Sodium valproate induces apoptosis in the rat hepatoma cell line, FaO

Sodium valproate (VPA) is clinically employed as an anti-convulsant and, to a lesser extent, mood stabiliser. While the incidence of toxicity associated with the clinical use of valproate is low, serious hepatotoxicity makes up a significant percentage. Rats treated with high doses of sodium valproate are subject to hepatotoxicity, and the study of the molecular mechanisms underlying this phenomenon may shed further light on the human situation. Exposure to sodium valproate results in the down regulation in rat liver of several transcripts whose products are involved in cellular energy homeostasis, resulting in time-dependent fluctuations in cellular ATP, possibly resulting in cell death. To further examine this, classical markers of apoptosis were examined in the rat hepatoma cell line FaO following sodium valproate exposure. Concentrations greater than 300 muM sodium valproate resulted in a transient wave of apoptosis, as assessed by chromatin condensation and DNA fragmentation assay. Analysis indicated that Fas-ligand and caspase-11 expression were increased at the transcriptome level, while caspase-3 was activated at the proteome level during the exposure period. These data demonstrates that sodium valproate causes cell death through apoptosis in a rat liver cell line, and provides information on the possible molecular mechanisms underlying this phenomenon in vivo. (C) 2003 Elsevier Ireland Ltd. All rights reserved.