate to remove glycogen. 4. The specific radioactivity of muscle protein labelled in vivo with (14)C-labelled amino acids does not decrease progressively after triamcinolone administration. After 2h there is an apparent stimulation of incorporation which leads to an overall discrepancy between measurements of protein-synthetic activity made in vivo and in vitro. 5. There is a significant increase in muscle-glycogen concentration between 8 and 12h after the administration of triamcinolone acetonide (20mg/kg), although a significant decrease occurs after 4h. The fall in glycogen concentration may be due to a decrease in the rate of synthesis of protein essential for glucose uptake into the tissues. 6. As judged by (a) incorporation of (14)C-labelled amino acids into protein, (b) [(3)H]uridine and [(32)P]-orthophosphate incorporation into RNA, (c) the rate of induction of tryptophan pyrrolase and (d) changes in the pool sizes of taurine and tryptophan, the responses in liver followed the same time-course as those in muscle after administration of the drug.

Inhibitory effects of phenylhydrazine on the induction of tryptophan pyrrolase in rats.

(1) The effects of phenylhydrazine treatment on both tryptophan pyrrolase activity in intact and adrenalectomized rats and the inducible response of the enzyme to the hormone and the substrate in adrenalectomized rats were investigated. (2) The administration of phenylhydrazine in intact rats as well as adrenalectomized rats resulted in increase in the level of tryptophan pyrrolase. (3) No effects of phenylhydrazine on tryptophan pyrrolase was observed in rats which were induced by administration of glucocorticoid. (4) The induction of the enzyme by the substrate was depressed significantly when phenylhydrazine was administered during 4-24 h before sacrifice. (5) Suppressive effects of phenylhydrazine on the tryptophan-induced enzyme activity seems to be associated with the disturbance of porphyrin metabolism in rats.

Suppression of tryptophan pyrrolase induction in porphyric animals.

Nachweis, dass Phenylhydrazin die von Tryptophan, nicht aber von Kortison hervorgerufene Induktion der Tryptophanpyrrolase in der Rattenleber hemmt. Die Hemmung der Enzyminduktion durch Phenylhydrazin durfte auf Anomalien des Porphyrin-stoffwechsees beruhen.