AMELIORATIVE EFFECT OF HESPERIDIN ON CARBON TETRACHLORIDE INDUCED LIVER FIBROSIS IN RATS
DOI:
https://doi.org/10.22159/ijpps.2017v9i7.17611Keywords:
Liver fibrosis, CCl4, Corn oil, Silymarin, Hesperidin, RatAbstract
Objective: Exposure to carbon tetrachloride leads to serious liver injury and fibrosis. This study was aimed to evaluate the hepatoprotective effects of hesperidin against carbon tetrachloride (CCl4)-induced liver fibrosis in rats compared with the reference drug silymarin.
Methods: Wistar albino rats were divided into five groups, each of eight rats. Animals were allocated into a control group, corn oil group and fibrosis control group. The remaining two groups received in addition to CCl4, silymarin (100 mg/kg/d) as a reference treatment and hesperidin (200 mg/kg/d). At the end of experimental period, the biomarkers of specific fibrosis [hepatic transforming growth factor β1 (TGF-β1) and hydroxyproline (HYP)], liver function [serum alanine transaminase (ALT), aspartate transaminase (AST), albumin and total bilirubin], oxidative stress [hepatic malondialdehyde (MDA), glutathione (GSH) and catalase (CAT)], inflammatory [hepatic myeloperoxidase (MPO), serum tumor necrosis factor alpha (TNF-α)], relative liver weight, lipid profile [total cholesterol, serum triglycerides, high-density lipoprotein cholesterol (HDL-Ch) and low density lipoprotein cholesterol (LDL-Ch)] were evaluated, supported by liver histopathological study and immunohistochemistry of alpha-smooth muscle actin (α-SMA) in liver sections.
Results: Hesperidin significantly decreased hepatic transforming growth factor β1, hydroxyproline, the serum liver function markers of ALT, AST and total bilirubin, the hepatic content of MDA and MPO activity, the serum pro-inflammatory cytokine TNF-α, relative liver weight, and the serum lipid profile markers cholesterol, triglycerides and LDL. On the other hand, Hesperidin significantly increased albumin, the hepatic content of GSH and CAT, and serum lipid profile of LDL. In addition, liver sections obtained from these groups showed marked histopathological and immunohistochemistry of α-SMA improvement.
Conclusion: Hesperidin may be promising protective agent against liver fibrosis through improvement of liver function, modulation of the fibrous scar formation, anti-inflammatory and antioxidant potentials.
Downloads
References
Aoudjehane L, Boelle PY, Bisch G, Delelo R, Paye F, Scatton O, et al. Development of an in vitro model to test antifibrotic drugs on primary human liver myofibroblasts. Lab Invest 2016;96:672-9.
Achmad A, Fadiah RA, Mustofa, Prihadi AL. The incidence of liver fibrosis based on non-invasive markers and hepatotoxic drug used in hepatitis b patients. Asian J Pharm Clin Res 2014;7:287-90.
Mohamed SH, Elbastawisy YM. Efficacy of curcumin in protecting the rat liver from CCl4-induced injury and fibrogenesis. Histological and immunohistochemical study. Life Sci J 2013;10:2824-35.
Brenner DA. Molecular pathogenesis of liver fibrosis. Trans Am Clin Climatol Assoc 2009;120:361-8.
Essawy AE, Abdel-moneim AM, Khayyat LI, Elzergy AA. Nigella sativa seeds protect against hepatotoxicity and dyslipidemia induced by carbon tetrachloride in mice. J Appl Pharm Sci 2012;2:21-5.
Ohta Y, Sahashi D, Sasaki E, Ishiguro I. Alleviation of carbon tetrachloride-induced chronic liver injury and related dysfunction by L-tryptophan in rats. Ann Clin Biochem 1999;36:504-10.
El-Demerdash E, Abdel Salam OM, El-Batran SA, Abdallah HMI, Shaffie NM. Inhibition of the renin-angiotensin system attenuates the development of liver fibrosis and oxidative stress in rats. Clin Exp Pharmacol Physiol 2008;35:159-67.
Pari L, Karthikeyan A, Karthika P, Rathinam A. Protective effects of hesperidin on oxidative stress, dyslipidaemia and histological changes in iron-induced hepatic and renal toxicity in rats. Toxicol Reports 2014;2:46-55.
Elshazly SM, Mahmoud AAA. Antifibrotic activity of hesperidin against dimethylnitrosamine-induced liver fibrosis in rats. Naunyn Schmiedebergs Arch Pharmacol 2014;387:559-67.
Barnes S. Nutritional genomics, polyphenols, diets, and their impact on dietetics. J Am Diet Assoc 2008;108:1888-95.
Ghosh A, Ghosh T, Jain S. Silymarin-a review on the pharmacodynamics and bioavailability enhancement approaches. J Pharm Sci Technol 2010;2:348-55.
Hui AY, Leung WK, Yuen Chan HL, Chan FKL, Yin Go MY, Chan KK, et al. Effect of celecoxib on experimental liver fibrosis in rat. Liver Int 2006;26:125-36.
Shah B, Shah G. Antifibrotic effect of heparin on liver fibrosis model in rats. World J Gastrointest Pharmacol Ther 2012;3:86-92.
Reitman S, Frankel S. A colorimetric method for the determination of serum glutamic oxalacetic and glutamic pyruvic transaminases. Am J Clin Pathol 1957;28:56-63.
Doumas BT, Watson WA, Biggs HG. Albumin standards and the measurement of serum albumin with Bromocresol Green. Clin Chim Acta 1997;258:21-30.
Malloy HT, Evelyn KA. The determination of bilirubin with the photoelectric colorimeter. J Biol Chem 1937;119:481-90.
Brouckaert P, Libert C, Everaerdt B, Takahashi N, Cauwels A, Fiers W. Tumor necrosis factor, its receptors and the connection with interleukin 1 and interleukin 6. Immunobiology 1993;187:317-29.
Watson D. A simple method for the determination of serum cholesterol. Clin Chim ACTA 1960;5:637-43.
Fossati P, Prencipe L. Serum triglycerides determined colorimetrically with an enzyme that produces hydrogen peroxide. Clin Chem 1982;28:2077-80.
Castelli WP, Doyle JT, Gordon T, Hames CG, Hjortland MC, Hulley SB, et al. HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study. Circulation 1977;55:767-72.
Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without the use of the preparative ultracentrifuge. Clin Chem 1972;18:499-502.
Blanchette F, Day R, Dong W, Laprise MH, Dubois CM. TGF beta1 regulates gene expression of its own converting enzyme furin. J Clin Invest 1997;99:1974.
Patiyal SN, Katoch SS. BETA-adrenoceptor agonist clenbuterol down-regulates matrix metalloproteinase (MMP-9) and results in an impairment of collagen turnover in mice left ventricle. Japan J Physiol 2005;55:165-72.
Satoh K. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim acta 1978;90:37-43.
Beutler E, Duron O, Kelly BM. Improved method for the determination of blood glutathione. J Lab Clin Med 1963;61:882-8.
Aebi H. Catalase in vitro. Methods Enzymol 1984;105:121-6.
Weiss SJ, Klein R, Slivka A, Wei M. Chlorination of taurine by human neutrophils: evidence for a hypochlorous acid generation. J Clin Invest 1982;70:598.
Hassan SK, Mousa AM, El-sammad NM. Attenuation of carbon tetrachloride and ethanol-induced hepatic fibrosis in rats by calligonum comosum shoot extract. Asian J Pharm Clin Res 2017;10:83-91.
Hou YL, Tsai YH, Lin YH, Chao JCJ. Ginseng extract and ginsenoside Rb1 attenuate carbon tetrachloride-induced liver fibrosis in rats. BMC Complementary Altern Med 2014;14:415.
Li R, Guo W, Fu Z, Ding G, Zou Y, Wang Z. Hepatoprotective action of Radix Paeoniae Rubra aqueous extract against CCl4-induced hepatic damage. Molecules 2011;16:8684-93.
Tirkey N, Pilkhwal S, Kuhad A, Chopra K. Hesperidin, a citrus bioflavonoid, decreases the oxidative stress produced by carbon tetrachloride in rat liver and kidney. BMC Pharmacol 2005;5:1-8.
Czeczot H, Scibior D, Skrzycki M, Podsiad M. Glutathione and GSH-dependent enzymes in patients with liver cirrhosis and hepatocellular carcinoma. Acta Biochim Pol 2006;53:237-41.
Fouad AA, Albuali WH, Jresat I. Protective effect of hesperidin against cyclophosphamide hepatotoxicity in rats. Int J Biol Biomol Agric Food Biotechnol Eng 2014;8:730-3.
Reynolds WF, Patel K, Pianko S, Blatt LM, Nicholas JJ, McHutchison JG. A genotypic association implicates myeloperoxidase in the progression of hepatic fibrosis in chronic hepatitis C virus infection. Genes Immun 2002;3:345-9.
Jeong WI, Jeong DH, Do SH, Kim YK, Park HY, Kwon OD, et al. Mild hepatic fibrosis in cholesterol and sodium cholate diet-fed rats. J Vet Med Sci 2005;67:235-42.
Andritoiu CV, Ochiuz L, Andritoiu V, Popa M. Effect of apitherapy formulations against carbon tetrachloride-induced toxicity in Wistar rats after three weeks of treatment. Molecules 2014;19:13374-91.
Wang X, Hasegawa J, Kitamura Y, Wang Z, Matsuda A, Shinoda W, et al. Effects of hesperidin on the progression of hypercholesterolemia and fatty liver induced by high-cholesterol diet in rats. J Pharmacol Sci 2011;117:129-38.
Gressner AM, Weiskirchen R, Breitkopf K, Dooley S. Roles of TGF-beta in hepatic fibrosis. Front Biosci 2002;7:793-807.
Aldaba-Muruato LR, Moreno MG, Shibayama M, Tsutsumi V, Muriel P. Allopurinol reverses liver damage induced by chronic carbon tetrachloride treatment by decreasing oxidative stress, TGF-β production and NF-κB nuclear translocation. Pharmacology 2013;92:138-49.
Pérez-Vargas JE, Zarco N, Shibayama M, Segovia J, Tsutsumi V, Muriel P. Hesperidin prevents liver fibrosis in rats by decreasing the expression of nuclear factor-κB, transforming growth factor-β and connective tissue growth factor. Pharmacology 2014;94:80-9.
Domitrović R, Jakovac H, Tomac J, Šain I. Liver fibrosis in mice induced by carbon tetrachloride and its reversion by luteolin. Toxicol Appl Pharmacol 2009;241:311-21.
Kidd PM. Bioavailability and activity of phytosome complexes from botanical polyphenols: the silymarin, curcumin, green tea, and grape seed extracts. Altern Med Rev 2009;14:226-46.