Biochemical Changes in the Liver of Mice after Exposure to Different Doses of Diclofenac Sodium

Authors: Deepak Mohan, Sushma Sharma

Abstract:

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are a group of widely used drugs for the treatment of rheumatoid diseases and to relieve pain and inflammation due to their analgesic anti-pyretic and anti-inflammatory properties. The therapeutic and many of the toxic effects of NSAIDs result from reversible inhibition of enzymes in the cyclooxygenase (COX) group. In the present investigation the effect of the drug on the concentration of lipids, and on the activity of the enzymes i.e. acid and alkaline phosphatase, GOT, GPT and lipid peroxidase were studied. There was a significant enhancement in the activities of both acid and alkaline phosphatase after 21 days of treatment. Proportionate increase in the MDA contents was observed after different days of diclofenac treatment. Cellular damage in the liver resulted in decrease in the activity of both GOT (Glutamate oxaloacetate transaminase) and GPT (Glutamate pyruvate transaminase) in both low and high dose groups. Significant decrease in the liver contents was also observed in both dose groups.

Keywords: Anti-inflammatory, cyclooxygenase, glutamate oxaloacetate transaminase, malondialdehyde.

Digital Object Identifier (DOI): doi.org/10.5281/zenodo.1131495

References:

[1] M.A. Zaragoza, M.V. Alfonso, and C.E. Roig, “NSAID induced hepatotoxicity: Aceclofenac and diclofenac,” Rev. Esp. Enferm. Dig. 87: (1995). pp. 472-475
[2] F.F. Rubatelli, M.L. Chiozza, V. Zanardo, and F. Cantrutti, “Effect on neonate of maternal treatment with indomethacin”. J. Pediatr. 94: (1979) pp 161-165.
[3] S.Subramanian, “Diclofenac induced toxic manifestations in adjuvant induced arthritic rats peripheral and reproductive organs of male wistar rats” Rattus norvagicus. J. Toxicol. Environ. Health Sci. 1(1): 2009 pp.12-21.
[4] W. Bloom, and D.W. Fawcett, A textbook of histology, W.B. Saunders Company. Igaka Sholin Ltd., Tokyo, 1968.
[5] N. Mumoli, M. Cei, and A. Cosimi, “Drug related hepatotoxicity”. N. Eng. J. Med. 354(20): 2006 pp.2191-2194
[6] N.R Pumford, T. G Myers, J.C. Davila, R.J. Highet, and L.R. Pohl, “Immunochemical detection of liver protein adducts of non-steroidal anti-inflammatory drug Diclofenac”. Chem. Res. Toxicol. 6: 1993 pp. 147-150.
[7] M.N. Swartz, “Mitochondrial toxicity: new adverse drug effects” N. Eng. J Med. 333: 1995 pp. 1146-1154.
[8] O.H. Lowry, N.J. Rosebrough, A.L. Fair and R.J. Randall, “Protein measurements with folin-phenol reagent” J. Biol. Chem. 193: 1951 pp 265-275.
[9] S.V. Pandey, R. Parvin and Venkitasubramanian, “Microdetermination of lipids and serum total fatty acids”. Anal. Biochem.6: 1963 pp 415.
[10] R.S. Dhindsa, P.P. Dhindsa and T.A. Thorpe, “Leaf senescence correlated with increased level of membrane permeability and lipid peroxidation and decreased level of SOD and catalase”. J. Exp. Bot. 32(126): 1981 pp. 93.
[11] H.U. Bergmeyer and E. Bernt, In: Methods of enzymatic analysis (Ed. H.U. Bergmeyer) Academic Press, New York and London. 1965 pp. 387.
[12] L. Weil and M.A. Russel, “Study on plasma phosphatase activity in relation to fat metabolism in rats”. J. Biol. Chem. 136(1): 1940 pp 9-22.
[13] K. Begriche, J. Massart, M.A. Robin, A. Borgne-Sanchez, and B. Fromenty “Drug-induced toxicity on mitochondria and lipid metabolism: mechanistic diversity and deleterious consequences for the liver” J. Hepatol. 54: 2011 pp.773-794.
[14] G. Vanithakumari, and K. Sakthi Shree, “Alleviation of diclofenac induced testicular toxicity by Vitamin E supplementation in albino rat” In: Perspectives in Animal Ecology and Reproduction (Eds. V.K. Gupta and A. K. Verma) Daya Publishing House, New Delhi 2007 pp. 480-502.
[15] A.E. El-Naggar, and H. Hussein, “Protective and therapeutic effects of fucoidan, brown algae extract, against diclofenac sodium hepatonephrotoxicity in rat” Egypt. J. Comp. Path. & Clinic. Path. 23(1): 2007 pp. 154-173
[16] N.T. Taib, B.M. Jarrar, and M.M. Mubarak, “Ultrastructural alterations in renal tissues of rabbit induced by Diclofenac sodium (Voltaren)”. Saudi Med. J. 25(10): 2004 pp.1360-1365.
[17] H. Stierlin, and J.W. Faigle, “Biotransformation of diclofenac sodium (Voltaren) in animals and man: Quantitative determination of the unchanged drug and principal phenolic metabolites in urine and bile” Xenobiotica 9: 1979 pp. 611-621.
[18] K. Yapar, O. Atakisi, E. Uzlu, M. Citil, M. Uzun, and H.M. Metin Erdogan, “Protective effect of L-carnitine against diclofenac sodium toxicity in mice” Revue. Med. Vet. 159(6): 2008 pp.363-367.
[19] S. Konyalioglu, A. Er, K. Uney, and M. Elmas, “Effect of flunixin meglumin on the antioxidant status in endotoxemia” Acta Vet. Beograd. 57: 2007 pp. 241-246
[20] X.U. He, Y.J. Luo, P. Wang, L.Y. Wang, H. Fu, G. Zhao, and Q.E. Liu, “Effects of extract from Ginkgo biloba on carbon tetrachloride induced liver injury in rats” World J. Gastroenterol. 12(24):2006 pp. 3924-3928.
[21] N. Akilavalli, J. Radhika, and P. Brindha, “Hepatoprotective activity of Ocimum sanctum Linn. against lead induced toxicity in albino rats” Asian J. Pharm. Clin. Res. 4(2): 2011 pp.84-87.
[22] T. Maity, A. Ahmad, N. Pahari, and S. Ganguly, “Hepatoprotective activity of Mikania scandens (L.) Wild against diclofenac sodium induced liver toxicity in rats” Asian J. Pharmaceut. & Clin. Res. 5(2): 2012 pp.185-189.
[23] A.A Hamza, “Curcuma longa, Glycyrrhiza glabra and Moringa oleifera ameliorate diclofenac induced hepatotoxicity in rats” Am. J. Pharmacol. Toxicol. 2: 2007 pp. 80-88
[24] T.Y. Musa, J.A. Oluwatope, C.E. Vans, and B.O. Victoe, “Increased liver alkaline phosphatase and aminotransferase activities following administration of ethanolic extract of Khaya senegalensis stem bark to rats” Biokemistry, 17(1): 2005 pp.27-32.
[25] E. Schmid and F.W. Schmidt, “Enzyme diagnosis in diseases of liver and biliary system” Adv. Clin. Enzymol. 1: 1979 pp.239-242.
[26] M.A. Akanji, O.A. Olagoke, and O.B. Oloyede, “Effect of chronic consumption of metabisulphite on the integrity of the kidney cellular system” Toxicol. 81:1993 pp. 173-179.
[27] M. Anusha, M. Venkateswarlu, V. Prabhakaran, S.S. Taj, B.P. Kumari, D. Ranganayakulu, “Hepatoprotective activity of aqueous extracts of Portulaca oleracea in combination with lycopene in rats” Ind. J. Pharmacol. 43: 2011 pp.563-570.
[28] G. Schmitz, H. Lepper, and C.J. Estler, “Changes in energy homeostasis and GSH depletion as possible mechanism of diclofenac induced cytotoxicity on isolated rat hepatocytes” Arch. Pharmacol. 77:1995 pp. 32-35.
[29] S. Chouhan, and S. Sharma, “Sub-chronic diclofenac sodium induced alterations of alkaline phosphatase activity in serum and skeletal muscle of mice” Ind. J. Exp. Biol. 49: 2011 pp. 446-456.
[30] M. Hui, and P.T. Cheng, “Tissue non-specific alkaline phosphatase may be a function related marker in renal proximal tubular epithelia and in vascular endothelia as it is in osteoblasts” Cell Physiol. Biochem., 6: 1996 pp.296.
[31] A. Mota, P. Silva, D. Nerves, C. Lemos, C. Calhau, D. Torres, D, F. Martel, H. Fraga, L. Ribeiro, M.N.M.P. Alcada, M.J. Pinho, M.R. Negrao, R. Pedrosa, S. Guerreiro, J.T. Guimaraes, I. Zevedo, and M.J. Martins, “Characterization of rat heart alkaline phosphatase isoenzymes and modulation of activity” Braz. J. Med. Biol. Res. 41:2008 pp. 600
[32] M.G. Amer, and I.A. El-Khishin, “Possible role of L-carnitine on diclofenac induced hepatotoxicity in adult male albino rats” (Histological, Immunohistochemical and Biochemical study). Egypt J. Histol. 33(2):2010 pp. 341-352.
[33] P.J Butterworth, and D.W. Moss, “The effect of urea on human kidney alkaline phosphatase” Biochem. J. 99: 1966 pp.9-10
[34] M.J. Hardonk, and J. Koudstaal, “Enzyme histochemistry as a link between biochemistry and morphology” Gustan Fisher, Stuttgart 1966 p. 40.
[35] A.R. Sharkoori, J. Alam, F. Aziz, F. Aslam, and M. Sabir, “Toxic effect of bifenthrin (Talstar) on the liver of Gallus domesticus” J. Ecotoxocol. & Environ. Monit. 21 (1): 1992 pp.1-11.
[36] M.M. Kaplin, “Laboratory tests. In: Diseases of the liver. (Eds. L. Schiff and E. R. Schiff) J.B. Lippincott, Philadelphia. 1993 pp. 108-144.
[37] M.B. de Araujo, F.A. Voltarelli, R.V.L. Contarteze, F.D.B. Manchado-Gobatto, and M.A.R. de Mello, “Oxidative stress in rats exercised at different intensities”. J. Chinese Clin. Med. 4:2009 pp. 11-18.
[38] R.J.T. Pennington, “Biochemical aspect of muscle disease”. In: Disorder of voluntary muscle. (Ed. J. N. Walton), Churchill, Livingstone, London 1974 pp. 506.
[39] T.M. Bush, T.L. Shlotzhauer and K.Imai, “Non-steroidal anti-inflammatory drugs, proposed guidelines for monitoring toxicity” West. J. Med., 155:1991 pp. 39-42.
[40] S.I. Alqasoumi, “Ameliorative effect of 10- gingerol on drug induced hepatotoxicity in albino rats” J. Med. Plant Res. 6(9):2012 pp. 1548-1555.
[41] J.S. Dawane, K.D. Borole, V.A. Pandit, D. Dhrubajyoti, S.S. Sahane, and M.N. Karandikar, “ Evaluation of nephro, hepato and gastro toxic potential of aqueous extract of Dashamula” Int. J. Res. Pharmaceut. Biomed. Sci. 3(1):2012 pp. 13-19.
[42] A.P. Manjrekar, V. Jisha, P.P. Bag, B. Adhikary, M.M. Pai, A. Hegde, and M. Nandini, “Effect of Phyllanthus niruri Linn. Treatment on liver, kidney and testes in CCL4 induced hepatotoxic rats” Ind. J. Exp. Biol. 46:2008 pp. 514-520.
[43] H. Singh, J.C. Chugh, A.M. Shembesh, A.A. Ben-Musa, and H.C. Mehta, “Hepatotoxicity of high dose salicylates therapy in acute rheumatic fever” Ann. Trop. Paediatr. 12:1932 pp. 37.
[44] P.E. Ebong, E.U. Eyong, and E.O. Udosen, “Effects of aspirin (acetylsalicylic acid) and cataflam (potassium diclofenac) on some biochemical parameters in rats” Afr. J. Med. Sci. 27(3-4): 1998 pp.243-249
[45] Y. Baravalia, Y. Vaghasiya, and S. Chanda, “Hepatoprotective effect of Woodfordia fruticosa Kurz flowers on diclofenac sodium induced liver toxicity in rats” Asian Pacific J. Tropic. Med. 2011 pp.342-346.
[46] S. Sreelatha, P.R. Padma, and M. Umadevi, “Protective effects of Coriandrum sativum extract on carbon tetrachloride induced hepatotoxicity in rats” Food Chem. Toxicol., 47: 2009 pp.702-708
[47] H. Wada, and E.E. Snell, “Enzymatic transamination of pyridoxamine- pyruvate transaminase” J. Biol. Chem. 237: 1962 pp.133-137.
[48] R.M. Wells, R.H. Mclntyre, A.K. Morgan, and P.S.Davies, “Physiological stress responses in big game fish after exposure: observation on plasma chemistry and blood factors” Comp. Biochem. Physiol. 64A: 1986 pp.565-571.
[49] S. Murmu, and V.K. Srivastava, “Toxicological effects of Bisphenol-A and preventive role of vitamin-C on enzymological activities (i.e. GOT, GPT, ACP and ALP) in kidney of Cirrhinus mrigala (HAM)” The Ecoscan 1:2012 pp. 193-196.
[50] M.T. Yakubu, J.O. Adebayo, E.C. Egwim, and V.B. Owoyele, “Increased liver alkaline phosphatase and aminotransferase activities following administration of ethanolic extract of Khaya senegalensis stem bark to rats” Biokemistry 17(1): 2005 pp. 27-32.
[51] S. T. Basavraj, D.T. Fefar, K.S. Prajapati, B.M. Jivani, K.B. Thakor, J.H. Patel, D.J. Ghodasara, B.P. Joshi, and V.V.Undhad, “Haematobiochemical alterations induced by diclofenac sodium toxicity in Swiss albino mice”. Vet. World 5(7): 2012 pp. 417-419.
[52] M.F. Dixon, J. Nimmo, and L.F. Prescot, “Experimental paracetamol induced hepatic necrosis. A histopathological study”. J. Pathol. 103: 1971 pp.225-227.
[53] D.W. Molander, F. Wroblewsk, and J.S. La Due, “Transaminase compared with cholinesterase and alkaline phosphatase: an index of hepatocellular integrity” 1955. Clin. Res. Proc. 314
[54] G.E. Swan, R. Cuthbert, M., Quevedo, R.E. Green, D.J. Pain, P. Bartles, A.A. Cunningham, N. Duncan, A.A. Meharg, J.L. Oaks, J. Parry-Jones, S. Schultz, M.A. Taggart, G. Verdoom, and K. Wolter, “Toxicity of Diclofenac to Gyps vultures” Biol. Lett. 2: 2006 pp.279-282.