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 stabilizer. 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 microM 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.
School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK.
Anna
A
Phillips
Tabitha
T
Bullock
Nick
N
Plant
D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000096:biosynthesis / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053222:Fas Ligand Protein; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014635:Valproic Acid / Q000633:toxicity*
D000927:Anticonvulsants; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D014635:Valproic Acid; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; C491071:Casp4 protein, rat; D053148:Caspase 3; D020169:Caspases