Thallium(I) and thallium(III) induce apoptosis in isolated rat hepatocytes by alterations in mitochondrial function and generation of ROS

Environmental metal toxins, generated through diverse anthropogenic activities, constitute one of the major contaminants that have led to global dispersion of these toxic metals in the ecosystem. Thallium is one of these widely dispersed metals that produce severe adverse effects on human and biological systems. The influence of thallium(I) and thallium(III) on the early events that trigger apoptosis signaling were examined in freshly isolated rat hepatocytes. In addition, the role of oxidative stress, and mitochondria in the induction of apoptosis were also investigated. Incubation of thallium(I) and thallium(III) with isolated rat hepatocytes generated reactive oxygen species (ROS), collapse of mitochondrial membrane potential, activation of caspases cascade, and appearance of apoptosis phenotype. Mitochondrial permeability transition (MPT) pore sealing agents (cyclosporine A and carnitine) and ATP generators (L-glutamine, fructose, and xylitol) inhibited the activation of caspase-3 and apoptosis, indicating that both the cations activated apoptosis signaling via mitochondrial pathway. Pretreatment of hepatocytes with antioxidants (α-tocopherol or deferoxamine) also blocked caspase-3 activation induced by these cations, suggesting that oxidative stress may be directly involved in a mitochondrial MPT pore opening and activation of caspases cascade. These findings contribute to a better understanding of the mechanisms that mediate thallium-induced apoptosis in isolated rat hepatocytes.