Metabolism of valproate to hepatotoxic intermediates.
A number of lines of evidence indicate that metabolites of valproate rather than the parent drug, mediate the microvesicular steatosis which characterizes valproate-associated liver injury. In this article, two mechanisms are discussed whereby valproate may cause hepatic steatosis through interference with the process of fatty acid beta-oxidation. In the first, valproate itself enters the mitochondrion where it completes for the enzymes and/or co-factors involved in the beta-oxidation of endogenous substrates, while in the second, valproate is metabolized via the hepatotoxic terminal olefin, delta 4-valproate, to a variety of chemically reactive intermediates which inhibit key enzymes in the beta-oxidation cycle.
Baillie
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TA
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
D000818:Animals; D001711:Biotransformation; D003065:Coenzyme A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism / Q000633:toxicity; D006801:Humans; D008099:Liver / Q000187:drug effects*; D008930:Mitochondria, Liver / Q000378:metabolism*; D051381:Rats; D014635:Valproic Acid / Q000378:metabolism* / Q000633:toxicity
D005229:Fatty Acids, Monounsaturated; C045022:2-propyl-4-pentenoic acid; D014635:Valproic Acid; D003577:Cytochrome P-450 Enzyme System; D003065:Coenzyme A