title: A comparison of hepatocyte cytotoxic mechanisms for thallium (I) and thallium (III).
abstract: Thallium (Tl) is a highly toxic heavy metal though up to now its mechanisms are poorly understood. In this study, we comparatively investigated the cytotoxic mechanisms of Tl(I) and Tl(III) in isolated rat hepatocytes. Both Tl(I) and Tl(III) cytotoxicities were associated with reactive oxygen species (ROS) formation, lipid peroxidation, collapse of mitochondrial membrane potential, activation of caspases cascade, lysosomal membrane leakiness, and cellular proteolysis. Hepatocyte glutathione (GSH) was also rapidly oxidized. GSH-depleted hepatocytes were more resistant to Tl(I)-induced cytotoxicity, ROS formation and lipid peroxidation. This suggests that Tl(I) is reductively activated by GSH. On the other hand, GSH-depleted hepatocytes were much more sensitive to Tl(III)-induced cytotoxicity, ROS formation, and lipid peroxidation. This suggests that GSH only plays an antioxidant role against Tl(III) cytotoxicity. Our results also showed that CYP2E1 involves in Tl(I) and Tl(III) oxidative stress cytotoxicity mechanism and both cations detoxified via methylation. In conclusion, both Tl(I) and Tl(III) cytotoxicities were associated with mutual mitochondrial/lysosomal injuries (cross-talk) initiated by increased ROS formation resulted from metal-CYP2E1 destructive interaction or metal-induced disruption of mitochondrial electron transfer chain.
authors.affiliation: Faculty of Pharmacy, Shaheed Beheshti University of Medical Sciences, Tehran, Iran. j.pourahmadjaktaji@utoronto.ca
authors.forename: Jalal
authors.initials: J
authors.lastname: Pourahmad
authors.forename: Mohammad Reza
authors.initials: MR
authors.lastname: Eskandari
authors.forename: Bahram
authors.initials: B
authors.lastname: Daraei
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002412:Cations / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism; D004579:Electron Transport; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects / Q000502:physiology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects* / Q000502:physiology; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013793:Thallium / Q000633:toxicity*
chemical_list: D002412:Cations; D017382:Reactive Oxygen Species; D013793:Thallium; D019392:Cytochrome P-450 CYP2E1; D005978:Glutathione