Melatonin-lycopene combination improves methotrexate-induced liver toxicity in rats via anti-inflammatory effect

Ratlarda, melatonin-likopen kombinasyonu antiinflamatuvar etki ile metotraksat ilişkili toksisiteyi iyileştirebilir


Abstract views: 170 / PDF downloads: 44

Authors

  • Hatice Sezen Department of Clinical Biochemistry, Faculty of Medicine, Harran University, Sanliurfa
  • Yusuf Yücel Department of General Surgery, Faculty of Medicine, Harran University, Sanliurfa
  • Sezen Koçarslan Department of Pathology, Faculty of Medicine, Harran University, Sanliurfa
  • Emin Savik Department of Clinical Biochemistry, Faculty of Medicine, Harran University, Sanliurfa
  • Hasan Bilinç Department of Clinical Biochemistry, Faculty of Medicine, Harran University, Sanliurfa
  • Nurten Aksoy Department of Clinical Biochemistry, Faculty of Medicine, Harran University, Sanliurfa

DOI:

https://doi.org/10.5152/EurJTher.2016.004

Keywords:

Methotrexate-induced hepatotoxicity, melatonin, lycopene, oxidative stress, inflammation

Abstract

Introduction: This study aimed to investigate the effect of melatonin (MLT)-lycopene (LYC) combination on methotrexate-induced hepatotoxicity (MIT).
Materials and Methods: Twenty-seven Sprague-Dawley adult male rats were divided into 3 equal groups: Group I= control group, fed with oral corn oil; Group II, a single dose of methotrexate (MTX) was injected into the rats and they were fed with oral corn oil; Group III, rats were treated with a melatonin-lycopene combination for 5 days after a single dose of MTX intraperitoneal. Serum aspartate and alanine aminotransferase activities were measured as hepatic function tests. The supernatant fraction of the liver tissue homogenate was used to measure the levels of total antioxidant capacity (TAC) and total oxidant status (TOS) in order to assess the presence of oxidative stress, tumour necrosis factoralpha, and interleukin 1beta, which in turn indicate the presence of inflammation. Five sections from each rat liver tissue were prepared for histopathological examination and stained with hemotoxileosin. Then the specimens were examined under a light microscope and was evaluated semi-quantitatively.
Results: This study showed that serum aspartate aminotransferase and tissue proinflammatory cytokines such as tumour necrosis factoralpha and interleukin 1beta increased with MTX use and decreased significantly when using a combination of MLT-LYC, but oxidative stress parameters such as TOS and OSI did not change in MIT.
Conclusion: The LYC-MLT combination improved the acute toxic effects of MTX on the liver. It improved both liver function and the histopathology level. However, these effects seem to be associated with the anti-inflammatory effect than the reduction of oxidative stress.

Metrics

Metrics Loading ...

References

LoVecchio F, Katz K, Watts D, Wood I. Four-year experience with methotrexate exposures. J Med Toxicol 2008;4(3):149-50.

Kose E, Sapmaz HI, Sarihan E, Vardi N, Turkoz Y, Ekinci N. Beneficial effects of montelukast against methotrexate-induced liver toxicity: a biochemical and histological study. Scientific World Journal 2012;1-6.

Zimecki M, Artym J. Effect of methotrexate on the immune response in selected experimental models. Postepy Hig Med Dosw (Online) 2004;58:226-35.

Cronstein BN. Molecular mechanism of methotrexate action in inflammation. Inflammation 1992;16(5):411-23.

Ghaffari AR, Noshad H, Ostadi A, Ghojazadeh M, Asadi P. The effects of milk thistle on hepatic fibrosis due to methotrexate in rat. Hepat Mon 2011;11(6):464-8.

Akbulut S, Elbe H, Eris C, Dogan Z, Toprak G, Otan E, et al. Cytoprotective effects of amifostine, ascorbic acid and N-acetylcysteine against methotrexate-induced hepatotoxicity in rats. World J Gastroenterol 2014;20(29):10158-65.

Pandit A, Sachdeva T, Bafna P. Drug-Induced Hepatotoxicity: A Review. JAPS 2012;02(05):233-43.

Bath RK, Brar NK, Forouhar FA, Wu GY. A review of methotrexateassociated hepatotoxicity. J Dig Dis 2014;15(10):517-24.

Olsen NJ, Spurlock CF 3rd, Aune TM. Methotrexate induces production of IL-1 and IL-6 in the monocytic cell line U937. Arthritis Res Ther 2014;16(1):17.

Tamilselvi E, Haripriya D, Hemamalini M, Pushpa G, Swapna S. Association of disease severity with IL-1 levels in methotrexatetreated psoriasis patients. Scand J Immunol 2013;78(6):545-53.

Coleshowers CL, Oguntibeju OO, Ukpong M, Truter EJ. Effects of methotrexate on antioxidant enzyme status in a rodent model. Medical Technology SA 2010;24(1):5-9.

Hadi NR, Al-Amran FG, Swadi A. Metformin ameliorates methotrexateinduced hepatotoxicity. J Pharmacol Pharmacother 2012;3(3):248-53.

Bayramoglu G, Bayramoglu A, Altuner Y, Uyanoglu M, Colak S. The effects of lycopene on hepatic ischemia/reperfusion injury in rats. Cytotechnology 2015;67(3):487-91.

Hyeyoung K. Inhibitory mechanism of lycopene on cytokine expression in experimental pancreatitis. Ann Acad NY. Sci 2011:1229(1):99-102.

Darwish SF, El-Bakly WM, Arafa HM, El-Demerdash E. Targeting TNF-α and NF-κB activation by bee venom: role in suppressing adjuvant induced arthritis and methotrexate hepatotoxicity in rats. PLoS One 2013;8(11):e79284.

Yonar ME. Protective effect of lycopene on oxidative stress and antioxidant status in Cyprinus carpio during cypermethrin exposure. Environ Toxicol 2013;28(11):609-16.

Igielska-Kalwat J, Goscianska J, Nowak I. Carotenoids as natural antioxidants. Postepy Hig Med Dosw (Online) 2015;69:418-28.

Marcotorchino J, Romier B, Gouranton E, Riollet C, Gleize B, Desmoulins CM, at al. Lycopene attenuates LPS-induced TNF-α secretion in macrophages and inflammatory markers in adipocytes exposed to macrophage-conditioned media. Molecular Nutrition & Food Research 2012;56(5):725-32.

Biddle M, Moser D, Song EK, Heo S, Payne-Emerson H, Dunbar SB, et al. Higher dietary lycopene intake is associated with longer cardiac event-free survival in patients with heart failure. Eur J Cardiovasc Nurs 2013;12(4):377-84.

Popov SS, Shulgin KK, Popova TN, Pashkov AN, Agarkov AA, de Carvalho MA. Effects of Melatonin-Aided Therapy on the Glutathione Antioxidant System Activity and Liver Protection. J Biochem Mol Toxicol 2015. doi: 10.1002/jbt.21705.

Kolli VK, Abraham P, Isaac B, Kasthuri N. Preclinical efficacy of melatonin to reduce methotrexate-induced oxidative stress and small intestinal damage in rats. Dig Dis Sci 2013;58(4):959-69.

Kurus M, Esrefoglu M, Sogutlu G, Atasever A. Melatonin prevents cyclosporine-induced hepatotoxicity in rats. Med Princ Pract 2009;18(5):407-10.

Chen J, Chen G, Li J, Qian C, Mo H, Gu C, et al. Melatonin attenuates inflammatory response-induced brain edema in early brain injury following a subarachnoid hemorrhage: a possible role for the regulation of pro-inflammatory cytokines. J Pineal Res 2014;57(3):340-7.

Oguz E, Kocarslan S, Tabur S, Sezen H, Yilmaz Z, Aksoy N. Effects of Lycopene Alone or Combined with Melatonin on MethotrexateInduced Nephrotoxicity in Rats. Asian Pac J Cancer Prev 2015;16(14):6061-6.

Yucel Y, Tabur S, Gozeneli O, Kocarslan S, Seker A, Buyukaslan H, et al. The effects of lycopene on intestinal injury due to methotrexate in rats. Redox Rep 2016;21(3):113-8.

Jahovic N, Cevik H, Sehirli AO, Yeğen BC, Sener G. Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats. J Pineal Res 2003;34(4):282-7.

Beştaş A, Kahramanoglu M, Erhan OL, Bolat E, Ozercan I, Gürsu F, et al. The role of the antioxidants lycopene and vitamin E in the prevention of halothane-induced hepatotoxicity. Methods Find Exp Clin Pharmacol 2008;30(8):627-31.

Erel O. A novel automated direct measurement method for total antioxidant capacity using a new generation, more stable ABTS radical cation. Clin Biochem 2004;37:277-85.

Erel O. A new automated colorimetric method for measuring total oxidant status. Clin Biochem 2005;38:1103-11.

Rabus M, Demirbağ R, Sezen Y, Konukoğlu O, Yildiz A, Erel O, et al. Plasma and tissue oxidative stress index in patients with rheumatic and degenerative heart valve disease. Turk Kardiyol Dern Ars 2008;36(8):536-40.

Kim JC, Kim KH, Chung MK. Testicular cytotoxicity of DA-125, a new anthracycline anticancer agent, in rats. Reprod Toxicol 1999;13(5):391-7.

Magami Y, Azuma T, Inokuchi H, Kokuno S, Moriyasu F, Kawai K, et al. Cell proliferation and renewal of normal hepatocytes and bile duct cells in adult mouse liver. Liver 2002;22(5):419-25.

Sener G, Ekşioğlu-Demiralp E, Cetiner M, Ercan F, Yeğen BC. Betaglucan ameliorates methotrexate-induced oxidative organ injury via its antioxidant and immunomodulatory effects. Eur J Pharmacol 2006;542(1-3):170-8.

Uraz S, Tahan V, Aygun C, Eren F, Unluguzel G, Yuksel M, et al. Role of ursodeoxycholic acid in prevention of ethotrexate-induced liver toxicity. Dig Dis Sci 2008;53(4):1071-7.

Vardi N, Parlakpinar H, Cetin A, Erdogan A, Cetin Ozturk I. Protective effect of beta-carotene on methotrexate-induced oxidative liver damage. Toxicol Pathol 2010;38:592-7.

Dalaklioglu S, Genc GE, Aksoy NH, Akcit F, Gumuslu S. Resveratrol ameliorates methotrexate-induced hepatotoxicity in rats via inhibition of lipid peroxidation. Hum Exp Toxicol 2013;32:662-71.

Giannoulia-Karantana A, Vlachou A, Polychronopoulou S, Papassotiriou I, Chrousos GP. Melatonin and immunomodulation: connections and potential clinical applications. Neuroimmunomodulation 2006;13(3): 133-44.

Sewerynek E, Melchiorri D, Reiter RJ, Ortiz GG, Lewinski A. Lipopolysaccharide-induced hepatotoxicity is inhibited by the antioxidant melatonin. Eur J Pharmacol 1995;293(4):327-34.

Zavodnik LB, Zavodnik IB, Lapshina EA, Belonovskaya EB, Martinchik DI, Kravchuk RI, et al. Protective effects of melatonin against carbon tetrachloride hepatotoxicity in rats. Cell Biochem Funct 2005;23(5):353-9.

Rezzani R, Buffoli B, Rodella L, Stacchiotti A, Bianchi R. Protective role of melatonin in cyclosporine A-induced oxidative stress in rat liver. Int Immunopharmacol 2005;5(9):1397-405.

Túnez I, Muñoz MC, Medina FJ, Salcedo M, Feijóo M, Montilla P. Comparison of melatonin, vitamin E and L-carnitine in the treatment of neuro- and hepatotoxicity induced by thioacetamide. Cell Biochem Funct 2007;25(2):119-27.

Tai SH, Chen HY, Lee EJ, Chen TY, Lin HW, Hung YC, et al. Melatonin inhibits postischemic matrix metalloproteinase-9 (MMP9) activation via dual modulation of plasminogen/plasmin system and endogenous MMP inhibitor in mice subjected to transient focal cerebral ischemia. J Pineal Res 2010;49(4):332-41.

Swarnakar S, Paul S, Singh LP, Reiter RJ. Matrix metalloproteinases in health and disease: regulation by melatonin. J Pineal Res 2011;50(1):8-20.

Qin W, Lu W, Li H, Yuan X, Li B, Zhang Q, et al. Melatonin inhibits IL1β-induced MMP9 expression and activity in human umbilical vein endothelial cells by suppressing NF-κB activation. J Endocrinol 2012;214(2):145-53.

Bhuvaneswari V, Nagini S. Lycopene: a review of its potential as an anticancer agent. Curr Med Chem Anticancer Agents 2005;5(6):627-35.

Anusha M, Venkateswarlu M, Prabhakaran V, Taj SS, Kumari BP, Ranganayakulu D. Hepatoprotective activity of aqueous extract of Portulaca oleracea in combination with lycopene in rats. Indian J Pharmacol 2011;43(5):563-7.

Jamshidzadeh A, Baghban M, Azarpira N, Mohammadi Bardbori A, Niknahad H. Effects of tomato extract on oxidative stress induced toxicity in different organs of rats. Food Chem Toxicol 2008;46(12):3612-5.

Downloads

Published

2023-05-10

How to Cite

Sezen, H., Yücel, Y., Koçarslan, S., Savik, E., Bilinç, H., & Aksoy, N. (2023). Melatonin-lycopene combination improves methotrexate-induced liver toxicity in rats via anti-inflammatory effect: Ratlarda, melatonin-likopen kombinasyonu antiinflamatuvar etki ile metotraksat ilişkili toksisiteyi iyileştirebilir. European Journal of Therapeutics, 22(3), 129–135. https://doi.org/10.5152/EurJTher.2016.004

Issue

Section

Original Articles