A Comprehensive Study on the Variations in Urinary Concentrations of Endogenous Gamma-Hydroxybutyrate (GHB)

LeBeau, Marc A.; Montgomery, Madeline A.; Morris-Kukoski, Cynthia L.; Schaff, Jason E.; Deakin, Anna; Levine, Barry

doi:10.1093/jat/30.2.98

Cited by 57 publications

(39 citation statements)

References 34 publications

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“…Further evaluation shows that GHB also activates mouse and rat GPR81s with EC 50 values at 3.5 and 5 mM, respectively. Endogenous concentrations of GHB in human urine have been reported in the 1-20 M range (49). Acute systemic exposure after administration of 4.5 g of GHB in humans yields a plasma C max of ϳ1 mM (50,51).…”

Section: Discussionmentioning

confidence: 99%

Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81

Liu

Zhu

et al. 2009

Journal of Biological Chemistry

436

439

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Lactic acid is a well known metabolic by-product of intense exercise, particularly under anaerobic conditions. Lactate is also a key source of energy and an important metabolic substrate, and it has also been hypothesized to be a signaling molecule directing metabolic activity. Here we show that GPR81, an orphan G-protein-coupled receptor highly expressed in fat, is in fact a sensor for lactate. Lactate activates GPR81 in its physiological concentration range of 1-20 mM and suppresses lipolysis in mouse, rat, and human adipocytes as well as in differentiated 3T3-L1 cells. Adipocytes from GPR81-deficient mice lack an antilipolytic response to lactate but are responsive to other antilipolytic agents. Lactate specifically induces internalization of GPR81 after receptor activation. Site-directed mutagenesis of GPR81 coupled with homology modeling demonstrates that classically conserved key residues in the transmembrane binding domains are responsible for interacting with lactate. Our results indicate that lactate suppresses lipolysis in adipose tissue through a direct activation of GPR81. GPR81 may thus be an attractive target for the treatment of dyslipidemia and other metabolic disorders. GPR81(1) is an orphan G-protein-coupled receptor that is highly homologous to GPR109a and GPR109b. GPR109a and GPR109b were recently identified as receptors for niacin (also known as nicotinic acid) (2, 3) and subsequently characterized as receptors for the endogenous ketone body ␤-hydroxybutyrate (4). Niacin has been used clinically for a half-century as an effective treatment for dyslipidemia (5); however, its utility is somewhat hampered by a target-related effect on dendritic Langerhans cells, which release prostaglandin D2 in response to GPR109a stimulation, resulting in a cutaneous flushing response (6 -8). GPR81 is highly expressed in fat, similar to GPR109a, but is not expressed significantly in spleen; nor is it highly detected in any other tissue, and it has thus been hypothesized to be a potential target for the treatment of dyslipidemia that would be analogous to GPR109a/niacin but without the potential side effects (9).In this report, we demonstrate the initial identification of the ligand activity for GPR81 from the rat tissue extracts, the purification of L-lactate from porcine brain as the source of the ligand activity, and the pharmacological characterization of L-lactate as a ligand for GPR81. In addition, we show that in its physiological concentration range, L-lactate effectively inhibits lipolysis in adipocytes from humans, mice, and rats. Adipocytes from GPR81-deficient mice lack responses to L-lactate, indicating that the antilipolytic effect of L-lactate is mediated by GPR81. Despite a long history of being considered as waste or a by-product of metabolism, L-lactate has maintained some attention as a potential signaling molecule (10). As early as the 1960s, researchers have demonstrated significant effects of lactate on adipocytes (11); however, the mechanism by which this occurs has remained unknown. Our...

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Section: Discussionmentioning

confidence: 99%

Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81

Liu

Zhu

et al. 2009

Journal of Biological Chemistry

436

439

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“…In the results of the study, GHB concentrations of 207 subjects ranged from 0.00 to 2.70 mcg/mL, with a median concentration of 0.28 mcg/mL [7]. Despite the fact that no urine sample had a GHB level of greater than 2.70 mcg/mL, LeBeau et al [12] offer support of the 10 mcg/mL cut-off due to the possibility of in vitro production. A study by Elliott [6] also investigated the proposed cut-off level.…”

Section: Discussionmentioning

confidence: 88%

Evidence for Elevated Endogenous Urinary Gamma-Hydroxybutyric Acid Levels: Two Case Reports

Capote¹,

Pyzikiewicz²,

Ilogu³

et al. 2015

J Addict Res Ther

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Gamma-hydroxybutyric Acid (GHB) is a naturally occurring metabolite of the inhibitory neurotransmitter, gammaaminobutyric acid (GABA) that is found in every human cell. Exogenously synthesized in 1960 for possible use as a surgical anaesthetic, GHB exhibits a weak analgesic effect and the potential for seizure-like activity. Since its brief use as an anaesthetic, GHB has been abused as an illicit drug for its euphoric, sedative, and anabolic effects. GHB is now a popular drug-facilitated sexual assault (DFSA) drug, or a "date rape" drug, due to its colourless, odourless, and tasteless properties. Various street names include "G," "Georgia home boy," "liquid ecstasy," "scoop," and "soap." Due to GHB's recreational popularity, the metabolite is now included in the urine toxicology panels of patients undergoing rehabilitation for drug and alcohol addiction. However, exogenous GHB is indistinguishable from naturally produced GHB, which is an important factor to consider when evaluating the urine toxicology panels of patients. Two recent cases exist regarding patients undergoing outpatient rehabilitation who have tested positive for urinary GHB while denying any substance use. The subjects tested positive according to currently accepted cut-off levels on gas chromatography/mass spectrometry analysis (GC-MS) from a purely analytical perspective. From a forensic and indeed clinical perspective, it was found that the subjects had not used GHB. It can be said that these were false positives. Positive urine tests for GHB not only hinder the rehabilitative process, but can also put a patient's employment status in jeopardy, and may result in legal implications as well. Providers, as well as their patients, depend on the most up-to-date clinical data to render appropriate treatment and to protect against unnecessary repercussions. Therefore, the cut-off level of urinary GHB, as well as any factors that may affect increased endogenous production, must be thoroughly examined in order to facilitate accurate identification of drug abusers and to avoid false positives.

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“…Chez le vivant, les concentrations physiologiques sont inférieures à 2 mg/L dans le sang et 10 mg/L dans l'urine selon le consensus de la Société de Toxicologie de Belgique et du Luxembourg (BLT, 9 novembre 2000) et un groupe d'expert de l'UNODC [4]. Les dernières valeurs endogènes du GHB dans l'urine publiées sont les suivantes : -0,00-2,70 mg/L (n = 207) [5] -0,16-2,14 mg/L, volontaires sains [6] -0,17-3,03 mg/L, diabétiques [6] -<1,46 mg/L (n = 50) [7] -0,64-4,20 (n = 50) [8].…”

Section: Discussionunclassified

Une série de nouveaux cas d’intoxications par le GHB ou la GBL. Dosages dans le sang, l’urine et les phanères

et al. 2012

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Résumé -Introduction : Depuis 1999, l'acide gamma-hydroxybutyrique (GHB) est classé sur la liste I des substances vénéneuses pour la forme injectable réservée à l'usage hospitalier, et sur la liste des stupéfiants pour les formes orales. Ce classement a conduit peu à peu les utilisateurs à se tourner vers un de ses précurseurs chimiques, non classé, la gammabutyrolactone (GBL). L'utilisation du GHB/GBL dans un but de soumission chimique comme « drogue du viol » reste relativement rare. Le principal usage détourné est en fait à but récréatif, mais la marge thérapeutique étant étroite, le surdosage est un risque certain avec risque de décès, plus particulièrement en cas d'association à l'alcool. Cas et méthodes : Les analyses toxicologiques des cas présentés ont été réalisées sur le sang périphérique prélevé sur conservateur, et lorsque disponibles, sur l'urine par chromatographie en phase gazeuse couplée à la spectrométrie de masse (CPG-SM). Les phanères disponibles (cheveux, poils pubiens, ongles) ont été analysés par chromatographie en phase gazeuse couplée à la spectrométrie de masse tandem triple quadripôle (CPG-SM/SM). Dans trois cas les analyses ont été effectuées sur des produits de saisie. Résultats et discussion : Dans 7 cas de mono-intoxication au GHB/GBL les concentrations sanguines mesurées étaient comprises entre 285 et 815 mg/L pour les cas mortels (n = 4), et entre 74 et 158 mg/L pour les cas non mortels (n = 3). Dans les 4 cas non mortels et avec présence de toxiques associés (alcool, MDMA, cannabis, méthadone), les concentrations sanguines de GHB étaient comprises entre 86 et 184 mg/L. L'analyse des cheveux a montré dans 2 cas des pics de concentrations de GHB sur le segment correspondant à la période des faits, respectivement 9,8 ng/mg et 9,6 ng/mg, signant une prise ponctuelle ; ces concentrations sont corrélées à la présence de GHB exogène dans le sang et l'urine contemporains des faits. Dans un cas, des concentrations de GHB de 62 ng/mg dans les poils pubiens et de 105 ng/mg dans les ongles étaient liées à une consommation régulière de GHB/GBL. Conclusion : La consommation de GHB/GBL peut être mortelle. Une consommation ponctuelle est difficilement mise en évidence par l'analyse segmentaire des cheveux, la présence d'autres éléments tels que l'analyse de l'urine ou des produits de saisie est déterminante pour conclure. Les consommations chroniques sont facilement mises en évidence dans les phanères (cheveux, poils, ongles). La preuve de consommation de GBL s'est faite grâce à l'analyse simultanée des produits saisis.Mots clés : GHB, GBL, sang, urine, cheveux, poils pubiens, ongles Abstract -Introduction: Since 1999, gamma-hydroxybutyric acid (GHB) is a prescription drug only for hospital use for intra-venous injection. It is classified as a narcotic if used orally. Scheduling GHB led the users to use mainly one of its chemical precursors, the gamma-butyrolactone (GBL) which is not classified. The use of GHB/GBL in a purpose of drug facilitated sexual assault remains rare. The main diverted us...

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A Comprehensive Study on the Variations in Urinary Concentrations of Endogenous Gamma-Hydroxybutyrate (GHB)

Cited by 57 publications

References 34 publications

Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81

Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81

Evidence for Elevated Endogenous Urinary Gamma-Hydroxybutyric Acid Levels: Two Case Reports

Une série de nouveaux cas d’intoxications par le GHB ou la GBL. Dosages dans le sang, l’urine et les phanères

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