Plasma and Brain Tryptophan Changes in Experimental Acute Hepatic Failure

Curzon, G.; Kantamanem, B. D.; Winch, J. E.; Rojas-Bueno, A.; Murray-Lyon, I M; Williams, Roger

doi:10.1111/j.1471-4159.1973.tb04233.x

Cited by 116 publications

(36 citation statements)

References 22 publications

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“…It has been repeatedly reported that tryptophan concentrations significantly increase in plasma and in CSF of patients affected by liver disorders or in animal models of hepatic failure (Hirayama, 1971;Curzon et al, 1973;Ono et al, 1978;Sourkes, 1978;Bengtsson et al, 1991;Bergqvist et al, 1995a,b). It has also been demonstrated that the administration of large doses of tryptophan to patients affected by hepatic disorders or to rats and dogs with a portocaval shunt negatively affects their behavior and may lead to coma that, however, is not due to ammonia overload because equivalent doses of other amino acids were not toxic (Sherlock, 1975;Bucci et al, 1980;RossiFanelli et al, 1982).…”

Section: Discussionmentioning

confidence: 99%

“…It has also been shown that the tryptophan concentration is significantly increased in plasma and CSF of patients with liver failure or in blood and brain of animal models of acute or chronic liver damage (Hirayama, 1971;Curzon et al, 1973;Ono et al, 1978;Sourkes, 1978) and that administration of large doses of tryptophan to patients affected by hepatic disorders or to dogs with a portocaval shunt may lead to coma (Sherlock, 1975;Rossi-Fanelli et al, 1982). Because coma cannot be ascribed to a tryptophan-induced increase in blood ammonia level, these observations strongly suggest that a neuroactive tryptophan metabo-the University of Florence.…”

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confidence: 99%

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Oxindole, a Sedative Tryptophan Metabolite, Accumulates in Blood and Brain of Rats with Acute Hepatic Failure

Carpenedo

Mannaioni

Moroni

1998

Journal of Neurochemistry

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Rats treated with oxindole (10-100 mg/kg p.), a putative tryptophan metabolite, showed decreased spontaneous locomotor activity, loss of the righting reflex, hypotension, and reversible coma. Brain oxindole levels were 0.05 ± 0.01 nmol/g in controls and increased to 8.1 ± 1.7 or 103 ±15 nmol/g after its administration at doses of 10 or 100 mg/kg i.p., respectively. To study the role that oxindole plays in the neurological symptoms associated with acute liver failure, we measured the changes of its concentration in the brain after massive liver damage, and we investigated the possible metabolic pathways leading to its synthesis. Rats treated with either thioacetamide (0.2 and 0.4 g/kg i.p., twice) or galactosamine (1 and 2 g/kg i.p.) showed acute liver failure and a large increase in blood or brain oxindole concentrations (from 0.05 ± 0.01 nmol/g in brains of controls to 1.8 ± 0.3 nmol/g in brains of thioacetamidetreated animals). Administration of tryptophan (300-1,000 mg/kg p.o.) caused a twofold increase, whereas administration of indole (10-100 mg/kg p.o.) caused a 200-fold increase, of oxindole content in liver, blood, and brain, thus suggesting that indole formation from tryptophan is a limiting step in oxindole synthesis. Oral administration of neomycin, a broad-spectrum, locally acting antibiotic agent able to reduce intestinal flora, significantly decreased brain oxindole content. Taken together, our data show that oxindole is a neurodepressant tryptophan metabolite and suggest that it may play a significant role in the neurological symptoms associated with acute liver impairment.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Oxindole, a Sedative Tryptophan Metabolite, Accumulates in Blood and Brain of Rats with Acute Hepatic Failure

Carpenedo

Mannaioni

Moroni

1998

Journal of Neurochemistry

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“…This fraction can be increased in conditions in which the plasma concentration of unesterified fatty acids (UFA) increases as these substances decrease the binding of tryptophan to albumin Curzon, Friedel & Knott, 1973;Curzon, Kantamaneni, Winch, RojasBueno, Murray-Lyon & Williams, 1973;Curzon & Knott, 1974;.…”

Section: Introductionmentioning

confidence: 99%

Effect of Aminophylline on Tryptophan and Other Aromatic Amino Acids in Plasma, Brain and Other Tissues and on Brain 5‐hydroxytryptamine Metabolism

Curzon

Fernando

1976

British J Pharmacology

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1Aminophylline and other methylxanthines increase brain tryptophan and hence 5-hydroxytryptamine turnover. The mechanism of this effect of aminophylline was investigated. 2 At lower doses (t> 100 mg/kg i.p.) the brain tryptophan increase could be explained by the lipolytic action of the drug, i.e. increased plasma unesterified fatty acid freeing plasma tryptophan from protein binding so that it became available to the brain. 3 Plasma unesterified fatty acid did not increase when aminophylline (100 mg/kg i.p.) was given to nicotinamide-treated rats but as both plasma total and free tryptophan rose, a tryptophan increase in the brain still occurred. 4 The rise in brain tryptophan concentration following the injection of a higher dose of the drug (150 mg/kg i.p.) could no longer be explained by a rise of plasma free tryptophan as the ratio of brain tryptophan to plasma free tryptophan rose considerably. Plasma total tryptophan fell and the plasma insulin concentration rose. 5The increase of brain tryptophan concentration after injection of 150 mg/kg aminophylline appeared specific for this amino acid as brain tyrosine and phenylalanine did not increase. However as their plasma concentrations fell the brain/plasma ratio for all three amino acids rose. 6 The higher dose of aminophylline increased the muscle concentration of tryptophan but that of tyrosine fell and that of phenylalanine remained unaltered. The liver concentrations were not affected. 7 The aminophylline-induced increases of the ratio of brain tryptophan to plasma free tryptophan no longer occurred when the drug was given to animals injected with the fl-adrenoceptor blocking agent propranolol or the diabetogenic agent streptozotocin. 8 The changes in brain tryptophan upon aminophylline injection may be explained by (a) increased availability of plasma tryptophan to the brain due to increased lipolysis and (b) increased effectiveness of uptake of tryptophan by the brain due to increased insulin secretion.

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“…In circumstances such as fasting and experimental hepatic coma (Curzon, Kantamaneni, Winch, Rojas-Bueno, Murray-Lyon & Williams, 1973) or following the administration of many drugs (Curzon & Knott, 1974;Knott & Curzon, 1975), the weakened binding of plasma tryptophan to albumin which results from an increase of plasma UFA appears to lead to increased brain tryptophan. Furthermore, a group of uninjected rats showed significant positive correlations between free trytophan in plasma and trytophan concentration in brain regions (Curzon, Kantamaneni, Fernando, Woods & Cavanagh, 1975 Another plasma amino acid, tyrosine, did not show similar changes to those of tryptophan.…”

Section: Discussionmentioning

confidence: 99%

Rapid Effects of Environmental Disturbance on Rat Plasma Unesterified Fatty Acid and Tryptophan Concentrations and Their Prevention by Antilipolytic Drugs

Curzon¹,

Knott²

1975

British J Pharmacology

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1Changes of plasma unesterified fatty acid (UFA) and tryptophan concentration in group-housed rats following removal of their cage-mates and the effects of antilipolytic drugs on these changes were investigated. 2 Removal of group-housed 24 h fasted rats but not fed rats from cages resulted in increased plasma UFA concentration in the remaining rats which was associated with significant increases of the proportion of free tryptophan but significant falls of total tryptophan concentration. These rapid changes were not associated with brain tryptophan changes. Plasma tyrosine concentration was unaffected. 3 The fall of plasma tryptophan did not appear to be due to passage into red cells as erythrocyte tryptophan concentration remained unchanged. 4 Plasma UFA concentrations correlated positively and significantly with corticosterone concentrations which were also increased following removal of cage-mates. 5 Plasma UFA increases and tryptophan changes in the fasting rats were both prevented by nicotinic acid or propranolol. Corticosterone concentration was increased by nicotinic acid but unaffected by propranolol. 6 The possible importance of these rapid changes of plasma tryptophan and of their prevention by antilipolytic drugs is discussed.

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Plasma and Brain Tryptophan Changes in Experimental Acute Hepatic Failure

Cited by 116 publications

References 22 publications

Oxindole, a Sedative Tryptophan Metabolite, Accumulates in Blood and Brain of Rats with Acute Hepatic Failure

Oxindole, a Sedative Tryptophan Metabolite, Accumulates in Blood and Brain of Rats with Acute Hepatic Failure

Effect of Aminophylline on Tryptophan and Other Aromatic Amino Acids in Plasma, Brain and Other Tissues and on Brain 5‐hydroxytryptamine Metabolism

Rapid Effects of Environmental Disturbance on Rat Plasma Unesterified Fatty Acid and Tryptophan Concentrations and Their Prevention by Antilipolytic Drugs

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