title: Glutathione mediated reductive activation and mitochondrial dysfunction play key roles in lithium induced oxidative stress and cytotoxicity in liver.
abstract: 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.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Zanjan University of Medical Sciences, Zanjan, Iran.
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Eskandari
authors.forename: Javad Khalili
authors.initials: JK
authors.lastname: Fard
authors.forename: Mir-Jamal
authors.initials: MJ
authors.lastname: Hosseini
authors.forename: Jalal
authors.initials: J
authors.lastname: Pourahmad
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism*; D019803:Glutathione Disulfide / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D066298:In Vitro Techniques; D008094:Lithium / Q000633:toxicity*; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D045304:Cytochromes c; D008094:Lithium; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione; D019803:Glutathione Disulfide