Liver and Brain Tryptophan Metabolism Following Hydrocortisone Administration to Rats and Gerbils

Green, A. R.; Young, Simon N.

doi:10.1111/j.1476-5381.1975.tb07360.x

Cited by 51 publications

(21 citation statements)

References 30 publications

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“…However, when they perfused for 6 h, adding hydrocortisone to the medium, they found few significant changes of pyrrolase activity in terms of either tryptophan removal from the medium or appearance of kynurenine, the product of pyrrolase activity. This is at variance with in vivo studies which have demonstrated that steroids and tryptophan produce significant alterations in the rate of expired 14C02 from DL-[ring 2-'4C]-tryptophan (Moran & Sourkes, 1963;Green, 1969;Green et al, 1975b;Young & Sourkes, 1975). Kim & Miller (1969) however were also unable to find a statistically significant increase in "4CO2 excretion using these techniques.…”

Section: Introductioncontrasting

confidence: 43%

“…There is some error in these results deriving from plasma tryptophan trapped in the blood vessels of the liver. Extracellular space in the liver has been calculated at 22.2% (Woods, Eggleston & Krebs, 1970 (Green et al, 1975b;Young & Sourkes, 1975).…”

Section: Discussionmentioning

confidence: 99%

“…Recent the major metabolic pathway degrading tryptophan evidence has suggested that when the activity of the ( Figure 1). Its activity is increased by corticosteroids enzyme is increased by hydrocortisone treatment, and tryptophan (Knox, 1951) and inhibited by plasma, liver and brain tryptophan concentrations decrease and the brain tryptophan change leads to a decreased rate of synthesis of the neurotransmitter 5-hydroxytryptamine (Green, Sourkes & Young, 1975b;Green, Woods, Knott & Curzon, 1975c), the product of another metabolic pathway of tryptophan ( Figure 1). One difficulty in interpreting previous data on the effect of drugs on pyrrolase activity is that the compounds were administered in vivo and subsequent measurement of pyrrolase activity was performed in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Tryptophan Metabolism in the Isolated Perfused Liver of the Rat: Effects of Tryptophan Concentration, Hydrocortisone and Allopurinol on Tryptophan Pyrrolase Activity and Kynurenine Formation

Green

Woods

Joseph³

1976

British J Pharmacology

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1 The effect of tryptophan concentration on the rate of kynurenine appearance and tryptophan disappearance in the medium perfused through the isolated liver of the rat has been investigated. The effect of pretreatment of the rat with hydrocortisone or allopurinol was also examined, together with the effects of these treatments on liver tryptophan pyrrolase activity measured in vitro at the beginning and end of perfusion. 2 Hydrocortisone (5 mg/kg) injection 3 h before perfusion resulted in a four-fold increase in kynurenine production by the liver during perfusion with a medium containing either 0.1 mmol/l or 1.0 mmol/l tryptophan. Injection of allopurinol (20 mg/kg) together with hydrocortisone and addition of allopurinol (4 mg/100 ml) to the medium abolished the hydrocortisone-induced rise of kynurenine in the 0.1 mmol/l tryptophan medium but not the 1.0 mmol/l tryptophan medium. 3 Injection of cycloheximide (30 mg/kg) with hydrocortisone (5 mg/kg) 3 h before perfusion inhibited the hydrocortisone-induced rise of kynurenine production and the increase in pyrrolase activity measured in vitro both before and at the end of perfusion with 1.0 mmol/l tryptophan. This last result suggests that protein synthesis is involved not only in hydrocortisone induction of pyrrolase but also in substrate induction. 4 Kynurenine production in the 1.0 mmol/l tryptophan medium was less in both saline-and hydrocortisone-treated older rats (335-450 g) compared to younger rats (180-220 g). In agreement with a previous study, pyrrolase activity in vitro was also lower in both saline-and hydrocortisonetreated older rats at the beginning of the perfusion although activity had risen equally in both young and older rats at the end of perfusion.5 There was little correlation between the rate of tryptophan disappearance from the medium and the activity of tryptophan pyrrolase either as measured in vitro or as indicated by the rate of kynurenine production. 6 In general, the production of kynurenine in the medium at the end of the 60 min perfusion was indicative of in vitro pyrrolase activity at the start of the perfusion. 7 It is concluded that while in vitro pyrrolase assay does not give a quantitative index of kynurenine production, it does provide a qualitative index. Furthermore, if kynurenine production in the isolated perfused liver of the rat is indicative of in vivo pyrrolase activity, then hydrocortisone must induce pyrrolase activity in vivo.

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Section: Introductioncontrasting

confidence: 43%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Tryptophan Metabolism in the Isolated Perfused Liver of the Rat: Effects of Tryptophan Concentration, Hydrocortisone and Allopurinol on Tryptophan Pyrrolase Activity and Kynurenine Formation

Green

Woods

Joseph³

1976

British J Pharmacology

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“…Beside the relationship between HPA axis hormones and cytokines, glucocorticoids stimulate the tryptophan metabolism through the KYN pathway in the liver, directly resulting in decreased CNS concentrations of serotonin. 152 …”

Section: The Inflammatory Hypothesis Of Depressionmentioning

confidence: 99%

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

2007

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Beside the well-known deficiency in serotonergic neurotransmission as pathophysiological correlate of major depression (MD), recent evidence points to a pivotal role of increased glutamate receptor activation as well. However, cause and interaction of these neurotransmitter alterations are not understood. In this review, we present a hypothesis integrating current concepts of neurotransmission and hypothalamus-pituitary-adrenal (HPA) axis dysregulation with findings on immunological alterations and alterations in brain morphology in MD. An immune activation including increased production of proinflammatory cytokines has repeatedly been described in MD. Proinflammatory cytokines such as interleukin-2, interferon-c, or tumor necrosis factor-a activate the tryptophan-and serotonin-degrading enzyme indoleamine 2,3-dioxygenase (IDO). Depressive states during inflammatory somatic disorders are also associated with increased proinflammatory cytokines and increased consumption of tryptophan via activation of IDO. An enhanced consumption of serotonin and its precursor tryptophan through IDO activation could well explain the reduced availability of serotonergic neurotransmission in MD. An increased activation of IDO and its subsequent enzyme kynurenine monooxygenase by proinflammatory cytokines, moreover, leads to an enhanced production of quinolinic acid, a strong agonist of the glutamatergic N-methyl-D-aspartate receptor. In inflammatory states of the central nervous system, IDO is mainly activated in microglial cells, which preferentially metabolize tryptophan to the NMDA receptor agonist quinolinic acid, whereas astrocytes -counteracting this metabolism due to the lack of an enzyme of this metabolism -have been observed to be reduced in MD. Therefore the type 1/type 2 immune response imbalance, associated with an astrocyte/microglia imbalance, leads to serotonergic deficiency and glutamatergic overproduction. Astrocytes are further strongly involved in re-uptake and metabolic conversion of glutamate. The reduced number of astrocytes could contribute to both, a diminished counterregulation of IDO activity in microglia and an altered glutamatergic neurotransmission. Further search for antidepressant agents should take into account anti-inflammatory drugs, for example, cyclooxygenase-2 inhibitors, might exert antidepressant effects by acting on serotonergic deficiency, glutamatergic hyperfunction and antagonizing neurotoxic effects of quinolinic acid. Molecular Psychiatry (2007) 12, 988-1000; doi:10.1038/sj.mp.4002006; published online 24 April 2007 Keywords: major depression; psychoneuroimmunology; IDO; glutamate; immune system; serotonin Glutamate in depressionGlutamatergic neurotransmission is involved in depression and interacts with the serotonergic and noradrenergic systems The common therapeutic mechanism of antidepressant drugs is the enhancement of serotonergic and/or noradrenergic neurotransmission. On the basis of this pharmacological profile of antidepressant drugs, neurochemical research on major depression ...

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“…This in turn would presumably decrease brain tryptophan. Recent evidence suggests that variations in activity of this enzyme can alter brain tryptophan concentrations (Green, Sourkes & Young, 1975;Green, Woods, Knott & Curzon, 1975).…”

Section: Discussionmentioning

confidence: 99%

Effects of Monoamine Oxidase Inhibition by Clorgyline, Deprenil or Tranylcypromine on 5‐hydroxytryptamine Concentrations in Rat Brain and Hyperactivity Following Subsequent Tryptophan Administration

Green¹,

Youdim²

1975

British J Pharmacology

149

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1 The effect of various doses of tranylcypromine on the degree of inhibition of rat brain monoamine oxidase (MAO) using 5-hydroxytryptamine (5-HT), dopamine and phenylethylamine as substrates has been examined 120 min after injection of the inhibitor. The concentration of brain 5-HT was also examined both after tranylcypromine alone and also when L-tryptophan (100 mg/kg) had been given 30 min after the tranylcypromine. 2 All doses of tranylcypromine greater than 2.5 mg/kg totally inhibited MAO oxidation of 5-HT, phenylethylamine and dopamine as measured in vitro and produced a similar rise of brain 5-HT in vivo. When tryptophan was also given, there was a further rise of brain 5-HT, which was comparable after all doses of tranylcypromine above 2.5 mg/kg and the characteristic syndrome of hyperactivity made its appearance. 3 Clorgyline (a 'Type A' MAO inhibitor), in doses up to 10 mg/kg, did not totally inhibit MAO activity towards phenylethylamine although it did inhibit 5-HT oxidation by 100%. Deprenil (a 'Type B' MAO inhibitor) at doses up to 10 mg/kg did not fully inhibit 5-HT oxidation although phenylethylamine oxidation was inhibited almost completely. Administration of either compound alone did not produce as great an accumulation of brain 5-HT as that seen after tranylcypromine (2.5 mg/kg) and subsequent administration of tryptophan did not cause hyperactivity or the rise of brain 5-HT seen after tranylcypromine (2.5 mg/kg) plus tryptophan. 4 Administration of clorgyline plus deprenil (2.5 mg/kg of each) almost totally inhibited oxidation of both 5-HT and phenylethylamine; subsequent tryptophan administration resulted in a rise of brain 5-HT nearly as great as that seen fQllowing tranylcypromine (2.5 mg/kg) plus tryptophan and the animals became hyperactive. 5 No evidence was found pointing to the formation of any other 5-substituted indole in the brain following tranylcypromine plus L-tryptophan administration as suggested by others. 6 It is concluded that while 5-HT may normally be metabolized in the brain by 'Type A' MAO in vivo, when this form is inhibited, 5-HT can still be metabolized by 'Type B' enzyme. It is only when both forms are almost totally inhibited that the largest rise of brain 5-HT is seen and subsequent tryptophan administration produces the hyperactivity syndrome.

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Liver and Brain Tryptophan Metabolism Following Hydrocortisone Administration to Rats and Gerbils

Cited by 51 publications

References 30 publications

Tryptophan Metabolism in the Isolated Perfused Liver of the Rat: Effects of Tryptophan Concentration, Hydrocortisone and Allopurinol on Tryptophan Pyrrolase Activity and Kynurenine Formation

Tryptophan Metabolism in the Isolated Perfused Liver of the Rat: Effects of Tryptophan Concentration, Hydrocortisone and Allopurinol on Tryptophan Pyrrolase Activity and Kynurenine Formation

The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression

Effects of Monoamine Oxidase Inhibition by Clorgyline, Deprenil or Tranylcypromine on 5‐hydroxytryptamine Concentrations in Rat Brain and Hyperactivity Following Subsequent Tryptophan Administration

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