Binding of a valproate metabolite to the trifunctional protein of fatty acid oxidation.
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.
Baldwin
G S
GS
Department of Surgery, Austin Hospital, Heidelberg, Victoria, Australia.
Abbott
F S
FS
Nau
H
H
D000818:Animals; D000927:Anticonvulsants / Q000378:metabolism* / Q000633:toxicity; D005227:Fatty Acids / Q000378:metabolism; D005753:Gastric Mucosa / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000473:pathology; D046911:Macromolecular Substances; D063991:Mitochondrial Trifunctional Protein; D009097:Multienzyme Complexes / Q000302:isolation & purification / Q000378:metabolism*; D010084:Oxidation-Reduction; D011485:Protein Binding; D013552:Swine; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000633:toxicity
D000927:Anticonvulsants; D005227:Fatty Acids; D046911:Macromolecular Substances; D009097:Multienzyme Complexes; D014635:Valproic Acid; D063991:Mitochondrial Trifunctional Protein