Identification and quantitation of 1,4-butanediol in mammalian tissues: an alternative biosynthetic pathway for gamma-hydroxybutyric acid

Barker, Steven A.; Snead, O. Carter; Poldrugo, Flavio; Liu, Chun-Che; Fish, F.; Settine, R. L.

doi:10.1016/0006-2952(85)90662-8

Cited by 35 publications

(11 citation statements)

References 25 publications

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“…compounds are present in rat brain at concentrations of ϳ1/10 of those of GHB (40,41). These alternate routes may be of relevance to the synthesis of GHB under limiting conditions.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Catabolism of γ-Hydroxybutyrate in SH-SY5Y Human Neuroblastoma Cells

Lyon¹,

Johnston

Watson

et al. 2007

Journal of Biological Chemistry

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␥-Hydroxybutyrate (GHB) is an endogenous metabolite synthesized in the brain. There is strong evidence to suggest that GHB has an important role as a neurotransmitter or neuromodulator. The human aldo-keto reductase AKR7A2 has been proposed previously to catalyze the NADPH-dependent reduction of succinic semialdehyde (SSA) to GHB in human brain. In this study we have used RNA interference to evaluate the role of AKR7A2 in GHB biosynthesis in human neuroblastoma SH-SY5Y cells. Quantitative reverse transcription-PCR analysis and immunoblotting revealed that short interfering RNA molecules directed against AKR7A2 led to a significant reduction in both AKR7A2 transcript and protein levels 72 h post-transfection. We have shown that reduced expression of AKR7A2 results in a 90% decrease in SSA reductase activity of cell extracts. Furthermore, we have shown using gas chromatography-mass spectrometry that a decrease in the level of AKR7A2 was paralleled with a significant reduction in intracellular GHB concentration. This provides conclusive evidence that AKR7A2 is the major SSA reductase in these cells. In contrast, short interfering RNA-dependent reduction in AKR7A2 levels had no effect on the GHB dehydrogenase activity of the extracts, and inhibitor studies suggest that another enzyme characteristic of an NAD-dependent alcohol dehydrogenase may be responsible for catalyzing this reverse reaction. Together these findings delineate pathways for GHB metabolism in the brain and will enable a better understanding of the relationship between GHB biosynthesis and catabolism in disease states and in drug overdose.

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“…compounds are present in rat brain at concentrations of ϳ1/10 of those of GHB (40,41). These alternate routes may be of relevance to the synthesis of GHB under limiting conditions.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Catabolism of γ-Hydroxybutyrate in SH-SY5Y Human Neuroblastoma Cells

Lyon¹,

Johnston

Watson

et al. 2007

Journal of Biological Chemistry

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“…However, there is growing evidence that GHB is behaviorally, biochemically, and physiologically distinct from GABA. GHB prodrugs gamma-butyrolactone (GBL) and 1, are also present in the brain and are converted to GHB (Barker et al 1985;Doherty et al 1975). Additionally, GHBspecific binding sites, uptake systems, synthesizing enzymes, and metabolizing enzymes in the CNS have been identified (Maitre et al 2000).…”

Section: Introductionmentioning

confidence: 97%

Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons

2005

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“…The physiological role of GHB in the periphery where it can be found in the absence of GABA is even less clear. There may be other precursors of GHB than GABA (26, 33) and 1, 4-butanediol (34,35). Defmition of the metabolic role of extraneuronal GHB will require detailed studies in intact animals.…”

Section: Discussionmentioning

confidence: 99%

Metabolism of [U-14C]-4-hydroxybutyric acid to intermediates of the tricarboxylic acid cycle in extracts of rat liver and kidney mitochondria

Gibson

Nyhan

1989

Eur. J. Drug Metab. Pharmacokinet.

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The metabolism of [U-14C]-4-hydroxybutyric acid (GHB) was investigated in sonicates of mitochondria of rat heart, kidney and liver. The conversion of this precursor to 14C-organic acids was monitored and quantified by sequential liquid-partition chromatography on hydrated columns of silicic acid using a concave-upward gradient of 2-methylbutan-2-ol in chloroform. Sonicates of liver and kidney mitochondria, but not heart, readily converted [U-14C]-GHB to 14C organic acids via a pathway of conversion to 14C-succinic acid, followed by further metabolism through the tricarboxylic acid cycle. This conversion was facilitated by exogenous NAD+ and NADP+. No evidence for the beta-oxidation of GHB was obtained in any of the mitochondrial sonicates. Studies with exogenous non-labelled succinic semialdehyde indicated that this compound was an intermediate in the conversion of GHB to succinic acid.

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Identification and quantitation of 1,4-butanediol in mammalian tissues: an alternative biosynthetic pathway for gamma-hydroxybutyric acid

Cited by 35 publications

References 25 publications

Synthesis and Catabolism of γ-Hydroxybutyrate in SH-SY5Y Human Neuroblastoma Cells

Synthesis and Catabolism of γ-Hydroxybutyrate in SH-SY5Y Human Neuroblastoma Cells

Involvement of gamma-hydroxybutyrate (GHB) and GABA-B receptors in the acute behavioral effects of GHB in baboons

Metabolism of [U-14C]-4-hydroxybutyric acid to intermediates of the tricarboxylic acid cycle in extracts of rat liver and kidney mitochondria

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