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Sodium valproate (VPA) is a potentially hepatotoxic antiepileptic drug. Risk of VPA-induced hepatotoxicity is increased in patients with mitochondrial diseases and especially in patients with POLG1 gene mutations. We used a HepG2 cell in vitro model to investigate the effect of VPA on mitochondrial activity. Cells were incubated in glucose medium and mitochondrial respiration-inducing medium supplemented with galactose and pyruvate. VPA treatments were carried out at concentrations of 0-2.0mM for 24-72 h. In both media, VPA caused decrease in oxygen consumption rates and mitochondrial membrane potential. VPA exposure led to depleted ATP levels in HepG2 cells incubated in galactose medium suggesting dysfunction in mitochondrial ATP production. In addition, VPA exposure for 72 h increased levels of mitochondrial reactive oxygen species (ROS), but adversely decreased protein levels of mitochondrial superoxide dismutase SOD2, suggesting oxidative stress caused by impaired elimination of mitochondrial ROS and a novel pathomechanism related to VPA toxicity. Increased cell death and decrease in cell number was detected under both metabolic conditions. However, immunoblotting did not show any changes in the protein levels of the catalytic subunit A of mitochondrial DNA polymerase γ, the mitochondrial respiratory chain complexes I, II and IV, ATP synthase, E3 subunit dihydrolipoyl dehydrogenase of pyruvate dehydrogenase, 2-oxoglutarate dehydrogenase and glutathione peroxidase. Our results show that VPA inhibits mitochondrial respiration and leads to mitochondrial dysfunction, oxidative stress and increased cell death, thus suggesting an essential role of mitochondria in VPA-induced hepatotoxicity.

Original publication

DOI

10.1016/j.tox.2015.03.001

Type

Journal article

Journal

Toxicology

Publication Date

04/05/2015

Volume

331

Pages

47 - 56

Keywords

HepG2, Hepatotoxicity, Mitochondrial respiration, Mitochondrial toxicity, Reactive oxygen species, Sodium valproate, Adenosine Triphosphate, Anticonvulsants, Cell Death, Cell Proliferation, Cell Respiration, Dose-Response Relationship, Drug, Drug-Induced Liver Injury, Electron Transport Chain Complex Proteins, Galactose, Glucose, Hep G2 Cells, Hepatocytes, Humans, Membrane Potential, Mitochondrial, Mitochondria, Liver, Mitochondrial Diseases, Oxidative Phosphorylation, Oxidative Stress, Pyruvic Acid, Reactive Oxygen Species, Superoxide Dismutase, Time Factors, Valproic Acid