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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.

Cisplatin is widely used chemotherapeutic agent for the treatment of several human malignancies. Dose-related nephrotoxicity is the major adverse effect of cisplatin. The cellular and molecular mechanisms behind the cisplatin nephrotoxicity have not yet been completely understood. In this study, cytotoxic effect of cisplatin on renal proximal tubular (RPT) cells was evaluated. Our results showed that cytotoxic action of cisplatin on RPT cells is mediated by reactive oxygen species (ROS) formation, decline of mitochondrial membrane potential, increase in caspase-3 activity and lysosomal membrane leakiness before cell lysis ensued. All of the above mentioned cisplatin-induced oxidative stress cytotoxicity markers were significantly (p < 0.05) prevented by ROS scavengers, antioxidants, mitochondrial permeability transition (MPT) pore sealing agents, endocytosis inhibitors and adenosine triphosphate (ATP) generators. Our results also showed that CYP2E1 involves in cisplatin oxidative stress cytotoxicity mechanism and intracellular nitric oxide enhancement protects the RPT cells against the cisplatin-induced cytotoxicity. It seems that cisplatin nephrotoxicity is associated with mutual mitochondrial/lysosomal potentiation (cross-talk) of oxidative stress in RPT cells. This cross-talk finally results in release of lysosomal digestive proteases and phospholipases and mitochondrial MPT pore opening leading to cytochrome c release and activation of caspases cascade which signal apoptosis.