An overview of ?-hydroxybutyrate catabolism: The role of the cytosolic NADP+-dependent oxidoreductase EC 1.1.1.19 and of a mitochondrial hydroxyacid-oxoacid transhydrogenase in the initial, rate-limiting step in this pathway

Kaufman, Elaine E.; Nelson, Thomas

doi:10.1007/bf00965839

Cited by 46 publications

(29 citation statements)

References 37 publications

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“…studies (Morris et al, 2005), which suggests effects of L-lactate on GHB metabolism. GHB is metabolized primarily by GHB dehydrogenase as well as a mitochondrial transhydrogenase (Kaufman and Nelson, 1991). Based on the current data, the direct effect of L-lactate on either pathway is unlikely, as this should have also increased GHB metabolism at the low dose of GHB and GBL, and nonrenal clearance was unchanged in these groups.…”

Section: Treatment Of Oral Ghb/gbl Overdosementioning

confidence: 75%

Effects of Monocarboxylate Transporter Inhibition on the Oral Toxicokinetics/Toxicodynamics ofγ-Hydroxybutyrate andγ-Butyrolactone

Morse

Morris

2013

J Pharmacol Exp Ther

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Respiratory depression and death secondary to respiratory arrest have occurred after oral overdoses of g-hydroxybutyrate (GHB) and its precursor g-butyrolactone (GBL). GHB is a substrate for monocarboxylate transporters (MCTs), and increasing GHB renal clearance or decreasing GHB absorption via MCT inhibition represents a potential treatment strategy for GHB/GBL overdose. In these studies, GHB and GBL were administered in doses of 1.92, 5.77, and 14.4 mmol/kg orally with and without MCT inhibition to determine effects of this treatment strategy on the oral toxicokinetics and toxicodynamics of GHB and GBL. The competitive MCT inhibitor L-lactate was administered by intravenous infusion starting 1 hour after GHB and GBL administration. Oral administration of L-lactate and the MCT inhibitor luteolin was also evaluated. Respiratory depression was measured using plethysmography. Intravenous L-lactate, but not oral treatments, significantly increased GHB renal and/or oral clearances. At the low dose of GHB and GBL, i.v. L-lactate increased GHB renal clearance. Due to the increased contribution of renal clearance to total clearance at the moderate dose, increased renal clearance translated to an increase in oral clearance. At the highest GHB dose, oral clearance was increased without a significant change in renal clearance. The lack of effect of i.v. L-lactate on renal clearance after a high oral GHB dose suggests possible effects of i.v. L-lactate on MCT-mediated absorption. The resulting increases in oral clearance improved respiratory depression. Intravenous L-lactate also reduced mortality with the high GBL dose. These data indicate i.v. L-lactate represents a potential treatment strategy in oral overdose of GHB and GBL.

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Section: Treatment Of Oral Ghb/gbl Overdosementioning

confidence: 75%

Effects of Monocarboxylate Transporter Inhibition on the Oral Toxicokinetics/Toxicodynamics ofγ-Hydroxybutyrate andγ-Butyrolactone

Morse

Morris

2013

J Pharmacol Exp Ther

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“…In contrast, we identified M4 succinate and other multilabeled citric acid cycle intermediates. These are formed by the oxidation of 4-hydroxybutyrate to succinate via succinate semialdehyde, as shown by the Kaufman group (14,39,40). This is the only known pathway of 4-hydroxybutyrate catabolism.…”

Section: Volume 284 • Number 48 • November 27 2009mentioning

confidence: 96%

“…4-Hydroxybutyrate is used for the treatment of narcolepsy (13). Its known metabolism (14,15) proceeds via oxidation to succinic semialdehyde and then to succinate, an intermediate of the citric acid cycle. The five-carbon 4-hydroxypentanoate is also a drug of abuse (16).…”

mentioning

confidence: 99%

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

Zhang

Kombu

Kasumov

et al. 2009

Journal of Biological Chemistry

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4-Hydroxyacids are products of ubiquitously occurring lipid peroxidation (C 9 , C 6 ) or drugs of abuse (C 4 , C 5 ). We investigated the catabolism of these compounds using a combination of metabolomics and mass isotopomer analysis. Livers were perfused with various concentrations of unlabeled and labeled saturated 4-hydroxyacids (C 4 to C 11 ) or 4-hydroxynonenal. All the compounds tested form a new class of acyl-CoA esters, 4-hydroxy-4-phosphoacyl-CoAs, characterized by liquid chromatography-tandem mass spectrometry, accurate mass spectrometry, and 31 P-NMR. All 4-hydroxyacids with five or more carbons are metabolized by two new pathways. The first and major pathway, which involves 4-hydroxy-4-phosphoacylCoAs, leads in six steps to the isomerization of 4-hydroxyacylCoA to 3-hydroxyacyl-CoAs. The latter are intermediates of physiological ␤-oxidation. The second and minor pathway involves a sequence of ␤-oxidation, ␣-oxidation, and ␤-oxidation steps. In mice deficient in succinic semialdehyde dehydrogenase, high plasma concentrations of 4-hydroxybutyrate result in high concentrations of 4-hydroxy-4-phospho-butyryl-CoA in brain and liver. The high concentration of 4-hydroxy-4-phospho-butyryl-CoA may be related to the cerebral dysfunction of subjects ingesting 4-hydroxybutyrate and to the mental retardation of patients with 4-hydroxybutyric aciduria. Our data illustrate the potential of the combination of metabolomics and mass isotopomer analysis for pathway discovery.4-Hydroxy-n-acids are involved in different areas of mammalian metabolism. Some unsaturated 4-hydroxyacids are derived from 4-hydroxynonenal and 4-hydroxyhexenal, which are products of lipid peroxidation (1). The metabolism of 4-hydroxynonenal has been extensively studied, especially its conjugation with glutathione (2), covalent modification of proteins (3, 4), and conversion to 4-hydroxynonenoate, 4-hydroxynonanoate and 1,4-dihydroxynonene, as well as its role in inflammatory processes (1, 5-11). However, the catabolism of its carbon skeleton has not been unraveled. The four-carbon 4-hydroxybutyrate is a physiological neurotransmitter derived from ␥-aminobutyrate. Humans with inborn disorder of succinic semialdehyde dehydrogenase have high 4-hydroxybutyrate concentrations in body fluids, mental retardation, and seizures (12). 4-Hydroxybutyrate is also a drug of abuse that impairs the capacity to exercise judgment for unknown reasons. 4-Hydroxybutyrate is used for the treatment of narcolepsy (13). Its known metabolism (14, 15) proceeds via oxidation to succinic semialdehyde and then to succinate, an intermediate of the citric acid cycle. The five-carbon 4-hydroxypentanoate is also a drug of abuse (16). The calcium salt of a compound closely related to 4-hydroxypentanoate, levulinate (4-ketopentanoate, 4-ketovalerate), is used as an oral or intravenous source of calcium in humans.We conducted a study on the catabolism of C 4 to C 11 4-hydroxyacids in perfused rat livers using a combination of metabolomics (17,18) and mass isotopomer analysis 2 (19)....

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“…The reversibility of the GABA transaminase and γ-hydroxybutyric acid dehydrogenase reactions provides a metabolic path between γ-hydroxybutyric acid and GABA and the conversion of γ-hydroxybutyric acid into GABA in vitro has been reported (van-Bemmelen et al, 1985;Vayer et al, 1985). It is unclear, however, if this occurs to any extent in vivo (discussed in Mandel et al, 1987;Kaufman and Nelson, 1991;Cash, 1994). β-Oxidation is also a potential route of γ-hydroxybutyric acid degradation, however, this does not appear to be a major pathway.…”

Section: 4-butanediol Metabolismmentioning

confidence: 87%

A review of evidence leading to the prediction that 1,4-butanediol is not a carcinogen

Irwin

2005

J. Appl. Toxicol.

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1,4-Butanediol is an industrial chemical used primarily as an intermediate in the manufacture of other organic chemicals. It has recently been associated with deaths, addiction and withdrawal related to its promotion and use as a dietary supplement. The rapid absorption and conversion of 1,4-butanediol to gamma-hydroxybutyric acid (GHB, or date rape drug) in animals and humans is well documented and is the basis for its abuse potential. A disposition and metabolism study conducted in F344 rats by the National Toxicology Program (NTP) confirmed the rapid conversion of 1-(14)C-1,4-butanediol to (14)CO2. Because of this, the toxicological profile of 1,4-butanediol resembles that of gamma-hydroxybutyric acid. Gamma-hydroxybutyric acid occurs naturally in the brain and peripheral tissues and is converted to succinate and metabolized through the TCA cycle. Although the function of gamma-hydroxybutyric acid in peripheral tissues is not known, the presence of specific high affinity receptors for gamma-hydroxybutyric acid suggests that it functions as a neuromodulator in the brain and neuronal tissue. Gamma-hydroxybutyric acid readily crosses the blood-brain barrier and elicits characteristic neuropharmacologic responses after oral, i.p., or i.v. administration. The same responses are observed after administration of 1,4-butanediol. The cyclic lactone of gamma-hydroxybutyric acid, gamma-butyrolactone, is also rapidly converted to gamma-hydroxybutyric acid by enzymes in the blood and liver in animals and humans, and produces pharmacological effects identical to those produced by 1,4-butanediol and gamma-hydroxybutyric acid. Gamma-butyrolactone was previously evaluated by the NTP in 14-day and 13-week prechronic toxicology studies and in 2-year chronic toxicology and carcinogenesis studies in F344 rats and B6C3F1 mice. No organ specific toxicity occurred. In the carcinogenesis studies there was an equivocal response in male mice based on a marginal increase in the incidence of pheochromocytomas of the adrenal medulla. Because the absence of chronic toxicity and significant carcinogenicity of gamma-hydroxybutyric acid were established in NTP prechronic and chronic studies with gamma-butyrolactone, it is concluded that similar results would be obtained in a 2-year study with 1,4-butanediol, and that 1,4-butanediol is not a carcinogen.

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An overview of ?-hydroxybutyrate catabolism: The role of the cytosolic NADP+-dependent oxidoreductase EC 1.1.1.19 and of a mitochondrial hydroxyacid-oxoacid transhydrogenase in the initial, rate-limiting step in this pathway

Cited by 46 publications

References 37 publications

Effects of Monocarboxylate Transporter Inhibition on the Oral Toxicokinetics/Toxicodynamics ofγ-Hydroxybutyrate andγ-Butyrolactone

Effects of Monocarboxylate Transporter Inhibition on the Oral Toxicokinetics/Toxicodynamics ofγ-Hydroxybutyrate andγ-Butyrolactone

Catabolism of 4-Hydroxyacids and 4-Hydroxynonenal via 4-Hydroxy-4-phosphoacyl-CoAs

A review of evidence leading to the prediction that 1,4-butanediol is not a carcinogen

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