Identification of phenylbutyrylglutamine, a new metabolite of phenylbutyrate metabolism in humans

Comte, Blandine; Kasumov, Takhar; Pierce, Bradley A.; Puchowicz, Michelle; Scott, Mary E.; Dahms, W.; Kerr, Douglas S.; Nissim, Itzhak; Brunengraber, Henri

doi:10.1002/jms.316

Cited by 25 publications

(20 citation statements)

References 23 publications

(33 reference statements)

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“…PBGN is presumably formed from the reaction of PB-CoA with glutamine, by analogy with the formation of PAGN from the reaction between PA-CoA and glutamine (Webster et al, 1976). In normal adult sub-jects who ingested a fairly low dose of PB (5 g/75 kg), we found that the total excretion of PB ϩ PA ϩ PAGN ϩ PBGN accounted for only half the ingested PB dose (Comte et al, 2002). The missing fraction of the dose may be disposed of either in urine as unknown metabolites, or in feces as unabsorbed PB and/or PB metabolites.…”

mentioning

confidence: 84%

“…[ 2 H 5 ]PB was prepared by aluminum chloride-catalyzed condensation of ␥-butyrolactone with [ 2 H 6 ]benzene as previously described (Comte et al, 2002). ␥-Phenyl-trans-crotonic acid was prepared by a Fridel-Crafts reaction of benzene with ethyl ␥-bromo-trans-crotonate, followed by acid hydrolysis of ethyl ␥-phenyl-trans-crotonate (Loffler et al, 1970 2 H]propanol is outlined in Fig.…”

Section: Methodsmentioning

confidence: 99%

“…First, the recovery of known urinary metabolites of PB (PAGN ϩ traces of PB and PA) was very variable, ranging from 50 to 90% of the ingested dose (Piscitelli et al, 1995, Comte et al, 2002. Since PB is known to have toxic effects at high doses, some of the unknown metabolites might contribute to its toxicity.…”

Section: New Phenylbutyrate Metabolitesmentioning

confidence: 99%

“…As part of these investigations, we recently identified phenylbutyrylglutamine (PBGN) as a new metabolite of PB (Comte et al, 2002). PBGN is presumably formed from the reaction of PB-CoA with glutamine, by analogy with the formation of PAGN from the reaction between PA-CoA and glutamine (Webster et al, 1976).…”

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confidence: 99%

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New Secondary Metabolites of Phenylbutyrate in Humans and Rats

et al. 2004

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:Phenylbutyrate is used to treat inborn errors of ureagenesis, malignancies, cystic fibrosis, and thalassemia. High-dose phenylbutyrate therapy results in toxicity, the mechanism of which is unexplained. The known metabolites of phenylbutyrate are phenylacetate, phenylacetylglutamine, and phenylbutyrylglutamine. These are excreted in urine, accounting for a variable fraction of the dose. We identified new metabolites of phenylbutyrate in urine of normal humans and in perfused rat livers. These metabolites result from interference between the metabolism of phenylbutyrate and that of carbohydrates and lipids. The new metabolites fall into two categories, glucuronides and phenylbutyrate ␤-oxidation side products. Two questions are raised by these data. First, is the nitrogen-excreting potential of phenylbutyrate diminished by ingestion of carbohydrates or lipids? Second, does competition between the metabolism of phenylbutyrate, carbohydrates, and lipids alter the profile of phenylbutyrate metabolites? Finally, we synthesized glycerol esters of phenylbutyrate. These are partially bioavailable in rats and could be used to administer large doses of phenylbutyrate in a sodium-free, noncaustic form.

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confidence: 84%

Section: Methodsmentioning

confidence: 99%

Section: New Phenylbutyrate Metabolitesmentioning

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New Secondary Metabolites of Phenylbutyrate in Humans and Rats

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“…Alanine Arachidonoyl [76] γ-Aminobutyric acid Arachidonoyl [76] Glutamic Acid β-Citryl and phenylacetyl [54,55,114] Glutamine Phenylacetyl, other arylacetyls, and 4-phenylbutyryl [55,114] Glycine c Arachidonoyl, benzoyl, butyryl, bile acids, decanoyl, hexanoyl, isobutyryl, 2-methylbutyryl, 3-methylcrotonyl, octanoyl, phenylacetyl and other arylacetyls, propionyl, suberyl, and tiglyl [7,55,57,65,76,84,115] Isoleucine Lactyl [116] Leucine Lactyl [116] Phenylalanine Succinoyl [117] Pyroglutamic acid Phenylacetyl [57] Serine Arachidonoyl [71] Taurine Bile acids, phenylacetyl and other arylacetyls, long chain, saturaturated acyl groups from C16:0-C26:0 d , long-chain, monounsaturated acyl groups from C18:1-C24:1 d [7,84,118] Valine Lactyl [116] a N-Acetyl and N-isovaleroylamino acids were not included in this table.…”

Section: Amino Acid B N-acyl Group Referencesmentioning

confidence: 99%

Biosynthesis, degradation and pharmacological importance of the fatty acid amides

Farrell

Merkler

2008

Drug Discovery Today

115

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The identification of two biologically active fatty acid amides, N-arachidonoylethanolamine (anandamide) and oleamide, has generated a great deal of excitement and stimulated considerable research. However, anandamide and oleamide are merely the best-known and best-understood members of a much larger family of biologically-occurring fatty acid amides. In this review, we will outline which fatty acid amides have been isolated from mammalian sources, detail what is known about how these molecules are made and degraded in vivo, and highlight their potential for the development of novel therapeutics. Keywords N-acylamino acid; N-acyldopamine; N-acylethanolamine; primary fatty acid amide; N-acylamideThe fatty acid amide bond has long been recognized in nature, being important in the structure of the ceramides [1] and the sphingolipids [2]. The first non-sphingosine based fatty acid amide isolated from a natural source was N-palmitoylethanolamine from egg yolk in 1957 [3]. Interest in the N-acylethanolamines (NAEs) dramatically increased upon the identification of Narachidonoylethanolamine (anandamide) as the endogenous ligand for the cannabinoid receptors in the mammalian brain [4]. It is now known that a family of NAEs is found in the brain and in other tissues [5,6].In addition to the NAEs, other classes of fatty acid amides have been characterized, namely the N-acylamino acids (NAAs) [7], the N-acyldopamines (NADAs) [8] and the primary fatty acid amides (PFAMs) [9,10] (Figure 1). Relative to NAEs, much less is currently known about the NAAs, the NADAs and the PFAMs, except that they are found in biological systems. The goal of this review is to summarize the current state of knowledge regarding the different classes of endogenous fatty acid amides and highlight their potential for drug discovery (see refs. [11-13] for earlier reviews) © 2008 Elsevier Ltd. All rights reserved.Corresponding author: Merkler, D.J (E-mail: merkler@cas.usf.edu) phone 813-974-3579; fax 813-974-1733. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.Teaser SentenceFatty acid amides are a family of mammalian bioactive compounds. These molecules and the enzymes involved in their metabolism provide an opportunity to develop new drugs to treat human disease. -palmitoyl-, N-stearoyl-and N-oleoylethanolamine [5,11], each compromising ≥25% of total brain NAEs. Other less abundant NAEs found in the brain are anandamide, N-linoleoyl-, N-linolenoyl-, N-dihomo-γ-linolenoyl-and N-docosatetraenoylethanolamine [11]. In addition to the brain, the NAEs are widespread in the peripheral tissues [5]. The mos...

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Phenylbutyrate decreases type I collagen production in human lung fibroblasts

Rishikof¹,

Ricupero²,

Liu³

et al. 2004

J of Cellular Biochemistry

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Fibrotic lung diseases are characterized by excess extracellular matrix production, in particular type I collagen. Phenylbutyrate (PB) is a non-toxic pharmacological compound that functions as a weak histone deacetylase inhibitor. In hepatic stellate cells, the synthesis of type I collagen expression is decreased by inhibiting histone acetylation. Our studies examined the regulation of type I collagen by PB in human lung fibroblasts. We found that PB decreases basal and transforming growth factor-beta-stimulated alpha1(I) collagen mRNA and protein levels. Northern blot analyses demonstrated that PB decreases steady-state alpha1(I) collagen mRNA levels by 78% without significantly changing the stability of the mRNA transcript. PB stimulates cAMP production and increases the acetylation of histone H4, but does not affect the activity of two transforming growth factor-beta (TGF-beta)-responsive luciferase reporter constructs. These data suggest that PB regulates type I collagen expression in human lung fibroblasts by mechanisms that include cAMP production and histone acetylation. PB may have therapeutic use in fibrotic lung diseases.

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Identification of phenylbutyrylglutamine, a new metabolite of phenylbutyrate metabolism in humans

Cited by 25 publications

References 23 publications

New Secondary Metabolites of Phenylbutyrate in Humans and Rats

New Secondary Metabolites of Phenylbutyrate in Humans and Rats

Biosynthesis, degradation and pharmacological importance of the fatty acid amides

Phenylbutyrate decreases type I collagen production in human lung fibroblasts

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