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Synthesis and stability study of a new major metabolite of ?-hydroxybutyric acid.

ABSTRACT: ?-Hydroxybutanoic acid (GHB) is used as a date-rape drug, which renders the victims unconscious and defenceless. Intoxications are very difficult to detect for forensic scientists due to rapid metabolism to endogenous levels of GHB. We recently discovered a new major metabolite, 2, of GHB (1) that could potentially extend the analytical detection window for GHB intoxications. Herein we disclose synthetic procedures based on a Koenigs-Knorr glucuronidation approach that provides GHB glucuronide 2 and a deuterium-labelled analogue d 4-2 of high purity suitable for analytical chemistry. In addition, we have assessed the stability of GHB glucuronide 2 by mimicking the natural pH range for urine, which is of importance in the development of new analytical methods. Using NMR we show that GHB glucuronide 2 is highly stable towards aqueous hydrolysis within the pH range normally observed for urine even at elevated temperature.

SUBMITTER: Nymann Petersen I

PROVIDER: S-EPMC3628683 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Synthesis and stability study of a new major metabolite of γ-hydroxybutyric acid.

Nymann Petersen Ida I Langgaard Kristensen Jesper J Tortzen Christian C Breindahl Torben T Sejer Pedersen Daniel D

Beilstein journal of organic chemistry 20130402

γ-Hydroxybutanoic acid (GHB) is used as a date-rape drug, which renders the victims unconscious and defenceless. Intoxications are very difficult to detect for forensic scientists due to rapid metabolism to endogenous levels of GHB. We recently discovered a new major metabolite, 2, of GHB (1) that could potentially extend the analytical detection window for GHB intoxications. Herein we disclose synthetic procedures based on a Koenigs-Knorr glucuronidation approach that provides GHB glucuronide 2 ...[more]

PMID: 23616808

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Modular isotopomer synthesis of ?-hydroxybutyric acid for a quantitative analysis of metabolic fates.

Project description:Herein we report a study combining metabolomics and mass isotopomer analysis used for investigation of the biochemical fate of ?-hydroxybutyric acid (GHB). Using various (13)C incorporation labeling patterns into GHB, we have discovered that GHB is catabolized by previously unknown processes that include (i) direct ?-oxidation to acetyl-CoA and glycolate, (ii) ?-oxidation to 3-hydroxypropionyl-CoA and formate, and (iii) cleavage of C-4 to yield 3-hydroxypropionate and CO2. We further utilized the unique attributes of our labeling patterns and the resultant isotopomers to quantitate relative flux down the identified pathways.

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2 Hydroxybutyric Acid-Producing Bacteria in Gut Microbiome and <i>Fusobacterium nucleatum</i> Regulates 2 Hydroxybutyric Acid Level In Vivo.

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Vancomycin pretreatment attenuates acetaminophen-induced liver injury through 2-hydroxybutyric acid

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| S-EPMC7775853 | biostudies-literature

Three new O-isocrotonyl-3-hydroxybutyric acid congeners produced by a sea anemone-derived marine bacterium of the genus Vibrio.

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?4?? GABA(A) receptors are high-affinity targets for ?-hydroxybutyric acid (GHB).

Project description:?-Hydroxybutyric acid (GHB) binding to brain-specific high-affinity sites is well-established and proposed to explain both physiological and pharmacological actions. However, the mechanistic links between these lines of data are unknown. To identify molecular targets for specific GHB high-affinity binding, we undertook photolinking studies combined with proteomic analyses and identified several GABA(A) receptor subunits as possible candidates. A subsequent functional screening of various recombinant GABA(A) receptors in Xenopus laevis oocytes using the two-electrode voltage clamp technique showed GHB to be a partial agonist at ???- but not ???-receptors, proving that the ?-subunit is essential for potency and efficacy. GHB showed preference for ?4 over ?(1,2,6)-subunits and preferably activated ?4?1? (EC(50) = 140 nM) over ?4?(2/3)? (EC(50) = 8.41/1.03 mM). Introduction of a mutation, ?4F71L, in ?4?1(?)-receptors completely abolished GHB but not GABA function, indicating nonidentical binding sites. Radioligand binding studies using the specific GHB radioligand [(3)H](E,RS)-(6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene)acetic acid showed a 39% reduction (P = 0.0056) in the number of binding sites in ?4 KO brain tissue compared with WT controls, corroborating the direct involvement of the ?4-subunit in high-affinity GHB binding. Our data link specific GHB forebrain binding sites with ?4-containing GABA(A) receptors and postulate a role for extrasynaptic ?4?-containing GABA(A) receptors in GHB pharmacology and physiology. This finding will aid in elucidating the molecular mechanisms behind the proposed function of GHB as a neurotransmitter and its unique therapeutic effects in narcolepsy and alcoholism.

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Codon and amino acid identity are major determinants of mRNA stability in humans

Project description:To investigate the effects of the coding sequence on mRNA decay, we globally analyzed the stability of endogenous mRNAs as well as those derived from the human ORFeome collection, which contains full-length coding sequences in the context of invariant UTRs.

2019-09-22 | GSE123165 | GEO

Ketone body therapy with D/L-β-hydroxybutyric acid solution in severe MADD.

Project description:ObjectivesMultiple acyl-CoA dehydrogenase deficiency (MADD) is a severe inborn disorder of mitochondrial fatty acid oxidation. The only treatment option for MADD is the use of exogenous ketone bodies, like sodium β-hydroxybutyrate (NaβHB). However, the use of ketone body salts leads to a high intake of accompanying minerals, which can lead to additional side effects. The use of mineral-free formulations could improve tolerability.MethodsIn this report, the use of a βHB acid (βHBA) in a patient with MADD is described. The production of D/L-βHBA was carried out using ion exchange chromatography (IEX) and using a precipitation method. During two inpatient treatment intervals, the tolerability as well as clinical and metabolic effects were monitored. D-βHB in serum, blood gas analysis, and standard blood measurements (like minerals) were used as control parameters.ResultsProduction of D/L-βHBA using the precipitation method was more effective than using IEX. The tube feed solution used had a minimum pH of 3.5. Capillary D-βHB measurements were between 0.1 and 0.4 mmol/L and venous were at 0.1 mmol/L or below. Minerals and serum pH were within the normal range. During application of D/L-βHBA, gastrointestinal discomfort occurred and no clinical improvement was observed.ConclusionsThe use of D/L-βHBA in the therapy of severe MADD could be a good addition to the use of classical ketone body salts. The observed gastrointestinal side effects were of a mild nature and could not be specifically attributed to the D/L-βHBA treatment. In short-term application, no clinical benefit and no substantial increase of D-βHB in serum were noted. No tendency towards acidosis or alkalosis was observed during the entire period of treatment.

| S-EPMC6610240 | biostudies-literature

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