Hepatoprotective Activity of Melatonin against Aluminium-Induced Toxicity and Oxidative Damage

Year 2020, Volume: 13 Issue: 1, 25 - 34, 27.07.2020

Sevim Tunalı , Ömür Karabulut Bulan , Güner Sarıkaya , Refiye Yanardağ

Abstract

Aluminium (Al) is a nonessential metal that exists widely throughout the environment, and acute and chronic diseases are associated to it increased biological availability. Melatonin (Mel) has been shown to be an effective antioxidant with antitumor, anti-inflammatory, anti-excitatory, immunomodulatory, neuroprotective and vasomotor effects. The aim of the present study was to examine the effect of Al exposure on liver tissue, and the potential protective effects of Mel on the Al exposed liver tissue. Wistar albino rats utilised were grouped as follows; Group I: control group given normal saline intraperitoneally, group II: Mel control (injected 2% ethanol in normal saline subcutaneously), group III: rats injected 10 mg/kg Mel subcutaneously, group IV: rats administered 5 mg/kg Al2(SO4)3 intraperitoneally, group V: rats concurrently injected both Al2(SO4)3 and Mel. In the Al group, lipid peroxidation and protein carbonyl levels, myeloperoxidase, lactate dehydrogenase, thromboplastic activities, glucose-6-phosphate dehydrogenase activities increased, while liver glutathione level, superoxide dismutase, glutathione peroxidase and glutathione-S-transferase activities decreased. From histological analysis, the control rat tissues exhibited normal histological appearances. In the group given solely Al, degenerative changes such as picnotic nuclei, lymphoid infiltrate, hyperemia, necrotic areas, vacuolization and sinusoidal dilatations were observed. These effects were reversed upon Mel administration. These findings indicate that Mel is a likely useful agent against hepatotoxicity in Al induced liver damage.

Keywords

Aluminium, melatonin, liver, toxicity, histopathology

References

• 1. Esparza JL, Gómez M, Domingo JL: Role of melatonin in aluminum-related neurodegenerative disorders: a review. Biol Trace Elem Res, 188: 60-67, 2019. DOI: 10.1007/s12011-018-1372-4.
• 2. Schetinger MRC, Bonan CD, Morsch VM, Bohrer D, Valentim LM, Rodrigues SR: Effects of aluminum sulfate on delta–aminolevulinate dehydratase from kidney, brain, and liver of adult mice. Braz J Med Biol Res, 32: 761-766, 1999. DOI: doi.org/10.1590/S0100-879X1999000600012.
• 3. Sun X, Cao Z, Zhang Q, Liu S, Xu F, Che J, Zhu Y, Li Y, Pan C, Liang W: Aluminum trichloride impairs bone and downregulates Wnt/β-cateninsignaling pathway in young growing rats. Food Chem Toxicol, 86: 154-162, 2015. DOI: 10.1016/j.fct.2015.10.005.
• 4. Yu H, Zhang J, Ji Q, Yu K, Wang P, Song M, Cao Z, Zhang X, Li Y: Melatonin alleviates aluminium chloride-induced immunotoxicity by inhibiting oxidative stress and apoptosis associated with the activation of Nrf2 signaling pathway. Ecotoxicol Environ Saf, 173: 131-141, 2019. DOI: 0.1016/j.ecoenv.2019.01.095.
• 5. González MA, Bernal CA, Mahieu S, Stella M, Carrillo M: The interactions between the chronic exposure to Aluminum and liver regeneration on bile flow and organic anion transport in rats. Biol Trace Elem Res, 127: 164-76, 2009. DOI: 10.1007/s12011-008-8234-4.
• 6. Karabulut-Bulan O, Bayrak BB, Arda-Pirincci P, Sarikaya-Unal G, Us H, Yanardag R: Role of exogenous melatonin on cell proliferation and oxidant/antioxidant system in aluminum-ınduced renal toxicity. Biol Trace Elem Res, 168: 141-9, 2015. DOI: 10.1007/s12011-015-0320-9.
• 7. Reiter RJ: Melatonin: lowering the high price of free radicals. News Physiol Sci, 15: 246-250, 2000. DOI: 10.1152/physiologyonline.2000.15.5.246.
• 8. Reiter RJ, Maestroni GJ: Melatonin in relation to the antioxidative defense and immune systems: possible implications for cell and organ transplantation. J Mol Med (Berl), 77: 36-9, 1999. DOI: 10.1007/s001090050297.
• 9. Reiter RJ, Tan DX, Manchester LC, Lopez-Burillo S, Sainz RM, Mayo JC: Melatonin: detoxification of oxygen and nitrogen-based toxic reactants. Adv Exp Med Biol, 527: 539-48, 2003 DOI: 10.1007/978-1-4615-0135-0_62.
• 10. Farias JG, Zepeda AB, Calaf GM: Melatonin protects the heart, lungs and kidneys from oxidative stress under intermittent hypobaric hypoxia in rats. Biol Res, 45: 81-85, 2012. DOI: 10.4067/S0716-97602012000100011.
• 11. Esparza JL, Gomez M, Romeu M, Mulero M, Sanchez DJ, Mallol J, Domingo JL: Aluminum-induced pro-oxidant effects in rats: protective role of exogenous melatonin. J Pineal Res, 35: 32-39, 2003. DOI: 10.1034/j.1600-079X.2003.00048.x.
• 12. Salido EM, Bordone M, De Laurentiis A, Chianelli M, Keller Sermiento MI, Dorfman D, Rosenstein RE: Therapeutic efficacy of melatonin in reducing retinal damage in an experimental model of early type 2 diabetes in rats. J Pineal Res, 54: 179-189, 2013. DOI: 10.1111/jpi.12008.
• 13. Beutler E: Glutathione in red cell metabolism: a manual of biochemical methods. 2nd ed. New York: Grune and Stratton, pp. 112-114, 1975.
• 14. Ledwozyw A, Michalak J, Stepien A, Kadziolka A: The relationship between plasma triglycerides, cholesterol, total lipids and lipid peroxidation products during human atherosclerosis. Clin Chim Acta, 155: 275–84, 1986. DOI: 10.1016/0009-8981(86)90247-0.
• 15. Levine RL, Garland D, Oliver CN, Amici A, Climent I, Lenz AG, Ahn BW, Shaltiel S, Stadtman ER: Determination of carbonyl content in oxidatively modified proteins. Methods Enzymol, 186: 464-478, 1990. DOI:10.1016/0076-6879(90)86141-h.
• 16. Wei H, Frenkel K: In vivo formation of oxidized DNA bases in tumor promoter treated mouse skin. Cancer Res, 51: 4443-4449, 1991.
• 17. Wroblewski F: Clinical significance of serum enzyme alterations with myocardial infarction. Am Heart J, 54: 219-224, 1957.
• 18. Ingram GIC, Hills M: Reference method for the one stage prothrombin time test on human blood. Thromb Hemoestas, 36: 237-238, 1976.
• 19. Pagla DE, Valentine WN: Studies on the quantitative and qualitative characterization of erythrocyte glutathione peroxidase. J Lab Clin Med, 70: 158-169, 1967.
• 20. Wendel A: Glutathione peroxidase. Methods Enzymol, 77: 325-333, 1981. DOI: 0.1016/S0076-6879(81)77046-0.
• 21. Habig W, Jacoby WB: Assays for differentation of glutathione-S-transferases. Methods Enzymol, 77: 398-405, 1981. DOI: 10.1016/s0076-6879(81)77053-8.
• 22. Betke K, Brewer GJ, Krikman HN, Luzzatto L, Motulsky AC, Domingo GJ, Price RN: Standardized method for G-6-PD assay of haemolysates. WHO Tech Rep Ser, 366: 30-32, 1967.
• 23. Mylroie AA, Collins H, Umbles C, Kyle J: Erythrocyte superoxide dismutase activity and other parameters of copper status in rats ingesting lead acetate. Toxicol Appl Pharmacol, 82: 512-520, 1981. DOI: 10.1016/0041-008x(86)90286-3.
• 24. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ: Protein measurement with the folin phenol reagent. J Biol Chem, 193: 265-275, 1957.
• 25. Belaid Nouira Y, Bakhta H, Haouas Z, Flehi-Slim I, Neffati F, Najjar MF, Cheikh HB: Fenugreek seeds, a hepatoprotector forage crop against chronic AlCl3 toxicity. BMC Vet Res, 9: 22, 2013. DOI: 10.1186/1746-6148-9-22.
• 26. Spencer AJ, Wood JA, Saunders HC, Freeman SL, Lote CJ: Aluminium deposition in liver and kidney following acute intravenous administration of aluminium chloride or citrate in conscious rats. Hum Exp Toxicol, 14: 787-794, 1995. DOI: 10.1177/096032719501401002.
• 27. Exley C: The pro-oxidant activity of aluminum. Free Radical Bio Med, 36:380-7, 2004. DOI: 10.1016/j.freeradbiomed.2003.11.017.
• 28. Zatta P, Kiss T, Suwalsky M, Berthon M: Aluminium (III) as a promoter of cellular oxidation. Coord Chem Rev, 228: 271-284, 2002. DOI: 10.1016/S0010-8545(02)00074-7.
• 29. Bächli E: History of tissue factor. Br J Haematol, 110: 248-55, 2000. DOI: 10.1046/j.1365-2141.2000.02055.x.
• 30. Ma P, Yan B, Zeng Q, Liu X, Wu Y, Jiao M, Liu C, Wu C, Yang X: Oral exposure of Kunming mice to diisononyl phthalate induces hepatic and renal tissue injury through the accumulation of ROS. Protective effect of melatonin. Food Chem Toxicol, 68: 247-56, 2014. DOI: 10.1016/j.fct.2014.03.027.
• 31. Yousef MI: Aluminium-induced changes in hemato-biochemical parameters, lipid peroxidation and enzyme activities of male rabbits: protective role of ascorbic acid. Toxicology 199: 47-57, 2004. DOI: 10.1016/j.tox.2004.02.014.
• 32. Bulan NÖ, Sarıkaya-Ünal G, Tunali S, Arda-Pirinççi P, Yanardağ R: Melatonin is a potent modulator of antioxidative defense and cellular proliferation against aluminum toxicity in rats. Turkısh J Biol, 39: 911-924, 2015. DOI: 10.3906/biy-1507-53.
• 33. Chevion M, Berenshtein E, Stadtman ER: Human studies related to protein oxidation: protein carbonyl content as a marker of damage. Free Radic Res, 33: s99-s108, 2000.
• 34. Kettle AJ, Winterbourn CC: Myeloperoxidase: a key regulator of neutrophil oxidant production. Redox Rep, 3: 3-15, 1997. DOI: 10.1080/13510002.1997.11747085.
• 35. Rajesh MG, Latha MS: Preliminary evaluation of the antihepatotoxic activity of Kamilari, a polyherbal formulation. J Ethnopharmacol, 91: 99-104, 2004. DOI: 10.1016/j.jep.2003.12.011.
• 36. Hammad MA, Abdel-Bakky MS, Walker LA, Ashfag MG: Tissue factor antisense deoxyoligonucleotide prevents monocrotaline/LPS hepatotoxicity in mice. J Appl Toxicol, 33: 774-83, 2013. DOI: 10.1002/jat.2728.
• 37. Hacihasanoglu Cakmak N, Yanardağ R: Edaravone, a free radical scavenger, protects liver against valproic acid ınduced toxicity. J Serb Chem Soc, 80: 627-637, 2015. DOI: 10.2298/JSC140812123C.
• 38. Martins RN, Harper CG, Stokes GB, Masters CL: Increased cerebral glucose-6-phosphate dehydrogenase activity in Alzheimer's disease may reflect oxidative stress. J Neurochem, 46: 1042-1045, 1986. DOI: 10.1111/j.1471-4159.1986.tb00615.x.
• 39. Bogdanovic M, Janeva AB, Bulat P: Histopathological changes in rat liver after a single high dose of aluminium. Arh Hig Rada Toksikol, 59: 97-101, 2008. DOI: 10.2478/10004-1254-59-2008-1859.
• 40. Zhu Y, Han Y, Zhao H, Li J, Hu C, Li Y, Zhang Z: Suppressive effect of accumulated aluminum trichloride on the hepatic microsomal cytochrome P450 enzyme system in rats. Food ChemToxicol, 51: 210-214, 2013. DOI: 10.1016/j.fct.2012.09.035.
• 41. Sinska E, Kanoniuk D, Kusiak A: Aluminium hemotoxicity mechanisms. Ann Univ Mariae Curie Sklodowska, 59: 411-416, 2004.
• 42. Buraimoh AA, Ojo SA, Hambolu JO, Adebisi SS: Effects of aluminium chloride exposure on the histology of the liver of adult wistar rat. IOSR J Pharm, 3: 525-533, 2012.
• 43. Bhasin P, Singla N, Dhawan DK: Protective role of zinc during aluminum-induced hepatotoxicity. Environ Toxicol, 29: 320-327, 2014. DOI: 10.1002/tox.21760.
• 44. Kutlubay R, Oğuz EO, Abban G, Turgut S: Amelioration of aluminium-induced liver damage by vitamin E Saudi Med J, 28: 197-200, 2007.
• 45. Li JY, Yin HZ, Gu X, Zhou Y, Zhang WH, Qin YM: Melatonin protects liver from intestine ischemia reperfusion injury in rats. World J Gastroenterol, 14: 7392-7396, 2008. DOI: https://dx.doi.org/10.3748/wjg.14.7392.
• 46. Contini MD, Millen N, Gonzalez M, Mahieu S: Melatonin prevents oxidative stress in ovariectomized rats treated with aluminium. Biol Trace Elem Res, 144: 924-943, 2011. DOI: 10.1007/s12011-011-9060-7.