The conjugation of phenylacetic acid in man, sub-human primates and some non-primate species

James, Margaret O.; Smith, Robert L.; Williams, R. T.; Reidenberg, Marcus M.

doi:10.1098/rspb.1972.0064

Cited by 143 publications

(17 citation statements)

References 14 publications

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“…As expected, injections of sodium acetate did not have any effect on amino acid levels. Plasma amino acids were not measured in the phenylacetatetreated group because, unlike man who acetylates phenylacetate with glutamine, mice metabolize phenylacetate as the glycine conjugate and the amino acid pattern might have been misleading (18).…”

Section: Resultsmentioning

confidence: 99%

Effect of Sodium Benzoate and Sodium Phenylacetate on Brain Serotonin Turnover in the Ornithine Transcarbamylase-Deficient Sparse-Fur Mouse

et al. 1988

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Herein we examine the effects of sodium benzoate and sodium phenylacetate on feeding and central serotonin turnover in a child with citrullinemia and in an animal model of congenital hyperammonemia, the ornithine transcarbamylase-deficient sparse-fur (spfly) mouse. In the child, when the benzoate/phenylacetate dosage was increased from 200 to 375 mg/kg/day each, feeding decreased. There was an accumulation of benzoate and phenylacetate in blood and cerebrospinal fluid a s well a s an increased concentration of 5-hydroxyindoleacetic acid, a neurochemical marker for serotonin turnover, in cerebrospinal fluid. In the mouse, sodium benzoate had a biphasic effect on both plasma ammonium levels and brain serotonin turnover. Two percent oral benzoate was associated with an increase in ammonium level, while a 3% dose led to a decrease in ammonium. There was a similar effect on serotonin turnover noted in both the hyperammonemic spfly and control CD-lly mice. Sodium phenylacetate did not have a consistent effect on serotonin turnover. The mechanism by which benzoate increases brain serotonin turnover appears to involve competition with tryptophan for albumin binding sites. This results in increased free tryptophan in serum and brain. W e speculate that some of the clinical symptoms of benzoate intoxication may be a consequence of altered serotonin turnover in the brain. We suggest that drug levels be monitored during therapy. 36excretion in children with inborn errors of urea synthesis (1). This has resulted in prolonged survival. However, both intravenous drugs used to treat acute hyperammonemia and inadvertent oral overdoses have been associated with clinical toxicity including anorexia, irritability, lethargy, and coma (1, 2). Symptoms of intoxication in part simulate those of hyperammonemia. The mechanism of these behavioral alterations is unclear. Bachmann et al. (3) re~orted increased brain uvtake of Tm. the precursor of serotbnin,tn rats injected with 1 mmol/kg of sddium benzoate. Increased brain uvtake of T m and increased brain serotonin turnover have also been reported in experimentally induced and naturally occurring hyperammonemia (4-7). These findings, together with data showing an association of anorexia with increased serotonin turnover in children with urea cycle disorders (8), suggest that benzoate intoxication may involve altered serotonin turnover.In studying the effect of benzoate and phenylacetate on serotonin turnover, we initially present a case report of a child with citrullinemia who developed toxic symptoms during high dose therapy and was found to have increased levels of the metabolite of serotonin, HIAA, in cerebrospinal fluid. We then examine in more detail the interaction of hyperammonemia and benzoate/ phenylacetate treatment on brain serotonin turnover in the chronically hyperammonemic ornithine transcarbamylase deficient sparse-fur (spf/y) mouse. METHODSBiochemical methods. Plasma ammonium was measured by a microfluorometric adaptation of a glutamate dehydrogenase method as previously d...

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Section: Resultsmentioning

confidence: 99%

Effect of Sodium Benzoate and Sodium Phenylacetate on Brain Serotonin Turnover in the Ornithine Transcarbamylase-Deficient Sparse-Fur Mouse

et al. 1988

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“…Long-term administration of phenylacetate was shown to reduce plasma glutamine levels and to be well-tolerated. 17 However, activity in patients with recurrent malignant glioma was low. 18 More recently, therapeutic approaches targeting amino acid transport were suggested including for example inhibition of the glutamine transporter SLC1A5 15 and inhibition of the glutamate-cystine antiporter xCT.…”

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confidence: 99%

Glutamate enrichment as new diagnostic opportunity in breast cancer

Budczies

Pfitzner

Győrffy

et al. 2014

Intl Journal of Cancer

114

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Exogenous glutamine is an important source of energy and molecular building blocks for many tumors. There is a renewed interest in therapeutically targeting glutamine metabolism due to the recent discovery of two novel glutaminase inhibitors. To quantify the dysregulation of the glutamate-glutamine equilibrium in breast cancer, metabolomics analysis of 270 clinical breast cancer samples and 97 normal breast samples was carried out using gas chromatography combined with time-of-flight mass spectrometry. Positive correlation between glutamate and glutamine in normal breast tissues switched to negative correlation between glutamate and glutamine in breast cancer tissues. Compared with the ratio of glutamate to glutamine in normal tissues, we found 56% of the ER1 tumor tissues and 88% of the ER2 tumor tissues glutamate-enriched. The glutamateto-glutamine ratio (GGR) significantly correlated with ER status (p 5 8.0E-09) and with tumor grade (p 5 3.3E-05). Higher levels of GGR were associated with prolonged overall survival in univariate analysis (HR 5 0.77, p 5 0.027) and in multivariate analysis (HR 5 0.73, p 5 0.038). GGR levels were reflected in an unsupervised clustering of metabolomics profiles. In a supervised analysis of metabolomics data and of genome-wide expression data, replacement of GGR by metabolite surrogate markers was feasible, while replacement of GGR by RNA markers had a limited accuracy. Functional analysis of the gene expression data showed negative correlation between glutamate enrichment and activation of peroxisome proliferator-activated receptor (PPAR) pathway. Our findings may have important implications for patient stratification related to utilization of glutaminase inhibitors.Altered energy metabolism is acknowledged as one of the emerging hallmarks of cancer. 1 Recently, there is a renewed interest in the metabolic transformation occurring in cancer cells and in targeting metabolic enzymes for cancer therapy. 2-4 However, the discovery of dysregulated metabolism in tumors dates back to the work of Otto Warburg in the 1920s. Warburg observed that cancer cells exhibit elevated glycolysis and that much of the generated pyruvate is fermented to lactate rather than feed to the TCA cycle and used for oxidative phosphorylation. 5,6 This phenomenon occurs under anaerobic and even under aerobic conditions ("aerobic glycolysis").A second change that occurs in central metabolism of many cancer cells is the alteration of glutamine metabolism. 7-9 Glutamine can be used to replenish the TCA cycle instead of glucose and feed in carbon and nitrogen for synthesis of nucleotides, several amino acids and glutathione. Further, glutamine can be used for energy production and in transformed cultured cells glutamine driven oxidative phosphorylation was recently shown to be the main source of

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“…In two adult male humans, an average of 91 % and 7 % of a 1 mg/kg bw oral dose of [carboxy-14C]phenylacetic acid is excreted within 24 hours as glutamine and taurine conjugates, respectively. Unlike most other animals, only a trace of the glycine conjugate has been detected in humans (James et al, 1972). The distribution and type of conjugation is relatively unaffected by continued ingestion of phenylacetic acid.…”

Section: Iii32 Metabolism Of Phenetyl Alcohol Phenyl Acetaldehyde mentioning

confidence: 99%

“…Greater than approximately 94 % of an 80 mg/kg dose of phenylacetic acid given by intraperitoneal injection is excreted as the glycine conjugate in rats (James et al, 1972). In rats, endogenous levels of unconjugated phenylacetic acid may occur at dose levels at which glycine conjugation is capacity-limited, presumably by the supply of endogenous glycine (Gregus et al, 1993).…”

Section: Iii32 Metabolism Of Phenetyl Alcohol Phenyl Acetaldehyde mentioning

confidence: 99%

Flavouring Group Evaluation 14, Revision 1 (FGE.14Rev1): Phenethyl alcohol, aldehyde, acetals, carboxylic acid and related esters from chemical group 15 and 22 - Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials

2009

EFSA Journal

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The conjugation of phenylacetic acid in man, sub-human primates and some non-primate species

Cited by 143 publications

References 14 publications

Effect of Sodium Benzoate and Sodium Phenylacetate on Brain Serotonin Turnover in the Ornithine Transcarbamylase-Deficient Sparse-Fur Mouse

Effect of Sodium Benzoate and Sodium Phenylacetate on Brain Serotonin Turnover in the Ornithine Transcarbamylase-Deficient Sparse-Fur Mouse

Glutamate enrichment as new diagnostic opportunity in breast cancer

Flavouring Group Evaluation 14, Revision 1 (FGE.14Rev1): Phenethyl alcohol, aldehyde, acetals, carboxylic acid and related esters from chemical group 15 and 22 - Opinion of the Scientific Panel on Food Additives, Flavourings, Processing Aids and Materials

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