A SEARCH FOR CELLULAR AND MOLECULAR MECHANISMS INVOLVED IN CHROMATE (CrVI) 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 peroxidation and loss of mitochondrial membrane potential which were prevented by catalase, antioxidants and ROS scavengers. Hepatocyte glutathione was also rapidly oxidized. Cr(VI) reduction was inhibited in glutathione depleted hepatocytes and glutathione depleted hepatocytes were also much more resistant to chromate induced cytotoxicity, ROS formation and lipid peroxidation. Inhibitors of cytochrome P450 or P450 reductase but not DT diaphorase prevented Cr(VI) induced cytotoxicity and ROS formation. This suggests that Cr(VI) is redu-ctively activated by both glutathione and cytochrome P450. Cr(VI) cytotoxicity also involved lysosomal injury and protease activation which were prevented by lysosomotropic agents, endocytosis inhibitors, protease inhibitors and ROS scavengers. In conclusion Cr(VI) induced cytotoxicity could be attributed to oxidative stress and lysosomal damage.