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Binding of a valproate metabolite to the trifunctional protein of fatty acid oxidation
Author(s) -
Baldwin Graham S.,
Abbott Frank S.,
Nau Heinz
Publication year - 1996
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(96)00267-0
Subject(s) - metabolite , chemistry , convulsant , anticonvulsant , valproic acid , beta oxidation , protein subunit , fatty acid , biochemistry , pharmacology , epilepsy , medicine , receptor , psychiatry , gene
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 (IC 50 = 42 μ M) to the α‐subunit of the trifunctional protein responsible for the second and third steps in the mitochondrial β‐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 α‐subunit of the trifunctional protein with consequent inhibition of fatty acid oxidation.