Immunohistochemical and molecular study on the protective effect of curcumin against hepatic toxicity induced by paracetamol in Wistar rats

BMC Complementary and Alternative Medicine

Tamer Ahmed Ismail²  Mohamed Abdo Nassan¹  Mohamed Mohamed Soliman³ 

[1] Department of Pathology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt;Department of Physiology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, Egypt;Department of Biochemistry, College of Veterinary Medicine, Faculty of Veterinary Medicine, Benha University, P.O. 13736, Moshtohor, Egypt

关键词: Wistar rats;    MMP-8 immunostaining;    Cytokines expression;    Paracetamol;    Hepatic toxicity;    Curcumin;   

Others  :  1085299
DOI  :  10.1186/1472-6882-14-457

 received in 2014-08-22, accepted in 2014-11-21,  发布年份 2014

【 摘 要 】

Background

An overdose of paracetamol is a frequent reason for liver and renal toxicity and possible death and curcumin has hepatoprotective properties against liver damage. The exact mechanism of such protection is not clear. Therefore, this study was conducted to examine the molecular levels of the protective effect of curcumin on paracetamol overdose induced hepatic toxicity in rats.

Methods

Male Wistar rats were allocated into 4 groups. Control group, administered corn oil; curcumin group, administered curcumin (400 mg/kg BW daily intra-gastric) dissolved in corn oil; paracetamol group, administered corn oil with a single dose of paracetamol (500 mg/kg BW intra-gastric) and protective group, administered curcumin with a single dose of paracetamol. Curcumin was administered for 7 successive days, while paracetamol was administered at day six of treatment. Blood and liver tissues were collected for biochemical, histopathological, immunohistochemical and molecular examination.

Results

Serum analysis revealed an alteration in parameters of kidney and liver. A decrease in the antioxidant activity of liver was recorded in paracetamol group while curcumin administration restored it. Histopathological findings showed an extensive coagulative necrosis in hepatocytes together with massive neutrophilic and lymphocytic infiltration. Immunostaining of liver matrix metalloproteinase-8 (MMP-8) in paracetamol administered rats showed an increase in MMP-8 expression in the area of coagulative necrosis surrounding the central vein of hepatic lobules. Curcumin administration decreased MMP-8 expression in liver of paracetamol administered rats. Gene expression measurements revealed that paracetamol decreased the expression of antioxidant genes and increased the expression of interleukin-1β (IL-1β), IL-8, tumor necrosis factor-α (TNF-α) and acute phase proteins. Curcumin administration ameliorated paracetamol-induced alterations in genes expression of antioxidant and inflammatory cytokines.

Conclusion

The results clarified the strong protective effect of curcumin on paracetamol induced hepatic toxicity in rats at the immunohistochemical and molecular levels.

【 授权许可】

   
2014 Soliman et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Altenburg JD, Bieberich AA, Terry C, Harvey KA, Vanhorn JF, Xu Z, Jo Davisson V, Siddiqui RA: A synergistic antiproliferation effect of curcumin and docosahexaenoic acid in SK-BR-3 breast cancer cells: unique signaling not explained by the effects of either compound alone. BMC Cancer 2011, 11:149. BioMed Central Full Text
• [2]Chattopadhyay I, Biswas K, Bandyopadhyay U, Banerjee RK: Turmeric and curcumin: biological actions and medicinal applications. Curr Sci 2004, 87:44-53.
• [3]Basnet P, Skalko-Basnet N: Curcumin: an anti-inflammatory molecule from 1081 a curry spice on the path to cancer treatment. Molecules 2011, 16:4567-4598.
• [4]Al-Jassabi S, Ahmed KA, Ameen M: Antioxidant effect of curcumin against microcystin-LR-induced renal oxidative damage in Balb/c mice. Trop J Pharm Res 2012, 11:5316.
• [5]Tajbakhsh S, Mohammadi K, Deilami I, Zandi K, Ramedani E, Asayesh G: Antibacterial activity of indium curcumin and indium diacetylcurcumin. Afr J Biotechnol 2008, 7:3832-3835.
• [6]Bereswill S, Munoz M, Fischer A, Plickert R, Haag L, Otto B, Kuhl AA, Loddenkemper C, Gobel UB, Heimesaat MM: Anti-inflammatory effects of resveratrol, curcumin and simvastatin in acute small intestinal inflammation. PLoS One 2010, 5(12):e15099.
• [7]Kutluay SB, Doroghazi J, Roemer ME, Triezenberg SJ: Curcumin inhibits herpes simplex virus immediate-early gene expression by a mechanism independent of p300/CBP histone acetyltransferase activity. Virology 2008, 373(1659):239-247.
• [8]Das L, Vinayak M: Anti-carcinogenic action of curcumin by activation of antioxidant defence system and inhibition of NF-KB signalling in lymphoma bearing mice. Biosci Rep 2012, 32:161-170.
• [9]Aziz MT, El Ibrashy IN, Mikhailidis DP, Rezq AM, Wassef MA, Fouad HH, Ahmed HH, Sabry DA, Shawky HM, Hussein RE: Signaling mechanisms of a water soluble curcumin derivative in experimental type 1 diabetes with cardiomyopathy. Diabetol Metab Syndr 2013, 5:5-13. BioMed Central Full Text
• [10]Jobin C, Braham C, Russo MP, Juma B, Narula AS, Brenner DA, Sartor RB: Curcumin blocks cytokine-mediated NF-κB activation and proinflammatory gene expression by inhibiting inhibitory factor I-κB kinase activity. J Immunol 1999, 163:3474-3483.
• [11]Somanawat K, Thong-Ngam D, Klaikeaw N: Curcumin attenuated paracetamol overdose induced hepatitis. World J Gastroenterol 2013, 19:1962-1967.
• [12]Morsy MA, Abdalla AM, Mahmoud AM, Abdelwahab SA, Mahmoud ME: Protective effects of curcumin, α-lipoic acid, and N-acetylcysteine against carbon tetrachloride-induced liver fibrosis in rats. J Physiol Biochem 2012, 68:29-35.
• [13]El-Agamy DS: Comparative effects of curcumin and resveratrol on aflatoxin B (1)-induced liver injury in rats. Arch Toxicol 2010, 84(5):389-396.
• [14]Girish C, Koner BC, Jayanthi S, Ramachandra Rao K, Rajesh B, Pradhan SC: Hepatoprotective activity of picroliv, curcumin and ellagic acid compared to silymarin on paracetamol induced liver toxicity in mice. Fundam Clin Pharmacol 2009, 6:735-745.
• [15]Li G, Chen JB, Wang C, Xu Z, Nie H, Qin XY, Chen XM, Gong Q: Curcumin protects against acetaminophen-induced apoptosis in hepatic injury. World J Gastroenterol 2013, 19:7440-7446.
• [16]Zhao C, Sheryl D, Zhou YX: Effects of combined use of diallyl disulfide and Nacetyl-cysteine onacetaminophen hepatotoxicity in beta-naphthoflavone pretreated mice. World J Gastroenterol 1998, 4:112-116.
• [17]Sun YM, Zhang HY, Chen DZ, Liu CB: Theoretical elucidation on the antioxidant mechanism of curcumin: a DFT study. Org Lett 2002, 4:2909-2911.
• [18]Hinson JA, Reid AB, McCullough SS, James LP: Acetaminophen-induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metab Rev 2004, 36:805-822.
• [19]Larson AM: Acetaminophen hepatotoxicity. Clin Liver Dis 2007, 11:525-548.
• [20]Zwingmann C, Bilodeau M: Metabolic insights into the hepatoprotective role of N-acetylcysteine in mouse liver. Hepatology 2006, 43:454-463.
• [21]Van Lint P, Libert C: Matrix metalloproteinase-8: cleavage can be decisive. Cytokine Growth Factor Rev 2006, 17:217-223.
• [22]Van Lint P, Wielockx B, Puimège L, Noël A, López-Otin C, Libert C: Resistance of collagenase-2 (matrix metalloproteinase-8)-deficient mice to TNF-induced lethal hepatitis. J Immunol 2005, 175(11):7642-7649.
• [23]Fink MP: Matrix metalloproteinase-8 as a potential drug target for the therapy of sepsis. Crit Care Med 2012, 40:655-656.
• [24]Zhou X, Lu J, Chen D, Wang W, Cai Q, Li T, Zhang J: Matrix metalloproteinase-8 inhibitors mitigate sepsis induced myocardial injury in rats. Chin Med J (Engl) 2014, 127(8):1530-1535.
• [25]Flora G, Gupta D, Tiwari A: Preventive efficacy of bulk and nanocurcumin against lead-induced oxidative stress in mice. Biol Trace Elem Res 2013, 152:31-40.
• [26]Saidi S, Azaza M, Windmolders P, van Pelt J, El-Feki A: Cytotoxicity evaluation and antioxidant enzyme expression related to heavy metals found in tuna by-products meal: an in vitro study in human and rat liver cell lines. Exp Toxicol Pathol 2013, 65(7-8):1025-1033.
• [27]Vera-Ramirez L, Perez-Lopez P, Varela-Lopez A, Ramirez-Tortosa M, Battino M, Quiles JL: Curcumin and liver disease. Bio Factors 2013, 39:88-100.
• [28]Zhang L, Gavin T, Geohagen BC, Liu Q, Downey KJ, LoPachin RM: Protective properties of 2-acetylcyclopentanone in a mouse model of acetaminophen hepatotoxicity. J Pharmacol Exp Ther 2013, 346(2):259-269.
• [29]Tarasub N, Junseecha T, Tarasub C, Na Ayutthaya WD: Protective effects of curcumin, vitamin C, or their combination on cadmium-induced hepatotoxicity. J Basic Clin Pharm 2012, 3(2):273-281.
• [30]Bancroft JD, Gamble M: Theory and Practice of Histological Techniques. 6th edition. Philadelphia: Churchill Livingstone Elsevier; 2008:126-127.
• [31]Kheradpezhouh E, Panjehshahin MR, Miri R, Javidnia K, Noorafshan A, Monabati A, Dehpou AR: Curcumin protects rats against acetaminophen-induced hepatorenal damages and shows synergistic activity with N-acetyl cysteine. Eur J Pharmacol 2010, 628:274-281.
• [32]Yousef MI, Omar SA, El-Guendi MI, Abdelmegid LA: Potential protective effects of quercetin and curcumin on paracetamol-induced histological changes, oxidative stress, impaired liver and kidney functions and haematotoxicity in rat. Food Chem Toxicol 2010, 48:3246-3326.
• [33]Evans JL, Goldfine ID, Maddux BA, Grodsky GM: Oxidative stress and stress activated signaling pathways: a unifying hypothesis of type 2 diabetes. Endo Rev 2002, 23:599-622.
• [34]Del Rio D, Stewart AJ, Pellegrini N: A review of recent studies on malondialdehyde as toxic molecule and biological marker of oxidative stress. Nutr Metab Cardiovasc Dis 2005, 15:316-328.
• [35]Priyadarsini KI, Maity DK, Naik GH, Kumar MS, Unnikrishnan MK, Satav JG, Mohan H: Role of phenolic O:H and methylene hydrogen on the free radical reaction and antioxidant activity of curcumin. Free Radical Biol Med 2003, 35:475-484.
• [36]Wright JS: Predicting the antioxidant activity of curcumin and curcuminoids. J Mol Struct (Theochem) 2002, 591:207-217.
• [37]Reyes-Gordillo K, Segovia J, Shibayama M, Vergara P, Moreno MG, Muriel P: Curcumin protects against acute liver damage in the rat by inhibiting NF-kappaB, proinflammatory cytokines production and oxidative stress. Biochim Biophys Acta 2007, 1770:989-996.
• [38]Maheswari RK, Singh AK, Gaddipati J, Srimal RC: Multiple biological activities of curcumin: a short review. Life Sci 2006, 78:2081-2087.
• [39]Samuhasaneeto S, Thong-Ngam D, Kulaputana O, Suyasunanont D, Klaikeaw N: Curcumin decreased oxidative stress, inhibited NF-kappaB activation, and improved liver pathology in ethanol-induced liver injury in rats. J Biomed Biotechnol 2009, 2009:981963.
• [40]Joe B, Lokesh BR: Role of capsaicin, curcumin and dietary n-3 fatty acids in lowering the generation of reactive oxygen species in rat peritoneal macrophages. Biochim Biophys Acta 1994, 1224:255-263.
• [41]Ganjali S, Sahebkar A, Mahdipour E, Jamialahmadi K, Torabi S, Akhlaghi S, Ferns G, Parizadeh SM, Ghayour-Mobarhan M: Investigation of the effects of curcumin on serum cytokines in obese individuals: a randomized controlled trial. Sci World J 2014, 2014:898361. 6 pages
• [42]Yang SQ, Lin HZ, Yin M, Albrecht JH, Diehl AM: Effect of chronic ethanol consumption on cytokine regulation of liver regeneration. Am J Physiol 1998, 275:G696-G704.
• [43]Jurenka JS: Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev 2009, 14:141-153.
• [44]Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A: IL-10 inhibits cytokine production by activated macrophages. J Immunol 1991, 147:3815-3822.
• [45]Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher BB: Interleukin-10 and related cytokines and receptors. Annu Rev Immunol 2004, 22:929-979.
• [46]Moore KW, de Waal MR, Coffman RL, O’Garra A: Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001, 19:683-765.
• [47]Anderson SP, Cattley RC, Corton JC: Hepatic expression of acute-phase protein genes during carcinogenesis induced by peroxisome proliferators. Mol Carcinog 1999, 26:226-238.
• [48]Richardson TA, Morgan ET: Hepatic cytochrome P450 gene regulation during endotoxin-induced inflammation in nuclear receptor knockout mice. J Pharmacol Exp Ther 2005, 314:703-709.
• [49]Kuribayashi T, Seita T, Honjo T, Yamazaki S, Momotani E, Yamamoto S: Impairment of α (2)-macroglobulin synthesis in experimental hepatopathic rats treated with turpentine oil. Exp Anim 2012, 61:125-130.
• [50]Lyoumi S, Tamion F, Petit J, Déchelotte P, Dauguet C, Scotté M, Hiron M, Leplingard A, Salier J, Daveau M, Lebreton JP: Induction and modulation of acute-phase response by protein malnutrition in rats: comparative effect of systemic and localized inflammation on interleukin-6 and acute-phase protein synthesis. J Nutr 1998, 128:166-174.