Alleviation of Cisplatin-Induced Hepatotoxic Damage: the Synergistic Effect of Morin and Hesperidin against Oxidative Stress

Document Type : Original paper


1 Espiye Vocational School, Giresun University, 28600, Giresun, Turkey

2 Biology Department, Science Faculty, Gazi University, 06500, Ankara, Turkey


Background and objectives: A key aspect of cisplatin-induced hepatotoxicity is oxidative stress. The current study was conducted to show, for the first time, the restoring and synergistic effects of morin and hesperidin against oxidative stress in hepatotoxicity. Methods: Fourty-two Wistar albino rats were randomly divided into seven groups: group A (control), group B (morin), group C (hesperidin), group D (cisplatin), group E (cisplatin+morin), group F (cisplatin+hesperidin), group G (cisplatin+morin+hesperidin). Throughout ten consecutive days, morin and/or hesperidin were given to rats and cisplatin was injected as a single dose (7 mg/kg) on the 4th day, and then the rats were sacrificed on the 11th day. Liver tissue samples collected from the rats were used for the measurement of malondialdehyde, nitric oxide, glutathione levels as well as myeloperoxidase, catalase and superoxide dismutase activities. Results: Administration of cisplatin elevated the malondialdehyde and nitric oxide levels and also reduced the glutathione levels and catalase activity in the liver. However, in the morin and/or hesperidin groups, glutathione level and catalase activity were higher but malondialdehyde and nitric oxide levels and myeloperoxidase activity were lower than the cisplatin-induced group. Conclusion: Our results indicated that pretreatment with these flavonoids can be used as protective treatment for cisplatin-induced hepatotoxicity.


Main Subjects

[1] Gehdoo RP. Anticancer chemotherapy and it’s anaesthetic implications (Current Concepts). Indian J Anaesth. 2009; 53(1): 18-29.
[2] Kidera Y, Kawakami H, Sakiyama T, Okamoto K, Tanaka K, Takeda M, Kaneda H, Nishina S, Tsurutani J, Fujiwara K, Nomura M, Yamazoe Y, Chiba Y, Nishida S, Tamura T, Nakagawa K. Risk factors for cisplatin-induced nephrotoxicity and potential of magnesium supplementation for renal protection. PLoS One. 2014. Article ID e101902.
[3] Ruggiero A, Rizzo D, Trombatore G, Maurizi P, Riccardi R. The ability of mannitol to decrease cisplatin-induced nephrotoxicity in children: real or not?. Cancer Chemother Pharmacol. 2015; 77(1): 19-26.
[4] Yilmaz HR, Sogut S, Ozyurt B, Ozugurlu F, Sahin S, Isik B, Uz E, Ozyurt H. The activities of liver adenosine deaminase, xanthine oxidase, catalase, superoxide dismutase enzymes and the levels of malondialdehyde and nitric oxide after cisplatin toxicity in rats: protective effect of caffeic acid phenethyl ester. Toxicol Ind Health. 2005; 21(3-4): 67-73.
[5] Lu Y, Cederbaum AI. Cisplatin-induced hepatotoxicity is enhanced by elevated expression of cytochrome P450 2E1. Toxicol Sci. 2006; 89(2): 515-523.
[6] Al-Malki AL, Sayed AAR. Thymoquinone attenuates cisplatin-induced hepatotoxicity via nuclear factor kappa- β. BMC Complement Altern Med. 2014; Aricle ID 282.
[7] De Martinis BS, Bianchi MD. Effect of vitamin C supplementation against cisplatin-induced toxicity and oxidative DNA damage in rats. Pharmacol Res. 2001; 44(4): 317-320.
[8] Ibrahim MY, Abdul AB, Wahab SIA, Elhassan MM, Alzubairi AS, Syam MM. Attenuation of cisplatin induced hepatotoxicity in rats using zerumbone. Res J Biol Sci. 2009; 4(7): 777-784.
[9] Ahmad RM, Al-Jawary AH. Effect of vitamin C on the hepatotoxicity induced by cisplatin in rats. Raf J Sci. 2012; 23(2): 23-33.
[10] Bentli R, Parlakpinar H, Polat A, Samdanci E, Sarihan ME, Sagir M. Molsidomine prevents cisplatin-induced hepatotoxicity. Arch Med Res. 2013; 44(7): 521-528.
[11] Ibrahim NA, El-Seedi HR, Mohammed MMD. Phytochemical investigation and hepatoprotective activity of Cupressus sempervirens L. leaves growing in Egypt. Nat Prod Res. 2007; 21(10): 857-866.
[12] Madrigal-Santillán E, Madrigal-Bujaidar E, Álvarez-González I, Sumaya-Martínez MT, Gutiérrez-Salinas J, Bautista M, Morales-González A, García-Luna Y, González-Rubio M, Aguilar-Faisal JL, Morales-González JA. Review of natural products with hepatoprotective effects. World J Gastroenterol. 2014; 20(40): 14787-14804. 
[13] Yue M, Zeng N, Xia Y, Wei Z, Dai Y. Morin exerts anti-arthritic effects by attenuating synovial angiogenesis via activation of peroxisome proliferator activated receptor-gama. Mol Nutr Food Res. 2018; Article ID e1800202.
[14] Wu TW, Zeng LH, Wu J, Fung KP. Morin: a wood pigment that protects three types of human cells in the cardiovascular system against oxyradical damage. Biochem Pharmacol. 1994; 47(6): 1099-1103.
[15] Kok LDS, Wong YP, Wu TW, Chan HC, Kwok TT, Fung KP. Morin hydrate: a potential antioxidant in minimizing the free-radicals- mediated damage to cardiovascular cells by anti-tumor drugs. Life Sci. 2000; 67(1): 91-99.
[16] Zeng LH, Fung KP, Wu TW. Morin hydrate protects cultured rat glomerular mesangial cells against oxyradical damage. Life Sci. 1994; 55(18): 351-357.
[17] Sivaramakrishnan V, Shilpa PNM, Praveen Kumar VR, Niranjali Devaraj S. Attenuation of N-nitrosodiethylamine-induced hepatocellular carcinogenesis by a novel flavonol-Morin. Chem Biol Interact. 2008; 171(1): 79-88.
[18] Gottlieb M, Leal-Campanario R, Campos-Esparza MR, Sanchez-Gomez MV, Alberdi E, Arranz A, Delgado-García JM, Gruart A, Matute C. Neuroprotection by two polyphenols following excitotoxicity and experimental ischemia. Neurobiol Dis. 2006; 23(2): 374-386.
[19] Merwid-Lad A, Trocha M, Chlebda-Sieragowska E, Sozański T, Szandruk M, Magdalan J, Ksiadzyna D, Piesniewska M, Fereniec-Golebiewska L, Kwiatkowska J, Szelag A. The impact of morin, a natural flavonoid, on cyclophosphamide-induced changes in the oxidative stress parameters in rat livers. Adv Clin Exp Med. 2014; 23(4): 505-509.
[20] Devi KP, Rajavel T, Nabavi SF, Setzer WN, Ahmadi A, Mansouri K, Nabavi SM. Hesperidin: a promising anticancer agent from nature. Ind Crops Prod. 2015; 76: 582-589.
[21] Kim HK, Jeong TS, Lee MK, Park YB, Choi MS. Lipid-lowering efficacy of hesperetin metabolites in high-cholesterol fed rats. Clin Chim Acta. 2003; 327(1): 129-137.
[22] Yamamoto M, Suzuki A, Jokura H, Yamamoto N, Hase T. Glucosyl hesperidin prevents endothelial dysfunction and oxidative stress in spontaneously hypertensive rats. Nutrition. 2008; 24(5): 470-476.
[23] Omar HA, Mohamed WR, Arafa ESA, Shehata BA, El Sherbiny GA, Arab HH, Nasser A, Elgendy AM. Hesperidin alleviates cisplatin-induced hepatotoxicity in rats without inhibiting its antitumor activity. Pharmacol Reports. 2016; 68(2): 349-356.
[24] Tirkey N, Pilkhwal S, Kuhad A, Chopra K. Hesperidin, a citrus bioflavonoid, and decreases the oxidative stress produced by carbon tetrachloride in rat liver and kidney. BMC Pharmacol. 2005; Article ID 15683547.
[25] Lim SC, Im YB, Bae CS, Han SI, Kim SE, Han HK. Protective effect of morin on the imipenem-induced nephrotoxicity in rabbits. Arch Pharm Res. 2008; 31(8): 1060-1065.
[26] Sahu BD, Kuncha M, Sindhura GJ, Sistla R. Hesperidin attenuates cisplatin-induced acute renal injury by decreasing oxidative stress, inflammation and DNA damage. Phytomedicine. 2013; 20(5): 453-460.
[27] Éboli LP, Netto AA, Azevedo RA, Lanzoni VP, Paula TS, Goldenberg A, Gonzalez AM. Evaluating the best time to intervene acute liver failure in rat models induced by d-galactosamine. Acta Cirurgica Brasileira. 2016; 31(12): 783-792.
[28] Dindar B, Kaltalioglu K, Coskun-Cevher S. Effect of dual growth factor administration on oxidative markers during acute stage wound healing in rats. Turk J Zool. 2017; 41: 841-847.
[29] Casini AF, Ferrali M, Pompella A, Maellaro E, Comporti M. Lipid peroxidation and cellular damage in extrahepatic tissues of bromobenzene-intoxicated mice. Am J Pathol. 1986; 123(3): 520-531.
[30] Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide. 2001; 5(1): 62-71.
[31] Aykac G, Uysal M, Yalcin AS, Kocak-Toker N, Sivas A, Oz H. The effect of chronic ethanol ingestion on hepatic lipid peroxide, glutathione, glutathione peroxidase and glutathione transferase in rats. Toxicol. 1985; 36(1): 71-76.
[32] Schierwagen C, Bylund-Fellenius AC, Lundberg C. Improved method for quantification of tissue PMN accumulation measured by myeloperoxidase activity. J Pharmacol Methods. 1990; 2(3): 179-186.
[33] Aebi H. Catalase in vitro. Methods Enzymol. 1984; 105: 121-126.
[34] Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem. 1988; 34(3): 497-500.
[35] Siddique YH, Ara G, Afzal M. Estimation of lipid peroxidation induced by hydrogen peroxide in cultured human lymphocytes. Dose Response. 2012; 10(1): 1-10.
[36] Avci A, Çetin R, Ergüder IB, Devrim E, Kiliçoglu B, Çandir Ö, Ozturk HS, Durak I.Cisplatin causes oxidation in rat liver tissues: possible protective effects of antioxidant food supplementation. Turk J Med Sci. 2008; 38(2): 117-120.
[37] Yu YN, Chen H, Li Y. Effect of Bicyclol on cisplatin-induced hepatotoxicity in the hepatocarcinoma 22 tumour-bearing mice. Basic Clin Pharmacol Toxicol. 2009; 104(4): 300-305.
[38] Singh MP, Jakhar R, Kang SC. Morin hydrate attenuates the acrylamide-induced imbalance in antioxidant enzymes in a murine model. Int J Mol Med. 2015; 36(4): 992-1000.
[39] Kaltalioglu K, Coskun-Cevher S. Potential of morin and hesperidin in the prevention of cisplatin-induced nephrotoxicity. Ren Fail. 2016; 38(8): 1291-1299.
[40] Gardner CR, Heck DE, Yang CS, Thomas PE, Zhang XJ, DeGeorge GL, Laskin JD, Laskin DL. Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat. Hepatology. 1998; 27(3): 748-754.
[41] Carnovale CE, Ronco MT. Role of nitric oxide in liver regeneration. Ann Hepatol. 2012; 11(5): 6366-6447.
[42] Srivastava RC, Farookh A, Ahmad N, Misra M, Hasan SK, Husain MM. Evidence for the involvement of nitric oxide in cisplatin-induced toxicity in rats. Biometals. 1996; 9(2): 139-142.
[43] Xiaoting L, Xiangyun Z, Shumei L, Minghua D, Liang X. Effect of hesperidin on expression of inducible nitric oxide synthase in cultured rabbit retinal pigment epithelial cells. In: Anderson R, Hollyfield J, LaVail M, Eds. Retinal degenerative diseases: advances in experimental medicine and biology. New York: Springer, 2010.
[44] Sakata K, Hirose Y, Qiao Z, Tanaka T, Mori H. Inhibition of inducible isoforms of cyclooxygenase and nitric oxide synthase by flavonoid hesperidin in mouse macrophage cell line. Cancer Lett. 2003; 199(2): 139-145.
[45] Chen WP, Wang YL, Tang JL, Hu PF, Bao JP, Wu LD. Morin inhibits interleukin-1β-induced nitric oxide and prostaglandin E2 production in human chondrocytes. Int Immunopharmacol. 2012; 12(2): 447-452.
[46] Dilshara MG, Jayasooriya RGPT, Lee S, Choi YH, Kim GY. Morin downregulates nitric oxide and prostaglandin E2 production in LPS-stimulated BV2 microglial cells by suppressing NF-κB activity and activating HO-1 induction. Environ Toxicol Pharmacol. 2016; 44: 62-68.
[47] Subash S, Subramanian P. Morin a flavonoid exerts antioxidant potential in chronic hyperammonemic rats: a biochemical and histopathological study. Mol Cell Biochem. 2009; 327(1-2): 153-161.
[48] Klebanoff SJ. Myeloperoxidase: friend and foe. J Leukoc Biol. 2005; 77(5): 598-625.
[49] Ma SF, Nishikawa M, Hyoudou K, Takahashi R, Ikemura M, Kobayashi Y, Yamashita F, Hashida M. Combining cisplatin with cationized catalase decreases nephrotoxicity while improving antitumor activity. Kidney Int. 2007; 72(12): 1474-1482.
[50] Cetin R, Devrim E, Kilicoglu B, Avci A, Candır O, Durak I. Cisplatin impairs antioxidant system and causes oxidation in rat kidney tissues: possible protective roles of natural antioxidant foods. J Appl Toxicol. 2006; 26(1): 42-46.
[51] Siddiqi A, Nafees S, Rashid S, Sultana S. Hesperidin ameliorates trichloroethylene-induced nephrotoxicity by abrogation of oxidative stress and apoptosis in wistar rats. Mol Cell Biochem. 2015; 406(1-2): 9-20.
[52] Niu C, Ma M, Han X, Wang Z, Li H. Hyperin protects against cisplatin-induced liver injury in mice. Acta Cir Bras. 2017; 32(8): 633-640.
[53] Omar HA, Mohamed WR, Arab HH, Arafa ESA. Tangeretin alleviates cisplatin-induced acute hepatic injury in rats: targeting MAPKs and apoptosis. PLoS One. 2016; Article ID e0151649.