A comparison of hepatocyte cytotoxic mechanisms for Cu2+ and Cd2+.
The molecular cytotoxic mechanisms of hepatocyte cell death induced by CuCl2, an essential redox transition metal has been compared with CdCl2, an environmental toxin. The ED50 concentrations found for Cu2+ and Cd2+ (i.e. 50% membrane lysis in 2 h) were 50 and 20 microM respectively. However reactive oxygen species ('ROS') formation, GSH oxidation and lipid peroxidation were induced by Cu2+ at these concentrations much more rapidly than by Cd2+. 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 alpha-tocopherol succinate. Hepatocyte GSH was protective as GSH depleted hepatocytes were much more susceptible to Cu2+ and Cd2+ than normal hepatocytes. It is concluded that Cu2+-induced cytotoxicity occurs as a result of a mitochondrial 'ROS' formation independently of cytosolic 'ROS' formation due to redox cycling.
Pourahmad
J
J
Faculty of Pharmacy, University of Toronto, Ont., Canada.
O'Brien
P J
PJ
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D002104:Cadmium / Q000633:toxicity*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D003300:Copper / Q000633:toxicity*; D016166:Free Radical Scavengers / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D000975:Antioxidants; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D002104:Cadmium; D003300:Copper; D005978:Glutathione