Protective Effect of Citric Acid Against Thioacetamide-Induced Oxidative Stress and Liver Tissue Damage
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Abstract
The effect of citric acid on liver and brain oxidative stress and liver tissue damage was studied. Rats were treated with thioacetamide at 300 mg/kg, intraperitoneally, for two successive days alone or together with orally administered citric acid at doses of 0.4 g/kg or 1g/kg. Rats were euthanized 24h after last treatments and their livers and brains were dissected out for determination of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide, and paraoxonase-1 (PON-1). Serum alanine aminotransferase and aspartate aminotransferase were determined and histological investigation for the liver tissue was carried out. Results showed that compared with the saline control, treatment with thioacetamine caused marked increase in liver and brain MDA and NO together with GSH depletion and inhibition of PON-1 activity. Serum aminotransferases were markedly increased in thioacetamide-treated rats. The histologic study showed distorted liver architecture, necrotic and apoptotic hepatocytes, fatty change, and ballooning degeneration. Citric acid reduced the increases in liver and brain MDA and NO contents and markedly increased GSH level and PON-1 activity. It also reduced the increments in activities of serum transaminases. These effects of citric acid were dose-dependent. Histologic examination confirmed that rats treated with citric acid at 1g/kg had markedly reduced liver damage. In conclusion, 1g/kg citric acid given at time of thioacetamide administration markedly reduced oxidative stress in both the liver and brain tissue and was able to restore liver architecture.
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E. R. Youness, O. M. Abdel-Salam, A. A. Sleem, and F. A. Morsy, “Protective Effect of Citric Acid Against Thioacetamide-Induced Oxidative Stress and Liver Tissue Damage”, Int.J.Halal.Res, vol. 5, no. 1, pp. 13-25, Jun. 2023.
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References
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Halliwell, B. (2001). Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs & Aging, 18(9), 685‒716.
Sies, H. (1997). Oxidative stress: oxidants and antioxidants. Experimental Physiology, 82(2), 291–295.
Halliwell, B. (2006). Oxidative stress and neurodegeneration: where are we now? Journal of Neurochemistry, 97, 1634–1658.
Valko, M., Leibfritz, D., Moncola, J., Cronin, M.T.D., Mazura, M., & Telser, J. (2007). Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry & Cell Biology, 39, 44–84.
Hoyt ,H.L., & Gewanter, H.L. (1992). Citrate. In: The Handbook of Environmenlal Chemistry,Vol. 3 Part F, (Hulzinger, O., ed.), Springer-Verlag-Berlin Heidelberg, pp.229- 241.
Fegan, J., Khan, R., Poindexter, J., & Pak, C.Y. (1992). Gastrointestinal citrate absorption in nephrolithiasis. Journal of Urology, 147, 1212-1214.
Abdel-Salam, O.M.E., Shaffie, N.M., Omara, E.A., & Yassen, N.N. (2018). Citric Acid an Antioxidant in Liver. The Liver: Oxidative Stress and Dietary Antioxidants (Patel, V., ed.), Chennai, India, Academic Press, pp. 183-198.
Bashir, S., Khan, N.A., & Gilani, A-H. (2012). Physiology of renal handling of citrate. In “Urolithiasis” (Talati, J.J. Tiselius H-G, Albala D.M., & Ye Z., eds.), Springer-Verlag, London, pp.183-185. .
Hess, B. (2011). Urinary citrate and citrate metabolism. In: Urinary Tract Stone Disease (Rao et al. eds.), Springer-Verlag London Limited, pp.181-184.
Unwin, R.J., Capasso, G., & Shirley, D.G. (2004). An overview of divalent cation and citrate handling by the kidney. Nephron, 98,15-20.
Fromm, H.J. & Hargrove, M.S. (2012). The tricarboxylic acid cycle. In: Essentials of Biochemistry (Fromm, H.J. & Hargrove, M.S., eds). Springer-Verlag, Berlin, Heidelberg, pp. 205–21.
Wallace, M.C., Hamesch, K., Lunova, M., Kim, Y., Weiskirchen, R., Strnad, P., & Friedman, S.L. (2015). Standard operating procedures in experimental liver research: thioacetamide model in mice and rats. Laboratory Animals, 49(S1), 21–29.
Nair, V., & Turner, G.A. (1984). The thiobarbituric acid test for lipid peroxidation: structure of the adduct with malondialdehyde. Lipids, 19,804–805.
Archer, S. (1993). Measurement of nitric oxide in biological models. The FASEB Journal, 7(2), 349–60.
Ellman, G.L. (1959). Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics, 82, 70–77.
Haagen, L., & Brock, A. (1992). A new automated method for phenotyping arylesterase (EC 3.1.1.2) based upon inhibition of enzymatic hydrolysis of 4-nitrophenyl acetate by phenyl acetate. European Journal of Clinical Chemistry and Clinical Biochemistry, 30,391–395..
Crowley, L.V. (1967). The Reitman-Frankel colorimetric transaminase procedure in suspected myocardial infarction. Clinical Chemistry, 13, 482-487.
Abdel-Salam, O.M.E., Mohammed, N.A., Sleem, A.A., Farrag, A.R. (2013). The effect of antidepressant drugs on thioacetamide-induced oxidative stress. European Review for Medical and Pharmacological Sciences, 17, 735-744.
De David, C., Rodrigues, G., Bona, S., Meurer, L., González-Gallego, J., Tuñón, M.J., & Marroni, N.P. (2011). Role of quercetin in preventing thioacetamide-induced liver injury in rats. Toxicologic Pathology, 39(6), 949-57.
Chen, T.M., Subeq,Y.M., Lee, R.P., Chiou, T.W., & Hs, B.G. (2008). Single dose intravenous thioacetamide administration as a model of acute liver damage in rats. International Journal of Experimental Pathology, 89, 223–231.
Abdel-Salam, O.M.E.,Youness, E.R., Sleem, A.A., & Morsy, F.A. (2022). Citric acid administration protects against insulin-induced hypoglycemic brain and liver injury. WSEAS TRANSACTIONS on BIOLOGY and BIOMEDICINE, 19, 31-40.
Abdel-Salam, O.M., Youness, E.R., Mohammed, N.A., Morsy, S.M., Omara, E.A., & Sleem, A.A. (2014a). Citric acid effects on brain and liver oxidative stress in lipopolysaccharide-treated mice. Journal of Medicinal Food, 17(5), 588–98.
Abdel-Salam, O.M., Youness, E.R., Mohammed, N.A., Yassen, N.N., Khadrawy, Y.A., El-Toukhy, S.E., et al. (2016). Novel neuroprotective and hepatoprotective effects of citric acid in acute malathion intoxication. Asian Pacific Journal of Tropical Medicine, 9(12), 1181–94.
Abdel-Salam, O.M.E., Morsy, S.M.Y., Youness, E.R., Yassen, N.N., Shaffie, N., & Sleem, A.A. (2020a). Citric acid protects dopaminergic cells against rotenone-induced neurodegeneration. Reactive Oxygen Species 9(27), 118–135.
Abdel-Salam, O.M.E., Sleem, A.A., Morsy, F.A. (2020b). Citric acid protects against toluene-induced brain neurodegeneration and liver damage in rats. Journal of Basic Pharmacology and Toxicology,4(2), 38-48..
La Du, B.N. (1992). Human Serum Paraoxonase: Arylesterase. Pergamon Press, New York, NY, USA.
Watson, A.D., Berliner, J.A., Hama, S.Y., La Du, B.N., Faull, K.F., Fogelman, A.M., et al. (1995). Protective effect of high density lipoprotein associated paraoxonase: inhibition of the biological activity of minimally oxidized low density lipoprotein. Journal of Clinical Investigation, 96(6), 2882‒91.
Ferre, N., Camps, J., Prats, E., Vilella, E., Paul, A., Figuera, L., & Joven, J. (2002). Serum paraoxonase activity: a new additional test for the improved evaluation of chronic liver damage. Clinical Chemistry, 48, 261–268.
Baskol, M., Baskol, G., Deniz, K., Ozbakir, O., & Yucesoy, M. (2005). A new marker for lipid peroxidation: serum paraoxonase activity in non-alcoholic steatohepatitis. Turkish Journal of Gastroenterology, 16(3), 119‒123.
Abdel-Salam, O.M.E., El-Shamarka, M.E-S., Hassan, N.S., & Abouelfadl, D.M. (2021). Effect of piracetam on brain oxidative stress and tissue damage following toluene exposure in rats. International Journal of Halal Research, 3(1), 8-23.
Camps, J., Marsillach, J., & Joven, J. (2009). Measurement of serum paraoxonase-1 activity in the evaluation of liver function. World Journal of Gastroenterology, 15(16),1929‒33..
Furlong, C.E., Marsillach, J., Jarvik, G.P., & Costa, L.G. (2016). Paraoxonases-1, -2 and -3: what are their functions? Chemico-Biological Interactions, 259(Pt B), 51–62.
Abdel-Salam, O.M.E., El-Shamarka, M.E-S., Shaffee, N., & Gaafar, A.E-D.M. (2014b). Study of the effect of Cannabis sativa on liver and brain damage caused by thioacetamide. Comparative Clinical Pathology, 23 (3), 495-507.
De Carvalho, M.A., Popov, S.S., Safonova, O.A., Makeeva, A.V., Matasova, L.V., Pashkov, A.N., & Popova, T.N. (2010). The effects of some substances-protectors on free-radical homeostasis in diseases associated with oxidative stress. In “Handbook of Free Radicals Formation, Types and Effects”. (Kozyrev D, & Slutsky V, eds.), Nova Science Publishers, pp. 291-303.
Kristinova, V., Aaneby, J., Mozuraityte, R., Storrø, I., & Rustad, T. (2014). The effect of dietary antioxidants on iron‐mediated lipid peroxidation in marine emulsions studied by measurement of dissolved oxygen consumption. European Journal of Lipid Science and Technology, 116, 857–871.
Tungsanga, K., Sriboonlue, P., Futrakul, P., Yachantha, C., & Tosukhowong, P. (2005). Renal tubular cell damage and oxidative stress in renal stone patients and the effect of potassium citrate treatment. Urological Research 33, 65-69.
Moncada, S., & Bolanos, J.P. (2006). Nitric oxide, cell bioenergetics and neurodegeneration. Journal of Neurochemistry, 97(6), 1676–89.
Forstermann, U., & Sessa, W.C. (2012). Nitric oxide synthases: regulation and function. European Heart Journal, 33(7), 829–37, 37a–37d.
Gritters, M., Grooteman, M.P., Schoorl, M., Schoorl, M., Bartels, P.C., Scheffer, P.G., et al. (2006). Citrate anticoagulation abolishes degranulation of polymorphonuclear cells and platelets and reduces oxidative stress during haemodialysis. Nephrology Dialysis Transplantation, 21(1), 153-159.
Ying, W., Chen, Y., Alano, C.C., & Swanson, R.A. (2002). Tricarboxylic acid cycle substrates prevent PARP-mediated death of neurons and astrocytes. Journal of Cerebral Blood Flow & Metabolism, 22(7), 774–779.
Izumi, Y., & Zorumski, C.F. (2010). Neuroprotective effects of pyruvate following NMDA-mediated excitotoxic insults in hippocampal slices. Neuroscience Letters, 478(3),131–135.
Puntel, R.L., Nogueira, C.W., & Rocha, J.B.T. (2005). Krebs cycle intermediates modulate thiobarbituric acid reactive species (TBARS) production in rat brain in vitro. Neurochemical Research, 30(2),225-235.
Haces, M.L., Hernandez-Fonseca, K., Medina-Campos, O.N., Montiel, T., Pedraza-Chaverri, J., & Massieu, L. (2008). Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions. Experimenal Neurology, 211(1),85–96.
Vascotto, C., & Tiribelli, C. (2015). Oxidative stress, antioxidant defenses, and the liver. In: Studies on Hepatic Disorders, Oxidative Stress in Applied Basic Research and Clinical Practice, (Albano E, Parola M, eds.), Springer International Publishing, Switzerland, pp. 41-64.
Gutteridge, J.M.C., & Halliwell, B. (1999). Antioxidant Protection and Oxygen Radical Signaling. In: Reactive Oxygen Species in Biological Systems (Gilbert and Colton, eds.), Kluwer Academic / Plenum Publishers, New York, pp. 189-218.
Halliwell, B. (2001). Role of free radicals in the neurodegenerative diseases: therapeutic implications for antioxidant treatment. Drugs & Aging, 18(9), 685‒716.
Sies, H. (1997). Oxidative stress: oxidants and antioxidants. Experimental Physiology, 82(2), 291–295.
Halliwell, B. (2006). Oxidative stress and neurodegeneration: where are we now? Journal of Neurochemistry, 97, 1634–1658.
Valko, M., Leibfritz, D., Moncola, J., Cronin, M.T.D., Mazura, M., & Telser, J. (2007). Free radicals and antioxidants in normal physiological functions and human disease. The International Journal of Biochemistry & Cell Biology, 39, 44–84.
Hoyt ,H.L., & Gewanter, H.L. (1992). Citrate. In: The Handbook of Environmenlal Chemistry,Vol. 3 Part F, (Hulzinger, O., ed.), Springer-Verlag-Berlin Heidelberg, pp.229- 241.
Fegan, J., Khan, R., Poindexter, J., & Pak, C.Y. (1992). Gastrointestinal citrate absorption in nephrolithiasis. Journal of Urology, 147, 1212-1214.
Abdel-Salam, O.M.E., Shaffie, N.M., Omara, E.A., & Yassen, N.N. (2018). Citric Acid an Antioxidant in Liver. The Liver: Oxidative Stress and Dietary Antioxidants (Patel, V., ed.), Chennai, India, Academic Press, pp. 183-198.
Bashir, S., Khan, N.A., & Gilani, A-H. (2012). Physiology of renal handling of citrate. In “Urolithiasis” (Talati, J.J. Tiselius H-G, Albala D.M., & Ye Z., eds.), Springer-Verlag, London, pp.183-185. .
Hess, B. (2011). Urinary citrate and citrate metabolism. In: Urinary Tract Stone Disease (Rao et al. eds.), Springer-Verlag London Limited, pp.181-184.
Unwin, R.J., Capasso, G., & Shirley, D.G. (2004). An overview of divalent cation and citrate handling by the kidney. Nephron, 98,15-20.
Fromm, H.J. & Hargrove, M.S. (2012). The tricarboxylic acid cycle. In: Essentials of Biochemistry (Fromm, H.J. & Hargrove, M.S., eds). Springer-Verlag, Berlin, Heidelberg, pp. 205–21.
Wallace, M.C., Hamesch, K., Lunova, M., Kim, Y., Weiskirchen, R., Strnad, P., & Friedman, S.L. (2015). Standard operating procedures in experimental liver research: thioacetamide model in mice and rats. Laboratory Animals, 49(S1), 21–29.
Nair, V., & Turner, G.A. (1984). The thiobarbituric acid test for lipid peroxidation: structure of the adduct with malondialdehyde. Lipids, 19,804–805.
Archer, S. (1993). Measurement of nitric oxide in biological models. The FASEB Journal, 7(2), 349–60.
Ellman, G.L. (1959). Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics, 82, 70–77.
Haagen, L., & Brock, A. (1992). A new automated method for phenotyping arylesterase (EC 3.1.1.2) based upon inhibition of enzymatic hydrolysis of 4-nitrophenyl acetate by phenyl acetate. European Journal of Clinical Chemistry and Clinical Biochemistry, 30,391–395..
Crowley, L.V. (1967). The Reitman-Frankel colorimetric transaminase procedure in suspected myocardial infarction. Clinical Chemistry, 13, 482-487.
Abdel-Salam, O.M.E., Mohammed, N.A., Sleem, A.A., Farrag, A.R. (2013). The effect of antidepressant drugs on thioacetamide-induced oxidative stress. European Review for Medical and Pharmacological Sciences, 17, 735-744.
De David, C., Rodrigues, G., Bona, S., Meurer, L., González-Gallego, J., Tuñón, M.J., & Marroni, N.P. (2011). Role of quercetin in preventing thioacetamide-induced liver injury in rats. Toxicologic Pathology, 39(6), 949-57.
Chen, T.M., Subeq,Y.M., Lee, R.P., Chiou, T.W., & Hs, B.G. (2008). Single dose intravenous thioacetamide administration as a model of acute liver damage in rats. International Journal of Experimental Pathology, 89, 223–231.
Abdel-Salam, O.M.E.,Youness, E.R., Sleem, A.A., & Morsy, F.A. (2022). Citric acid administration protects against insulin-induced hypoglycemic brain and liver injury. WSEAS TRANSACTIONS on BIOLOGY and BIOMEDICINE, 19, 31-40.
Abdel-Salam, O.M., Youness, E.R., Mohammed, N.A., Morsy, S.M., Omara, E.A., & Sleem, A.A. (2014a). Citric acid effects on brain and liver oxidative stress in lipopolysaccharide-treated mice. Journal of Medicinal Food, 17(5), 588–98.
Abdel-Salam, O.M., Youness, E.R., Mohammed, N.A., Yassen, N.N., Khadrawy, Y.A., El-Toukhy, S.E., et al. (2016). Novel neuroprotective and hepatoprotective effects of citric acid in acute malathion intoxication. Asian Pacific Journal of Tropical Medicine, 9(12), 1181–94.
Abdel-Salam, O.M.E., Morsy, S.M.Y., Youness, E.R., Yassen, N.N., Shaffie, N., & Sleem, A.A. (2020a). Citric acid protects dopaminergic cells against rotenone-induced neurodegeneration. Reactive Oxygen Species 9(27), 118–135.
Abdel-Salam, O.M.E., Sleem, A.A., Morsy, F.A. (2020b). Citric acid protects against toluene-induced brain neurodegeneration and liver damage in rats. Journal of Basic Pharmacology and Toxicology,4(2), 38-48..
La Du, B.N. (1992). Human Serum Paraoxonase: Arylesterase. Pergamon Press, New York, NY, USA.
Watson, A.D., Berliner, J.A., Hama, S.Y., La Du, B.N., Faull, K.F., Fogelman, A.M., et al. (1995). Protective effect of high density lipoprotein associated paraoxonase: inhibition of the biological activity of minimally oxidized low density lipoprotein. Journal of Clinical Investigation, 96(6), 2882‒91.
Ferre, N., Camps, J., Prats, E., Vilella, E., Paul, A., Figuera, L., & Joven, J. (2002). Serum paraoxonase activity: a new additional test for the improved evaluation of chronic liver damage. Clinical Chemistry, 48, 261–268.
Baskol, M., Baskol, G., Deniz, K., Ozbakir, O., & Yucesoy, M. (2005). A new marker for lipid peroxidation: serum paraoxonase activity in non-alcoholic steatohepatitis. Turkish Journal of Gastroenterology, 16(3), 119‒123.
Abdel-Salam, O.M.E., El-Shamarka, M.E-S., Hassan, N.S., & Abouelfadl, D.M. (2021). Effect of piracetam on brain oxidative stress and tissue damage following toluene exposure in rats. International Journal of Halal Research, 3(1), 8-23.
Camps, J., Marsillach, J., & Joven, J. (2009). Measurement of serum paraoxonase-1 activity in the evaluation of liver function. World Journal of Gastroenterology, 15(16),1929‒33..
Furlong, C.E., Marsillach, J., Jarvik, G.P., & Costa, L.G. (2016). Paraoxonases-1, -2 and -3: what are their functions? Chemico-Biological Interactions, 259(Pt B), 51–62.
Abdel-Salam, O.M.E., El-Shamarka, M.E-S., Shaffee, N., & Gaafar, A.E-D.M. (2014b). Study of the effect of Cannabis sativa on liver and brain damage caused by thioacetamide. Comparative Clinical Pathology, 23 (3), 495-507.
De Carvalho, M.A., Popov, S.S., Safonova, O.A., Makeeva, A.V., Matasova, L.V., Pashkov, A.N., & Popova, T.N. (2010). The effects of some substances-protectors on free-radical homeostasis in diseases associated with oxidative stress. In “Handbook of Free Radicals Formation, Types and Effects”. (Kozyrev D, & Slutsky V, eds.), Nova Science Publishers, pp. 291-303.
Kristinova, V., Aaneby, J., Mozuraityte, R., Storrø, I., & Rustad, T. (2014). The effect of dietary antioxidants on iron‐mediated lipid peroxidation in marine emulsions studied by measurement of dissolved oxygen consumption. European Journal of Lipid Science and Technology, 116, 857–871.
Tungsanga, K., Sriboonlue, P., Futrakul, P., Yachantha, C., & Tosukhowong, P. (2005). Renal tubular cell damage and oxidative stress in renal stone patients and the effect of potassium citrate treatment. Urological Research 33, 65-69.
Moncada, S., & Bolanos, J.P. (2006). Nitric oxide, cell bioenergetics and neurodegeneration. Journal of Neurochemistry, 97(6), 1676–89.
Forstermann, U., & Sessa, W.C. (2012). Nitric oxide synthases: regulation and function. European Heart Journal, 33(7), 829–37, 37a–37d.
Gritters, M., Grooteman, M.P., Schoorl, M., Schoorl, M., Bartels, P.C., Scheffer, P.G., et al. (2006). Citrate anticoagulation abolishes degranulation of polymorphonuclear cells and platelets and reduces oxidative stress during haemodialysis. Nephrology Dialysis Transplantation, 21(1), 153-159.
Ying, W., Chen, Y., Alano, C.C., & Swanson, R.A. (2002). Tricarboxylic acid cycle substrates prevent PARP-mediated death of neurons and astrocytes. Journal of Cerebral Blood Flow & Metabolism, 22(7), 774–779.
Izumi, Y., & Zorumski, C.F. (2010). Neuroprotective effects of pyruvate following NMDA-mediated excitotoxic insults in hippocampal slices. Neuroscience Letters, 478(3),131–135.
Puntel, R.L., Nogueira, C.W., & Rocha, J.B.T. (2005). Krebs cycle intermediates modulate thiobarbituric acid reactive species (TBARS) production in rat brain in vitro. Neurochemical Research, 30(2),225-235.
Haces, M.L., Hernandez-Fonseca, K., Medina-Campos, O.N., Montiel, T., Pedraza-Chaverri, J., & Massieu, L. (2008). Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions. Experimenal Neurology, 211(1),85–96.