Toxicological Evaluation of Disulfiram, Copper Gluconate and Disulfiram/Copper Gluconate Combination on Renal Function in Rodents

Abstract

This research work investigated and compared the chronic renal toxicological profile of disulfiram, copper gluconate and disulfiram/copper gluconate combination, in a 90-day time- and dose-dependent study in rodents. 88 rats weighing an average of 280 g divided into eleven groups consisting of 8 rats each were used for this experiment. The control groups received normal saline as placebo and 99.5% dimethyl sulfoxide (DMSO) (solvent control). Three oral doses (low, medium and high) of disulfiram (18.65 mg/kg, 37.3 mg/kg and 74.6 mg/kg), copper gluconate (3.75 mg/kg, 7.5 mg/kg and 15 mg/kg) and both drugs in combination were administered daily with those of the combination given 12 hours apart. Blood samples were collected via cardiac puncture in heparinised bottles and centrifuged, and the serum was decanted on 30, 45, 60 and 90 days for analysis. Renal function parameters—electrolytes (Na+, K+), urea and creatinine were evaluated. Results showed significant (p < 0.05) dose- and time-dependent increase in electrolyte level (Na+, K+), blood urea and creatinine respectively. The results are all pointers to the development of renal failure. It therefore appears that the DSF/CG combination is nephrotoxic and this effect is dose-dependent and synergistic.

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Georgewill, U. , Siminialayi, I. and Obianime, A. (2015) Toxicological Evaluation of Disulfiram, Copper Gluconate and Disulfiram/Copper Gluconate Combination on Renal Function in Rodents. Pharmacology & Pharmacy, 6, 86-93. doi: 10.4236/pp.2015.62011.

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1] World Health Organization (2008) World Cancer Report 2008. International Agency for Research on Cancer, Lyon.
[2] Chukwuma, M. (2006) Crude Oil Pollution Raises Cancer Risk among Nigerians. African Cancer Centre.
[3] Duran-Frigola, M. and Aloy, P. (2012) Recycling Side Effects into Clinical Markers for Drug Repositioning. Genome Medicine, 4, 3.
http://dx.doi.org/10.1186/gm302
[4] Li, Y.Y. and Jones, S.J. (2012). Drug Repositioning for Personalised Medicine. Genome Medicine, 4, 27.
[5] Blatt, J. and Corey, S.J. (2013) Drug Repositioning in Paediatrics and Pediatric Hematology Oncology. Drug Discovery Today, 18, 4-10.
http://dx.doi.org/10.1016/j.drudis.2012.07.009
[6] Cvek, B. (2011) Targeting Malignancies with Disulfiram(antabuse); Multidrug Resistance, Angiogenesis, and Proteasome. Current Cancer Drug Targets, 11, 332-337.
http://dx.doi.org/10.2174/156800911794519806
[7] Kast, R.E., Boockvar, J.A., Bruning, A., Capello, F., Chang, W.W., Cvek, B., Dou, Q.P., Duenas-Gonzalez, A., Efferth, T., Focosi, D., Ghaffari, S.H., Karpel-Massler, G., Ketola, K., Khoshnevisan, A., Keizman, D., Magne, N., Marosi, C., McDonald, K., Munoz, M., Paranjpe, A., Pourgholami, M.H., Sardi, I., Sella, A., Srivenugopal, K.S., Tucorri, M., Wang, W., Wirtz, C..R. and Halatsch, M.E. (2013) A Conceptually New Treatment Approach for Relapsed Glioblastoma; Coordinated Undermining of Survival Paths with Nine Repurposed Drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care. Oncotarget, 4, 502-530.
[8] Brar, S.S., Grigg, C., Wilson, K.S., Holder, W.D., Dreau, D., Austin, C., et al. (2010) Disulfiram Inhibits Activating Transcription Factor/Cyclic AMP Responsive Element Binding Protein and Human Melanoma Growth in a Metal-Dependent Manner in Vitro, in Mice and in a Patient with Cancer Cell Lines. Cancer Letters, 290, 104-113.
[9] Marikovsky, M., Nevo, N., Vadai, E. and Harris-Cerruti, C. (2002) Cu/Zn Superoxide Dismutase Plays a Role in Angiogenesis. International Journal of Cancer, 97, 34-41.
http://dx.doi.org/10.1002/ijc.1565
[10] Cen, D., Gonzalez, R.I., Buckmeier, J.A., Kahlon, R.S., Tohidian, N.B. and Meyskens Jr, F.L. (2002) Disulfiram Induces Apoptosis in Human Melanoma Cells: A Redox-Related Process. Molecular Cancer Therapeutics, 1, 197-204.
[11] Chen, D., Cui, Q.C., Yang, H.J. and Dou, Q.P. (2006) Disulfiram, a Clinically Used Anti-Alcoholism Drug and Copper-Binding Agent, Induces Apoptotic Cell Death in Breast Cancer Cultures and Xenografts via Inhibition of the Proteasome Activity. Cancer Research, 66, 10425-10433.
http://dx.doi.org/10.1158/0008-5472.CAN-06-2126
[12] Johansson, B. (1992) A Review of the Pharmacokinetics and Pharmacodynamics of Disulfiram and Its Metabolites. Acta Psychiatrica Scandinavica, 86, 15-26.
http://dx.doi.org/10.1111/j.1600-0447.1992.tb03310.x
[13] Kristenson, H. (1995) How to Get the Best out of Antabuse. Alcohol and Alcoholism, 30, 775-783.
[14] Skrott, Z. and Cvek, B. (2012) Diethyldithiocarbamate Complex with Copper: The Mechanism of Action in Cancer Cells. Mini-Reviews in Medicinal Chemistry, 12, 1184-1192.
http://dx.doi.org/10.2174/138955712802762068
[15] Papaioannou, M., Malonas, I., Kast, R.E. and Brüning, A. (2013) Disulfiram/Copper Causes Redox-Related Proteotoxicity and Concomitant Heat Shock Response in Ovarian Cancer Cells That Is Augmented by Auranofin-Mediated Thioredoxin Inhibition. Oncoscience, 1, 21-29.
[16] Ries, F. and Klastersky, J. (1986) Nephrotoxicity Induced by Cancer Chemotherapy with Special Emphasis on Cisplatin Toxicity. American Journal of Kidney Diseases, 8, 368-379.
http://dx.doi.org/10.1016/S0272-6386(86)80112-3
[17] Barbier, O., Jacquillet, G., Tauc, M., Cougnon, M. and Poujeol, P. (2005) Effect of Heavy Metals on, and Handling by, the Kidney. Nephron Physiology, 99, 105-110.
http://dx.doi.org/10.1159/000083981
[18] Owunari, G.U., Minakiri, S.I. and Wolfe, O.A. (2015) Effect of Disulfiram/Copper Gluconate Combination on Haematological Indices in Rodents. Pharmacology & Pharmacy, 6, 17-24.
http://dx.doi.org/10.4236/pp.2015.61003
[19] Grossmann, K.F., Blankenship, M.B., Akerley, W., Terrazas, M.C., Kosak, K.M., Boucher, K.M., Buys, S.S., Jones, K., Werner, T.L., Agarwal, N., Weis, J., Sharma, S., Ward, J. and Shami, P.J. (2011) Abstract 1308: A Phase I Clinical Study Investigating Disulfiram and Copper Gluconate in Patients with Advanced Treatment-Refractory Solid Tumors Involving the Liver. Cancer Research, 71, 1308.
http://dx.doi.org/10.1158/1538-7445.AM2011-1308
[20] Olurishe, T.O., Kwanashie, H.O., Anukar, J.A., Muktar, H. and Sambo, J.S. (2013) Renal Impact of Subacute Lamivudine-Artesunate Treatment in Wistar Rats. African Journal of Pharmacology and Therapeutics, 2, 48-53.
[21] Eaton, D.C. and Pooler, J.P. (2009) Vander’s Renal Physiology. 7th Edition, Lange Medical Books/McGraw-Hill, Medical Pub. Division, New York.
[22] Traynor, J., Mactier, R., Geddes, C.C. and Fox, J.G. (2006) How to Measure Renal Function in Clinical Practice. British Medical Journal, 333, 733-737.
http://dx.doi.org/10.1136/bmj.38975.390370.7C
[23] Allen, P.J. (2012) Creatine Metabolism and Psychiatric Disorders: Does Creatine Supplementation Have Therapeutic Value? Neuroscience & Biobehavioral Reviews, 36, 1442-1462.
http://dx.doi.org/10.1016/j.neubiorev.2012.03.005
[24] Gross, J.L., de Azevedo, M.J., Silveiro, S.P., Canani, L.H., Caramori, M.L. and Zelmanovitz, T. (2005) Diabetic Nephropathy: Diagnosis, Prevention, and Treatment. Diabetes Care, 28, 164-176.
http://dx.doi.org/10.2337/diacare.28.1.164

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