Hepatocyte lysis induced by environmental metal toxins may involve apoptotic death signals initiated by mitochondrial injury.
Addition of CdCl2, HgCl2 or K2Cr2O7 to isolated hepatocytes caused a rapid increase in reactive oxygen species ("ROS") formation and a decline in mitochondrial membrane potential. Later lipid peroxidation and cell lysis ensued. Cytotoxicity was prevented by "ROS" scavengers and various inhibitors of the mitochondrial permeability transition (MPT) eg. cyclosporin A, carnitine or trifluoperazine. Antioxidants prevented hepatocyte lysis induced by CdCl2, K2Cr2O7 but not HgCl2. Hepatocyte lysis was also prevented by various apoptosis inhibitors eg, cycloheximide, dactinomycin and a tetrapeptide caspase 3 inhibitor which suggests that metal induced hepatocyte lysis involves apoptotic death signals initiated by MPT and "ROS".
Pourahmad
J
J
Faculty of Pharmacy, University of Toronto, Ont., Canada.
Mihajlovic
A
A
O'Brien
P J
PJ
D000818:Animals; D017209:Apoptosis; D002104:Cadmium / Q000009:adverse effects*; D019256:Cadmium Chloride / Q000494:pharmacology; D053148:Caspase 3; D061945:Caspase Inhibitors; D002413:Cations, Divalent; D002478:Cells, Cultured; D002857:Chromium / Q000009:adverse effects*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D004781:Environmental Exposure; D022781:Hepatocytes / Q000166:cytology; D008564:Membrane Potentials; D008627:Mercuric Chloride / Q000494:pharmacology; D008628:Mercury / Q000009:adverse effects*; D008670:Metals; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D011192:Potassium Dichromate / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014118:Toxins, Biological
D061945:Caspase Inhibitors; D002413:Cations, Divalent; D008670:Metals; D017382:Reactive Oxygen Species; D014118:Toxins, Biological; D002104:Cadmium; D002857:Chromium; D008627:Mercuric Chloride; C505410:Casp3 protein, rat; D053148:Caspase 3; D008628:Mercury; D019256:Cadmium Chloride; D011192:Potassium Dichromate; D004121:Dimethyl Sulfoxide