A comparison of hepatocyte cytotoxic mechanisms for Cu 2+ and Cd 2+

Abstract

The molecular cytotoxic mechanisms of hepatocyte cell death induced by CuCl 2, an essential redox transition metal has been compared with CdCl 2, an environmental toxin. The ED50 concentrations found for Cu 2+ and Cd 2+ (i.e. 50% membrane lysis in 2 h) were 50 and 20 μM respectively. However reactive oxygen species (‘ROS’) formation, GSH oxidation and lipid peroxidation were induced by Cu 2+ at these concentrations much more rapidly than by Cd 2+. The decline of mitochondrial membrane potential though occurred at the same time and to the same extent for both metals. Furthermore the cytotoxicity and decline of mitochondrial membrane potential induced by these metals was prevented by the ‘ROS’ scavengers dimethyl sulfoxide, mannitol, catalase or SOD, as well as by desferoxamine, N,N diphenylphenylenediamine or α-tocopherol succinate. Hepatocyte GSH was protective as GSH depleted hepatocytes were much more susceptible to Cu 2+ and Cd 2+ than normal hepatocytes. It is concluded that Cu 2+-induced cytotoxicity occurs as a result of a mitochondrial ‘ROS’ formation independently of cytosolic ‘ROS’ formation due to redox cycling.