Lithium preparations are commonly used
drug in treating
mental disorders and bipolar diseases, but
metal's cytotoxic mechanisms have not yet been completely understood. In this study, we investigated the cytotoxic mechanisms of
lithium in freshly isolated rat hepatocytes.
Lithium cytotoxicity were associated with
reactive oxygen species (ROS) formation and collapse of mitochondrial membrane potential and
cytochrome c release into the hepatocyte cytosol. All of the mentioned
lithium-induced cytotoxicity markers were significantly (P < 0.05) prevented by ROS scavengers,
antioxidants,
mitochondrial permeability transition pore sealing agents and
adenosine triphosphate generators. Hepatocyte
glutathione (GSH) was also rapidly oxidized and GSH-depleted hepatocytes were more resistant to
lithium-induced oxidative stress markers. This suggests that
lithium is activated by GSH. Our results also showed that
CYP2E1 is involved in
lithium oxidative stress mechanism.
Lithium cytotoxicity was also associated with mitochondrial
injuries initiated by increased ROS formation resulted from metal-CYP2E1 destructive interaction or
metal-induced disruption of mitochondrial electron transfer chain. Methyl donors such as
betaine,
methionine, or
folic acid prevented
lithium cytotoxicity, and this suggests that this
metal is detoxified by phase II metabolic methylation. In conclusion
lithium-induced cytotoxicity could be attributed to oxidative stress and
mitochondrial dysfunction.