en Heavy Metal Induced Cell Necrosis: Involves Apoptosis Death Signals Initiated by Mitochondrial Injury عمومى General پژوهشي Research <span style="font-weight: bold">Introduction:</span> Severe industrial diseases result from the hepatic accumulation of mercury, cadmium or chromium in humans and on the other hand cadmium and dichromate and mercuric salts may induce lung or kidney cancer. Acute or chronic CdCl2, HgCl2 or dichromate administration induces hepatic and nephrotoxicity in rodents. Oxidative stress is often cited as a possible cause of metal induced cell death but the death signaling pathways involved have not yet been well investigated. <br> <span style="font-weight: bold">Method and Materials:</span> To search for death signaling mechanisms we used accelerated cytotoxicity mechanism screening techniques (ACMS) on isolated rat hepatocytes as our cellular model. <br><span style="font-weight: bold">Results:</span> Adding the CdC12, HgC12 or K2Cr2O7 to isolated hepatocytes caused a rapid increase in reactive oxygen species ("ROS") formation and a decline in mitochondrial membrane potential. Then lipid per-oxidation and cell-lysis ensued. Cytotoxicity was prevented by "ROS" scavengers and various inhibitors of the mitochondrial permeability transition (MPT) e.g. cyclosporin A, carnitine or trifluoperazine. Antioxidants prevented hepatocyte lysis induced by CdC12 , K2Cr207 but not HgC12. <br><span style="font-weight: bold">Conclusion:</span> Hepatocyte lysis was also prevented by various apoptosis inhibitors e.g. cycloheximide, dactinomycin and a tetrapeptide caspase 3 inhibitor which suggested that metal induced hepatocyte lysis involves apoptotic death signals initiated by MPT and "ROS". Chromium, Cadmium, Mercury, MPT, Lipid per oxidation, ROS, Apoptosis, Necrosis . Chromium, Cadmium, Mercury, MPT, Lipid per oxidation, ROS, Apoptosis, Necrosis . 6 6 http://ijt.arakmu.ac.ir/browse.php?a_code=A-10-2-6&slc_lang=en&sid=1 Jalal Pourahmad جلال پوراحمد j.pourahmadjaktaji@utoronto.ca 10031947532846003647 10031947532846003647 Yes Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Beheshti Medical University, Tehran, Iran. Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Beheshti Medical University, Tehran, Iran. Farzaneh Jokar فرزانه جوکار 10031947532846003648 10031947532846003648 No Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Beheshti Medical University, Tehran, Iran. Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Beheshti Medical University, Tehran, Iran. Mariam Rabiei مریم ربیعی 10031947532846003649 10031947532846003649 No Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Beheshti Medical University, Tehran, Iran. Faculty of Pharmacy and Pharmaceutical Sciences Research Center, Shahid Beheshti Medical University, Tehran, Iran. Peter J.O Brien Peter J.O Brien 10031947532846003650 10031947532846003650 No Faculty of Pharmacy, University of Toronto, Toronto, Canada Faculty of Pharmacy, University of Toronto, Toronto, Canada