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.