Benzoylglutamic acid, a metabolite of benzoic acid in Indian fruit bats

Idle, Jeffrey R.; Millburn, Peter; Williams, R. T.

doi:10.1016/0014-5793(75)80382-6

Cited by 11 publications

(2 citation statements)

References 5 publications

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“…Preliminary accounts of these findings were reported (Gopaul et al, 1997a,b) The discovery of VPA-GLU, in the biological fluids of humans, is intriguing due to its extreme rarity. To the best of our knowledge, the glutamate conjugate of benzoic acid in the Indian fruit bat (Idle et al, 1975) and p-nitrobenzoic acid in spiders (Smith, 1962) are the only two glutamate conjugates of a xenobiotic carboxylic acid reported in the literature. Conjugates of amino acids that are normally found are species-dependent and vary according to the structure of the carboxylic acid involved.…”

Section: Discussionmentioning

confidence: 97%

Amino Acid Conjugates: Metabolites of 2-Propylpentanoic Acid (Valproic Acid) in Epileptic Patients

Gopaul

Tang²,

Farrell³

et al. 2003

Drug Metab Dispos

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ABSTRACT:In this study, spectroscopic and chromatographic evidence is presented for the identification and characterization of the metabolites, valproyl glutamate (2-propylpentanoyl glutamate, VPA-GLU) and valproyl glutamine (2-propylpentanoyl glutamine, VPA-GLN) in the urine, serum, and cerebrospinal fluid (CSF) of patients on valproic acid (VPA) therapy. Moreover, the identification of valproyl glycine (2-propylpentanoyl glycine, VPA-GLY) in the serum and urine of patients on VPA, albeit in trace concentrations, is also reported here. The three amino acid conjugates excreted in urine accounted for about 1% of the VPA dose in four patients who were on VPA therapy chronically and had reached steady state. VPA-GLU was quantitatively the most prominent metabolite (0.66-13.1 g/mg creatinine) compared with VPA-GLN (0.78-9.93 g/mg creatinine) and VPA-GLY (trace-1.0 g/mg creatinine) in overnight urine samples of all patients studied (n ‫؍‬ 29). The relatively low serum concentrations of the three amino acid conjugates of VPA in six patients suggest that the metabolites are readily excreted once formed. In contrast, whereas VPA GLY was absent in the CSF of one patient on VPA, the concentrations of VPA-GLU and VPA-GLN in this CSF sample were 9 and 5 times, respectively, their corresponding serum concentrations.The antiepileptic drug, valproic acid (VPA 3 ), is primarily used for the management of generalized and absence seizures in children. Concerns over its teratogenicity and hepatotoxicity side effect have encouraged the need to develop analogs of VPA devoid of the adverse effects. However, this task is complicated by the fact that the mechanism of action of the drug itself remains to be understood.A large body of evidence has emerged to link the hepatotoxicity of VPA to its metabolism and has been reviewed over the years (Eadie et al., 1988;Abbott and Anari, 1999;Radatz and Nau, 1999). Moreover, a review of mass-balance studies indicated that the total recovery of a VPA dose cannot be completely accounted for in humans (Baillie and Sheffels, 1995), suggesting the existence of yet unknown metabolites. For all these reasons, despite the extensive work that has been conducted on the metabolism of VPA, the subject remains an area that warrants further investigation.

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Section: Discussionmentioning

confidence: 97%

Amino Acid Conjugates: Metabolites of 2-Propylpentanoic Acid (Valproic Acid) in Epileptic Patients

Gopaul

Tang²,

Farrell³

et al. 2003

Drug Metab Dispos

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“…PAA conjugation with GLY is also commonplace, especially among herbivores and rodent species [10]. Occasional bizarre reactions are encountered, such as the absence of GLY utilization for BA and its derivatives in certain bats [12, 13] that had been replaced by GLU usage [13, 14]. Overall, however, the principal amino acids used for conjugating and apparently detoxicating aromatic acids are GLY, GLN, and TAU.…”

Section: Amino Acids As Agents Of Conjugationmentioning

confidence: 99%

Dog bites man or man bites dog? The enigma of the amino acid conjugations

Beyoğlu

Smith

Idle

2012

Biochemical Pharmacology

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The proposition posed is that the value of amino acid conjugation to the organism is not, as in the traditional view, to use amino acids for the detoxication of aromatic acids. Rather, the converse is more likely, to use aromatic acids that originate from the diet and gut microbiota to assist in the regulation of body stores of amino acids, such as glycine, glutamate, and, in certain invertebrates, arginine, that are key neurotransmitters in the CNS. As such, the amino acid conjugations are not so much detoxication reactions, rather they are homeostatic and neuroregulatory processes. Experimental data have been culled in support of this hypothesis from a broad range of scientific and clinical literature. Such data include the low detoxication value of amino acid conjugations and the Janus nature of certain amino acids that are both neurotransmitters and apparent conjugating agents. Amino acid scavenging mechanisms in blood deplete brain amino acids. Amino acids glutamate and glycine when trafficked from brain are metabolized to conjugates of aromatic acids in hepatic mitochondria and then irreversibly excreted into urine. This process is used clinically to deplete excess nitrogen in cases of urea cycle enzymopathies through excretion of glycine or glutamine as their aromatic acid conjugates. Untoward effects of high-dose phenylacetic acid surround CNS toxicity. There appears to be a relationship between extent of glycine scavenging by benzoic acid and psychomotor function. Glycine and glutamine scavenging by conjugation with aromatic acids may have important psychosomatic consequences that link diet to health, wellbeing, and disease.

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A Metabolomic Perspective of Small Molecule Toxicity

Patterson

Idle

2009

General, Applied and Systems Toxicology

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Recent advances in small molecule profiling, including ultraperformance liquid chromatography and time‐of‐flight mass spectrometry, have given unprecedented views of the metabolic response to toxic stimuli. Metabolomics, the process of measuring the concentration changes in metabolites of biofluids such as urine, serum, sweat or saliva or that of intact cells, tissues or single‐celled organisms, is the missing piece of the omics puzzle (genomics, transcriptomics, proteomics) necessary for providing a holistic view (DNA, RNA, protein and metabolites) of the biological response to a toxicant. Furthermore, metabolomics is an essential addition to any toxicity biomarker‐screening programme, as evidenced by its strong foothold in both pharmaceutical and academic settings. Here we discuss metabolomic science with respect to its past and future contributions to the field of toxicology and describe blueprints necessary for conducting a well‐designed and robust metabolomics experiment from sample collection to data acquisition and analysis. Metabolomics holds great promise as a tool for advancing the field of toxicology by uncovering novel biomarkers of toxic responses and by significantly improving xenobiotic metabolite identification.

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Benzoylglutamic acid, a metabolite of benzoic acid in Indian fruit bats

Cited by 11 publications

References 5 publications

Amino Acid Conjugates: Metabolites of 2-Propylpentanoic Acid (Valproic Acid) in Epileptic Patients

Amino Acid Conjugates: Metabolites of 2-Propylpentanoic Acid (Valproic Acid) in Epileptic Patients

Dog bites man or man bites dog? The enigma of the amino acid conjugations

A Metabolomic Perspective of Small Molecule Toxicity

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