A search for Molecular Mechanisms involved In Arsenite As (III) Induced Hepatocyte Toxicity

In the following we have investigated the cytotoxic mechanisms of the oxyanion chromate (Cr(VI)). Cr(VI) cytotoxicity was associated with reactive oxygen species (ROS) formation, lipid peroxidationand loss of mitochondrial membrane potential which were prevented by catalase, antioxidants and ROSscavengers. Hepatocyte glutathione was also rapidly oxidized. Cr(VI) reduction was inhibited inglutathione depleted hepatocytes and glutathione depleted hepatocytes were also much more resistantto chromate induced cytotoxicity, ROS formation and lipid peroxidation. Inhibitors of cytochromeP450 or P450 reductase but not DT diaphorase prevented Cr(VI) induced cytotoxicity and ROSformation. This suggests that Cr(VI) is reductively activated by both glutathione and cytochrome P450.Cr(VI) cytotoxicity also involved lysosomal injury and protease activation which were prevented bylysosomotropic agents, endocytosis inhibitors, protease inhibitors and ROS scavengers. In conclusionCr(VI) induced cytotoxicity could be attributed to oxidative stress and lysosomal damage.