Binding of a valproate metabolite to the trifunctional protein of fatty acid oxidation

FEBS Lett. 1996 Apr 8;384(1):58-60. doi: 10.1016/0014-5793(96)00267-0.


The anti-convulsant drug valproate causes hepatic failure in a small percentage of patients. We now report that the valproate metabolite 2,4-dien-valproate binds (IC50 = 42 microM) to the alpha-subunit of the trifunctional protein responsible for the second and third steps in the mitochondrial beta-oxidation of fatty acids. Binding of valproate itself, or of the metabolites 2-envalproate, 4-en-valproate or 3-hydroxy-4-en-valproate, is considerably weaker. We conclude that valproate-induced hepatotoxicity may be due in part to the reversible binding of the valproate metabolite 2,4-dien-valproate or its CoA ester to the alpha-subunit of the trifunctional protein with consequent inhibition of fatty acid oxidation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anticonvulsants / metabolism*
  • Anticonvulsants / toxicity
  • Fatty Acids / metabolism
  • Gastric Mucosa / metabolism
  • Kinetics
  • Liver / drug effects
  • Liver / pathology
  • Macromolecular Substances
  • Mitochondrial Trifunctional Protein
  • Multienzyme Complexes / isolation & purification
  • Multienzyme Complexes / metabolism*
  • Oxidation-Reduction
  • Protein Binding
  • Swine
  • Valproic Acid / analogs & derivatives*
  • Valproic Acid / metabolism*
  • Valproic Acid / toxicity


  • Anticonvulsants
  • Fatty Acids
  • Macromolecular Substances
  • Multienzyme Complexes
  • Valproic Acid
  • Mitochondrial Trifunctional Protein