Effects of valproate on xenobiotic biotransformation in rat liver. In vivo and in vitro experiments.

Male Wistar rats were in vivo exposed for 2 weeks to 100 micrograms/ml sodium valproate by subcutaneous implantation of osmotic pumps and hepatocytes were isolated. As an in vitro model co-cultures of rat hepatocytes with epithelial cells were daily treated with valproate (25, 50, 100, 200 micrograms/ml) for 2 weeks. In both models the cytochrome P-450 content and the enzymatic activities of 7-ethoxycoumarin O-deethylase, aldrin epoxidase and glutathione S-transferase were determined in valproate-treated hepatocytes, in controls and in phenobarbital-induced cells. It appeared that in both systems the cytochrome P-450 content and the 7-ethoxycoumarin O-deethylase activity increased significantly after valproate treatment. On the other hand, the activities of aldrin epoxidase and glutathione S-transferase decreased. A cDNA probe, encoding rat P450IIB2 was used to determine whether mRNAs encoding the P450IIB subfamily were induced by valproate. It became clear that the inducing effect of valproate was even more pronounced in vitro than in vivo.