Effects of Anticonvulsants on the Formation of <i>γ</i>‐Hydroxybutyrate from <i>γ</i>‐Aminobutyrate in Rat Brain

Whittle, Susan R.; Turner, Anthony J.

doi:10.1111/j.1471-4159.1982.tb08710.x

Cited by 21 publications

(7 citation statements)

References 22 publications

(18 reference statements)

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“…Production of I4CO2 was markedly curtailed in the presence of malonic acid, and isotope accumulated in succinic acid. Valproic acid has been reported to inhibit GABA-aminotransferase and SSADH in ox brain (16) and rat brain (17)(18)(19)(20). We observed an inhibition of I4CO2 production from [U-14C]SSA in intact lymphoblasts in the presence of 5 mM valproic acid.…”

Section: I4c-ssa Oxidation In Human Lymphoblastssupporting

confidence: 52%

Oxidation of [U-14C]Succinic Semialdehyde in Cultured Human Lymphoblasts: Measurement of Residual Succinic Semialdehyde Dehydrogenase Activity in 11 Patients with 4-Hydroxybutyric Aciduria

1988

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ABSTRACT. The oxidation of [U-14C]succinic semialdehyde to 14C02 has been investigated in cultured lymphoblasts to develop a whole cell assay for succinic semialdehyde dehydrogenase. We have previously demonstrated deficiency of this enzyme in extracts of white cells derived from 13 patients with 4-hydroxybutyric aciduria. Major goals were the demonstration of greater residual succinic semialdehyde dehydrogenase activity in patient cell lines and the better representation of physiology in vivo. In 18 control lymphoblast lines, the conversion of [U-14~succinic semialdehyde to 14C02 was 1579 f 310 dpm. The mean value in lymphoblasts derived from 11 patients with deficiency of succinic semialdehyde dehydrogenase was 112 f 36 dpm approximating 7% of the mean control value. Analysis of organic acids produced from [U-14qsuccinic semialdehyde in control lymphoblasts indicated that 14C02 emanated from the tricarboxylic acid cycle; the major metabolic products were succinic and lactic acids. In the presence of 5mM malonic and 2-propylpentanoic (valproic) acids, I4CO2 production in a control lymphoblast line was decreased by 68 and 45%, respectively. The whole cell assay is less laborious than our previously described assay employing cell extracts, and the general trend was the demonstration of higher residual levels of activity for lymphoblasts derived from patients. (Pediatr Res 24: 455-460, 1988)

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Section: I4c-ssa Oxidation In Human Lymphoblastssupporting

confidence: 52%

Oxidation of [U-14C]Succinic Semialdehyde in Cultured Human Lymphoblasts: Measurement of Residual Succinic Semialdehyde Dehydrogenase Activity in 11 Patients with 4-Hydroxybutyric Aciduria

1988

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“…In contrast to the potent effect of valproate on nonspecific SSAR, specific SSAR is not affected by the drug [104]. However, Whittle and Turner [105], using rat brain homogenates, demonstrated that valproate inhibited the formation ofGHB in vitro, which would indicate that the specific SSAR is not exclusively responsible for GHB formation but that the nonspecific (valproate sensitive) aldehyde reductase may also contribute to a significant extent to this metabolic pathway. Inhibition of GHB formation by valproate could be of considerable interest since this amino acid has been shown to produce epileptogenic effects in several species [106].…”

Section: Neurochemical Effects Of Valproate On the Gaba Systemmentioning

confidence: 89%

Pharmacological effects and mechanisms of action

Löscher

1999

Valproate

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“…This is of interest in view of the fact that valproic acid has been reported to be an inhibitor of enzymes involved in GHB metabolism in ox brain (25) and rat brain (26)(27)(28)(29), succinic semialdehyde dehydrogenase and GABAtransaminase. The data when butyric acid was the substrate indicated clearly that~xidation was functional in the mitochondrial preparations under study.…”

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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Effects of Anticonvulsants on the Formation of γ‐Hydroxybutyrate from γ‐Aminobutyrate in Rat Brain

Cited by 21 publications

References 22 publications

Oxidation of [U-14C]Succinic Semialdehyde in Cultured Human Lymphoblasts: Measurement of Residual Succinic Semialdehyde Dehydrogenase Activity in 11 Patients with 4-Hydroxybutyric Aciduria

Oxidation of [U-14C]Succinic Semialdehyde in Cultured Human Lymphoblasts: Measurement of Residual Succinic Semialdehyde Dehydrogenase Activity in 11 Patients with 4-Hydroxybutyric Aciduria

Pharmacological effects and mechanisms of action

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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