Valproate-induced stimulation of calcium uptake by isolated rat liver mitochondria

Treatment with valproic acid (VPA) to control seizure has been associated with impaired mitochondrial structure and function. Previous studies showed enlarged mitochondrial matrix granules containing calcium in liver biopsies from epileptic children on the drug. We have now studied the effect of VPA on ⁴⁵Ca²⁺-uptake in isolated rat liver mitochondria. Therapeutic and lower VPA concentrations stimulated ⁴⁵Ca²⁺-uptake. VPA also induced a significant decline in mitochondrial glutathione (GSH) levels. The stimulation of ⁴⁵Ca²⁺-uptake was inversely correlated with GSH levels (r = -0.91). Addition of GSH to the incubation medium where ⁴⁵Ca²⁺-uptake was monitored in the presence of VPA reversed the stimulating effect of the drug. These findings suggest that the stimulation of ⁴⁵Ca²⁺-uptake by VPA is due to the decrease in GSH mediated by the drug.