Vanadium induces liver toxicity through reductive activation by glutathione and mitochondrial dysfunction


Pentavalent vanadium (V5+) (metavanadate salt) tox- icity is a challenging problem to the health professionals and has been recognized as an industrial hazard that adversely affects human and animal health, but its cytotoxic mechanisms have not yet been completely understood. In this study, we investigated the cytotoxic mechanisms of V5+ in freshly isolated rat hepatocytes. V5+ cytotoxicity was associated with reactive oxygen species (ROS) formation, collapse of mitochondrial membrane potential, lysosomal membrane rupture and cytochrome c release into the hepatocyte cytosol. All of the above mentioned V5+ -induced cytotoxicity markers were significantly (p < 0.05) prevented by ROS scavengers, antioxidants and mitochondrial permeability transition (MPT) pore sealing agents. Hepatocyte glutathione (GSH) was also rapidly oxidized and GSH-depleted hepatocytes were more resistant to lithium-induced oxidative stress markers. This suggests that V5+ is activated by GSH. Our findings also showed that the lysosomotropic agents prevented V5+ induced mitochondrial membrane potential collapse. On the other hand, mitochondrial MPT pore sealing agents inhibited lysosomal membrane damage caused by V5+. It can therefore be suggested that there is probably a toxic interaction (cross-talk) between mitochondrial and lysosomal oxidative stress generating systems, which potentiates ROS formation and further damages both sub-organelles in V5+-induced induced hepatotoxicity. In conclusion, V5+-induced cytotoxicity can be attributed to oxidative stress started from glutathione mediated metal reductive activation and continued by mitochondrial/lysosomal toxic interaction.

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Hosseini, M. , Seyedrazi, N. , Shahraki, J. and Pourahmad, J. (2012) Vanadium induces liver toxicity through reductive activation by glutathione and mitochondrial dysfunction. Advances in Bioscience and Biotechnology, 3, 1096-1103. doi: 10.4236/abb.2012.38134.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Soares, S.S., Martins, H., Gutiérrez-Merino, C. and Aureliano, M. (2008) Vanadium and cadmium in vivo effects in teleost cardiac muscle: Metal accumulation and oxidative stress markers. Comparative Biochemistry and Physiology. Part C, Pharmacology, Toxicology & Endocrinology, 147, 168-178. doi:10.1016/j.cbpc.2007.09.003
[2] International Agency for Research on Cancer (IARC) (2006) Cobalt in hard metals and cobalt sulfate, gallium arsenide, indium phosphide and vanadium pentoxide. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans, 86, 119-237.
[3] Ivancsits, S., Pilger, A., Diem, E., Scha Ver, A. and Rüdiger, H.W. (2002) Vanadate induces DNA strand breaks in cultured human fibroblasts at doses relevant to occupational exposure. Mutation Research, 519, 25-35. doi:10.1016/S1383-5718(02)00138-9
[4] Altamirano-Lozano, M., Valverde, M., Alvarez-Barrera, L., Molina, B. and Rojas, E. (1999) Genotoxic studies of vanadium pentoxide (V2O5) in male mice. II. Effects in several mouse tissues. Teratogenesis, Carcinogenesis, and Mutagenesis, 19, 243-255. doi:10.1002/(SICI)1520-6866(1999)19:4<243::AID-TCM1>3.0.CO;2-J
[5] Scibior, A., Zaporowska, H., Ostrowski, J. and Banach, A. (2006) Combined effect of vanadium(V) and chromium (III) on lipid peroxidation in liver and kidney of rats. Chemico-Biological Interactions, 159, 213-222. doi:10.1016/j.cbi.2005.11.008
[6] Shi, X. and Dalal, N.S. (1992) Hydroxyl radical generation in the NADH/microsomal reduction of vanadate. Free radical Research Communications, 17, 369-376. doi:10.3109/10715769209083141
[7] Shi, X., Jiang, H., Mao, Y., Ye, J. and Sayotti, U. (1996) Vanadium(IV)-mediated free radical generation and related 2-deoxyguanosine hydroxylation and DNA damage. Toxicology, 106, 27-38. doi:10.1016/0300-483X(95)03151-5
[8] Valko, M., Morris, H. and Cronin, M.T. (2005) Metals, toxicity and oxidative stress. Current Medicinal Chemistry, 12, 1161-1208. doi:10.2174/0929867053764635
[9] Yang, X.G., Yang, X.D., Yuan, L., Wang, K. and Crans, D.C. (2004) The permeability and cytotoxicity of insulinmimetic vanadium compounds. Pharmaceutical Research, 21, 1026-1033. doi:10.1023/B:PHAM.0000029293.89113.d5
[10] Soares, S.S., Gutie′rrezMerino, C. and Aureliano, M. (2007) Decavanadate induces mitochondrial membrane depolarization and inhibits oxygen consumption. Journal of Inorganic Biochemistry, 101, 789-796. doi:10.1016/j.jinorgbio.2007.01.012
[11] Macara, I.G., Kustin, K. and Cantley Jr. (1980) Glutathione reduces cytoplasmic vanadate. Mechanism and physiological implications. Biochimica et Biophysica Acta, 629, 95-106. doi:10.1016/0304-4165(80)90268-8
[12] Leonard, S.S., Harris, G.K. and Shi, X. (2004) Metalinduced oxidative stress and signal transduction. Free Radical Biology & Medicine, 37, 1921-1942. doi:10.1016/j.freeradbiomed.2004.09.010
[13] Shi, H., Hudson, L.G. and Liu, K.J. (2004) Oxidative stress and apoptosis in metal ioninduced carcinogenesis, Free Radical Biology & Medicine, 37, 582-593. doi:10.1016/j.freeradbiomed.2004.03.012
[14] Pourahmad, J., Hosseini, M.J., Eskandari, M.R. and Rahmani, F. (2012) Involvement of four different intracellular sites in chloroacetaldehyde-induced oxidative stress cytotoxicity. Iranian Journal of Pharmaceutical Research, 11, 265-276.
[15] Pourahmad, J., Hosseini, M.J., Bakan, S. and Ghazi- Khansari, M. (2011) Hepatoprotective activity of angiotensin-converting enzyme (ACE) inhibitors, captopril and enalapril, against paraquat toxicity. Pesticide Biochemis try and Physiology, 99, 105-110. doi:10.1016/j.pestbp.2010.11.006
[16] Galati, G., Teng, S., Moridani, M.Y., Chan, T.S. and O’Brien, P.J. (2000). Cancer chemoprevention and apoptosis mechanisms induced by dietary polyphenolics. Drug Metabolism and Drug Interactions, 17, 311-349. doi:10.1515/DMDI.2000.17.1-4.311
[17] Khan, S. and O’Brien, P.J. (1991) 1-Bromoalkanes as new potent nontoxic glutathione depletors in isolated rat hepatocytes. Biochemical and Biophysical Research Communications, 179, 436-441. doi:10.1016/0006-291X(91)91389-T
[18] Pourahmad, J., Eskandari, M.R., Alavian, G. and Shaki, F. (2010) Lysosomal membrane leakiness and metabolic biomethylation play key roles in methyl tertiary butyl ether-induced toxicity and detoxification. Toxicological Environental Chemistry, 94, 281-293. doi:10.1080/02772248.2011.643566
[19] Daraei, B., Pourahmad, J., Hamidi-Pour, N., Hosseini, M.J., Shaki, F. and Suleiman, M. (2012) Uranyl acetate induces oxidative stress and mitochondrial membrane potential collapse in the human dermal fibroblast primary cells. Iranian Journal of Pharmaceutical Research, 11, 495-501.
[20] Andersson, B.S., Aw, T.Y. and Jones, D.P. (1987) Mitochondrial transmembrane potential and pH gradient during anoxia. The American Journal of Physiology, 252, 349-355.
[21] Kamada, S., Kusano, H., Fujita, H., Ohtsu, M., Koya, R.C., Kuzumaki, N. and Tsujimoto, Y. (1998) A cloning method for caspase substrates that uses the yeast two-hybrid system: Cloning of the antiapoptotic gene gelsolin. Proceedings of the National Academy of Sciences of the United States of America, 95, 8532-8537. doi:10.1073/pnas.95.15.8532
[22] Gogvadze, V., Orrenius, S. and Zhivotovsky, B. (2006) Multiple pathways of cytochrome c release from mitochondria in apoptosis. Biochimica et Biophysica Acta, 1757, 639-647. doi:10.1016/j.bbabio.2006.03.016
[23] Evangelou, A.M. (2002) Vanadium in cancer treatment. Critical Reviews in Oncology/Hematology, 42, 249-265. doi:10.1016/S1040-8428(01)00221-9
[24] Scibior, A., Zaporowska, H., Ostrowski, J. and Banach, A. (2006) Combined effect of vanadium(V) and chromium (III) on lipid peroxidation in liver and kidney of rats. Chemico-Biological Interactions, 159, 213-222. doi:10.1016/j.cbi.2005.11.008
[25] Cortizo, A.M., Bruzzone, L., Molinuevo, S. and Etcheverry, S.B. (2000) A possible role of oxidative stress in the vanadium-induced cytotoxicity in the MC3T3E1 osteoblast and UMR106 osteosarcoma cell lines. Toxicology, 8, 89- 99. doi:10.1016/S0300-483X(00)00181-5
[26] Goldfine, A.B., Simonson, D.C., Folli, F., Patti, M.E. and Kahn, C.R. (1995) In vivo and in vitro studies of vanadate in human and rodent diabetes mellitus. Molecular and Cellular Biochemistry, 3, 217-231. doi:10.1007/BF01075941
[27] Merritt, K. and Brown, S.A. (1995) Distribution of titanium and vanadium following repeated injection of highdose salts. Journal of Biomedical Materials Research, 29, 1175-1178. doi:10.1002/jbm.820291003
[28] Green, D.R. and Reed, J.C. (1998) Mitochondria and apoptosis. Science, 281, 1309-1312. doi:10.1126/science.281.5381.1309
[29] Valko, M., Leibfritz, D., Moncol, J., Cronin, M.T., Mazur, M. and Telser, J. (2007) Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry & Cell Biology, 39, 44-84. doi:10.1016/j.biocel.2006.07.001
[30] Pompella, A., Visvikis, A., Paolicchi, A., De Tata, V. and Casini, A.F. (2003) The changing faces of glutathione, a cellular protagonist. Biochemical Pharmacology, 66, 1499-1503. doi:10.1016/S0006-2952(03)00504-5
[31] Pourahmad, J. and O’Brien, P.J. (2000) A comparison of hepatocyte cytotoxic mechanisms for Cu2+ and Cd2+ Toxicology, 143, 263-273.
[32] Chadha, V.D., Bhalla, P. and Dhawan, D.K. (2008) Zinc modulates lithium-induced hepatotoxicity in rats. Liver International, 28, 558-565. doi:10.1111/j.1478-3231.2008.01674.x
[33] Pourahmad, J. and O’Brien, P.J. (2001) Biological reactive intermediates that mediate chromium (VI) toxicity. Advances in Experimental Medicine and Biology, 500, 203-207. doi:10.1007/978-1-4615-0667-6_27
[34] Pourahmad, J., Ghashang, M., Ettehadi, H. and Ghalandari, A. (2006) A search for cellular and molecular mechanisms involved in depleted uranium toxicity. Environmental Toxicology, 21, 349-354. doi:10.1002/tox.20196
[35] Pourahmad, J., Eskandari, M.R. and Daraei, B. (2010) A comparison of hepatocyte cytotoxic mechanisms for thallium (I) and thallium (III). Environtal Toxicology, 25, 456- 467. doi:10.1002/tox.20590
[36] Riadh, N., Allagui, M.S., Bourogaa, E., Vincent, C., Croute, F. and Elfeki, A. (2011) Neuroprotective and neurotrophic effects of long term lithium treatment in mouse brain. Biometals, 24, 747-757. doi:10.1007/s10534-011-9433-6
[37] Kappus, H. and Sies, H. (1981) Toxic drug effects asso- ciated with oxygen metabolism: Redox cycling and lipid peroxidation. Cellular and Molecular Life Sciences, 37, 1233-1241. doi:10.1007/BF01948335
[38] Paolicchi, A., Minotti, G., Tonarelli, P., Tongiani, R., De Cesare, D., Mezzetti, A., Dominici, S., Comporti, M. and Pompella, A. (1999). γ-Glutamyl transpeptidase-dependent iron reduction and low density lipoprotein oxidation—A potential mechanism in atherosclerosis. Journal of Investigative Medicine, 47, 151-160.
[39] Tien, M., Bucher, J.R. and Aust, S.D. (1982) Thiol-dependent lipid peroxidation. Biochemical and Biophysical Research Communications, 107, 279-285. doi:10.1016/0006-291X(82)91701-6

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