A SEARCH FOR MOLECULAR MECHANISMS INVOLVED IN ARSENITE As(III) INDUCED HEPATOCYTE TOXICITY

In this study we have investigated the cytotoxic mechanisms of arsenite As(lll) in isolated rat hepatocytes. Our experimental design was based on Accelerated Cytotoxic Mechanisms Screening technique (ACMS) using the LC502hr concentration, 50 mu M . Arsenite cytotoxicity was associated with little oxidative stress and lysosomal damage did not occur. However arsenite cytotoxicity was associated with loss of mitochondrial membrane potential, which was inhibited by the ATP generators fructose, xylitol and glutamine; and also by MPT pore sealing agents such as carnitine, cyclosporin and trifluoperazine.in Arsenite induced cytotoxicity, mitochondrial membrane potential decline and also ROS formation were significantly increased by inactivating hepatocyte methionine synthase or hepatocyte methyl transferase but were prevented by methyl donors such as betaine, methionine , folic acid and methylcobalamine and this suggests that arsenite is detoxified by reductive methylation. The activity of caspase-3 enzyme the main mediator of apoptosis, was also significantly increased, following incubation of hepatocytes with different concentrations of arsenite. In conclusion arsenite induced cytotoxicity could be attributed to mitochondrial toxicity and ATP depletion.