Comparative analysis of in vivo and in vitro hepatotoxicity of valproic acid

Sodium valproate, also found as the free acid valproic acid (VPA), is metabolized via a cytochrome P$\sb{450}$-mediated mechanism yielding the potent hepatotoxin 2-n-propyl-4-pentenoic acid. Studies have proposed that VPA is activated to a hepatotoxic species by a two-step cytochrome P$\sb{450}$-mediated mechanism consisting of (a) desaturation and (b) unknown activation, possibly by epoxide formation, involving one or more cytochrome P$\sb{450}$ isozymes with subsequent covalent binding to cellular macromolecules. Whereas the precise mechanism of hepatotoxicity remains unknown, in vitro studies using rat liver slices in the presence of VPA have shown significant increases in liver damage upon pretreatment with phenobarbital; suggesting the possible role of the class 2B (phenobarbital inducible) cytochromes P$\sb{450}$ in the formation of 2-n-propyl-4-pentenoic acid. An in vitro assay for cytochrome P$\sb{450}$ induced hepatotoxicity that accurately and consistently correlates to the conditions present in an in vivo system would be invaluable in the evaluation of new chemical compounds. This research project employs such an assay and uses the cytochrome P$\sb{450}$ inactivator 1-aminobenzotriazole (ABT) to show a direct correlation between the in vivo and in vitro hepatotoxicity of VPA.