Abstract
Addition of CdCl2, HgCl2 or K2Cr2O7to 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,K2Cr2O7but not HgC12. 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”.
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References
Andersson, B.S., Aw, T.Y., Jones, D.P. (1987). Mitochondrial transmembrane potential and pH gradient during anoxia. Am J Physiol, 252 (4 Pt 1), C349–C355.
Eto, K. (1997) Pathology of Minamata disease. Toxicol. Pathol. 25 (6), 614–23.
Farber, E. (1971). Biochemical pathology. Annu. Rev. Pharmacol. 11, 71–96.
Flaks, B., Nicoll, J.W. (1974). Modification of toxic liver injury in the rat. I. Effect of inhibition of protein synthesis on the action of 2-acetylaminofluorene, carbon tetrachloride, 3’-methyl-4dimethylaminoazobenzene and diethylnitrosamine. Chem. Biol. Interact. 8 (3), 135–50.
Guo, T.L., Miller, M.A., Shapiro, I.M., Shenker, B.J. (1998). Mercuric chloride induces apoptosis in human T lymphocytes: evidence of mitochondria) dysfunction. Toxicol. Appl. Pharmacol. 153(2), 250–7.
Habeebu, S.S., Liu, J., Klaassen, C.D. (1998). Cadmium-induced apoptosis in mouse liver. Toxicol. Appl. Pharmacol. 149 (2), 203–9.
Horiguchi, H., Teranishi, H., Niiya, K., Aoshima, K., Katoh, T., Sakuragawa, N., Kasuya, M. (1994). Hypoproduction of erythropoietin contributes to anemia in chronic cadmium intoxication: clinical study on Itai-itai disease in Japan. Arch. Toxicol. 68 (10), 632–6.
Khan, S. and O’Brien, P.J. (1991). 1-bromoalkanes as new potent nontoxic glutathione depletors in isolated rat hepatocytes. Biochem. Biophys. Res. Commun. 179 (1), 436–41.
Kim, M.S., Kim, B.J., Woo, H.N., Kim, K.W., Kim, K.B., Kim, I.K., Jung, Y.K. (2000). Cadmium induces caspase-mediated cell death: suppression by Bc1–2. Toxicology 145 (1), 27–37.
Koizumi, T., Yokota, T., Shirakura, H., Tatsumoto, H., Suzuki, K.T. (1994). Potential mechanism of cadmium-induced cytotoxicity in rat hepatocytes: inhibitory action of cadmium on mitochondrial respiratory activity. Toxicology 92 (1–3), 115–25.
Kowaltowski,A.J., Naia-da-Silva, E.S., Castilho, R.F., Vercesi, A.E. (1998). Ca2+-stimulated mitochondrial reactive oxygen species generation and permeability transition are inhibited by dibucaine or Mg2+. Arch. Biochem. Biophys. 359 (1), 77–81.
Kurasaki, K., Nakamura, T., Mukai, T., Endo, T. (1995). Unusual findings in a fatal case of poisoning with chromate compounds. Forensic Science Intern. 75, 57–65.
Lemasters, J.J. (1999). Mechanisms of hepatic toxicity: necroapoptosis and the mitochondrial permeability transition. Shaped pathways to necrosis and apoptosis. Am. J. Physiol. 276, Gl–G6.
Lund, B.O., Miller, D.M., Woods, J.S. (1993). Studies on Hg(II)-induced H2O2 formation and oxidative stress in vivo and in vitro in rat kidney mitochondria. Biochem. Pharmacol. 45 (10), 2017–24.
Meisenholder, G.W., Martin, S.J., Green, D.R., Nordberg, J., Babior, B.M., Gottlieb, R.A. (1996). Events in apoptosis. Acidification is downstream of protease activation and BCL-2 protection. J. Biol. Chem. 271 (27), 16260–2.
Miksche, L.W., Lewalter, J. (1997). Health surveillance and biological effect monitoring for chromium-exposed workers. Regul. Toxicol. Pharmacol. 26 (1 Pt 2), S94–9.
Nieminen, A.L., Gores, G.T., Dawson, T.L., Herman, B., Lemaster, J.T. (1990). Toxic injury from mercuric chloride in rat hepatocytes. J. Biol. Chem. 265, 2399–408
Niknahad, H., Khan, S. and O’Brien, P.J. (1995). Hepatocyte injury resulting from the inhibition of mitochondrial respiration at low oxygen concentrations involves reductive stress and oxygen activation. Chemico-Biol. Interacns. 98, 27–44.
Pastorino, J.G., Snyder, J.W., Serroni, A., Hoek, J.B., Farber, J.L. (1993). Cyclosporin and carnitine prevent the anoxic death of cultured hepatocytes by inhibiting the mitochondrial permeability transition. J. Biol. Chem. 268 (19), 13791–8.
Pourahmad, J., O’Brien, P.J. (2000a). A comparison of hepatocyte cytotoxic mechanisms for Cu2+ and Cd2+. Toxicology 143 (3), 263–73.
Pourahmad, J., O’Brien, P.J. (2000b). Contrasting role of Na(+) ions in modulating Cu(+2) or Cd(+2) induced hepatocyte toxicity. Chem. Biol. Interact. 126 (2), 159–69.
Shen, H.M., Shi, C.Y., Shen, Y., Ong, C.N. (1996). Detection of elevated reactive oxygen species level in cultured rat hepatocytes treated with aflatoxin B1. Free Radic. Biol. Med. 21 (2), 139–146.
Siegers, C.P., Sharma, C.S., Younes, M. (1986) Hepatotoxicity of metals in glutathione depleted mice. Toxicol. Lett. 34, 185–91
Smith, M.T., Thor, H., Hartizell, P., Orrenius, S. (1982). The measurement of lipid peroxidation in isolated hepatocytes. Biochem. Pharmacol. 31 (1), 19–26.
Strubelt, O., Kremer, J., Tilse, A., Keogh, J., Pentz, R., Younes, M. (1996). Comparative studies on the toxicity of mercury, cadmium, and copper toward the isolated perfused rat liver. J. Toxicol. Environ. Health 47 (3), 267–83.
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Pourahmad, J., Mihajlovic, A., O’Brien, P.J. (2001). Hepatocyte Lysis Induced by Environmental Metal Toxins May Involve Apoptotic Death Signals Initiated by Mitochondrial Injury. In: Dansette, P.M., et al. Biological Reactive Intermediates VI. Advances in Experimental Medicine and Biology, vol 500. Springer, Boston, MA. https://doi.org/10.1007/978-1-4615-0667-6_38
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DOI: https://doi.org/10.1007/978-1-4615-0667-6_38
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