Influence of valproic acid on hepatic carbohydrate and lipid metabolism

Cord Michael Becker, Robert Harris

Research output: Contribution to journalArticle

147 Citations (Scopus)

Abstract

Valproic acid (dipropylacetic acid), an antiepileptic agent known to be hepatotoxic in some patients, caused inhibition of lactate gluconeogenesis, fatty acid oxidation, and fatty acid synthesis by isolated hepatocytes. The latter process was the most sensitive to valproic acid, 50% inhibition occurring at ca. 125 μm with cells from meal-fed female rats. The medium-chain acyl-CoA ester fraction was increased whereas coenzyme A (CoA), acetyl-CoA, and the long chain acyl-CoA fractions were decreased by valproic acid. The increase in the medium chain acyl-CoA fraction was found by high-pressure liquid chromatography to be due to the accumulation of valproyl-CoA plus an apparent CoAester metabolite of valproyl-CoA. Salicylate inhibited valproyl-CoA formation and partially protected against valproic acid inhibition of hepatic metabolic processes. Octanoate had a similar protective effect, suggesting that activation of valproic acid in the mitosol is required for its inhibitory effects. It is proposed that either valproyl-CoA itself or the sequestration of CoA causes inhibition of metabolic processes. Valproyl-CoA formation also appears to explain valproic acid inhibition of gluconeogenesis by isolated kidney tubules. No evidence was found for the accumulation of valproyl-CoA in brain tissue, suggesting that the effects of valproic acid in the central nervous system are independent of the formation of this metabolite.

Original languageEnglish
Pages (from-to)381-392
Number of pages12
JournalArchives of Biochemistry and Biophysics
Volume223
Issue number2
DOIs
StatePublished - 1983

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Carbohydrate Metabolism
Valproic Acid
Lipid Metabolism
Liver
Acyl Coenzyme A
Gluconeogenesis
Coenzyme A
Metabolites
Fatty Acids
High pressure liquid chromatography
Kidney Tubules
Acetyl Coenzyme A
Salicylates
Neurology
Anticonvulsants
Meals
valproyl-coenzyme A
Rats
Hepatocytes
Lactic Acid

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Molecular Biology

Cite this

Influence of valproic acid on hepatic carbohydrate and lipid metabolism. / Becker, Cord Michael; Harris, Robert.

In: Archives of Biochemistry and Biophysics, Vol. 223, No. 2, 1983, p. 381-392.

Research output: Contribution to journalArticle

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