Two-step activation of valproic acid (VPA) by hepatic cytochrome P-450.
There is now considerable evidence that the unsaturated metabolite of VPA, delta 4-VPA, may be responsible for VPA-induced hepatic injury. It is proposed that VPA is activated to a hepatotoxic species by a two-step cytochrome P-450-mediated mechanism consisting of 1) desaturation and 2) unknown activation, possibly by epoxide formation, involving one or more P-450 isozymes with subsequent covalent binding to cellular macromolecules. In vivo and in vitro experimental protocols are indicated for testing the proposed hypothesis.
D000818:Animals; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology*; D008954:Models, Biological; D014635:Valproic Acid / Q000378:metabolism*
D004852:Epoxy Compounds; D007527:Isoenzymes; D014635:Valproic Acid; D003577:Cytochrome P-450 Enzyme System