Glutathione mediated reductive activation and mitochondrial dysfunction play key roles in lithium induced oxidative stress and cytotoxicity in liver

Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine
M R EskandariJalal Pourahmad

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 foli...Continue Reading

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Citations

Jan 8, 2016·Metallomics : Integrated Biometal Science·M-J HosseiniN Arghavanifard
Jun 22, 2013·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Mohammad Reza EskandariHiman Heidari
Dec 17, 2014·Biochemical and Biophysical Research Communications·Icksoo Lee
Oct 23, 2016·Free Radical Biology & Medicine·Ghorban TaghizadehMohammad Sharifzadeh
Sep 3, 2016·Journal of Biochemical and Molecular Toxicology·Ahmad SalimiJalal Pourahmad
Jan 20, 2017·Advanced Pharmaceutical Bulletin·Javad Khalili FardMohammad Ali Eghbal
Oct 11, 2017·Biological Trace Element Research·Priti BhardwajDevinder Kumar Dhawan
Nov 27, 2018·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Enayatollah SeydiJalal Pourahmad
Nov 23, 2019·Physiological Research·M Ľupták, J Hroudová

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