DOI: http://dx.doi.org/10.18203/2319-2003.ijbcp20214886

Comparing the effect of statins on hepatic fibrosis induced by carbon tetrachloride in Wistar rats

Anupama Dhavaleshwar, Bharti Chogtu, Deepak Nayak, Praveen Kumar S. E.

Abstract


Background: The clinical studies have shown contrary results regarding hepatoprotective effect of statins. However, antifibrotic properties of statins in in vitro and in vivo experimental models have been demonstrated. The purpose of this study was to assess and compare the effect of statins on serum liver enzymes and their antifibrotic effects.

Methods: Forty two rats were divided into 7 groups (I to VII) (n=6). Liver toxicity was induced by injecting carbon tetrachloride (1 ml/kg). Control groups received corn oil (0.1 ml/100 gm) and carboxy methyl cellulose (0.50%) respectively. Group III to VII received carbon tetrachloride (CCl4) for 6 weeks and then groups IV, V, VI and VII received simvastatin (10 mg/kg), atorvastatin (15 mg/kg), rosuvastatin (2 mg/kg) and silymarin (50 mg/kg) for another 8 weeks respectively. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels were estimated in all the groups at baseline, 6 weeks and 14 weeks. At 14 weeks, histopathology of liver was done in all groups.

Results: At 14 weeks, all the test groups (IV, V and VI) showed a significant decrease in serum ALT, AST and ALP levels as compared to control (p<0.05) and group III (p<0.05). On intergroup comparison, liver enzymes in rats in group VI (rosuvastatin) and group V (atorvastatin) were decreased more in comparison to group IV (simvastatin) but the difference was not statistically significant except for AST levels where the difference was significant between the statins. There was decrease in hepatic fibrosis by statins with rosuvastatin being superior followed by atorvastatin and simvastatin.

Conclusions: In the present study statins decreased the serum AST, ALT and ALP levels and histopathological changes were reversed by statins in CCl4 induced hepatotoxic models.


Keywords


Statins, Hepatotoxicity, Carbon tetrachloride, Hepatic fibrosis

Full Text:

PDF

References


Chong LW, Hsu YC, Lee TF, Lin Y, Chiu YT, Yang KC, et al. Fluvastatin attenuates hepatic steatosis-induced fibrogenesis in rats through inhibiting paracrine effect of hepatocyte on hepatic stellate cells. BMC Gastroenterol. 2015;15:22.

Fujii T, Fuchs BC, Yamada S, Lauwers GY, Kulu Y, Goodwin JM, et al. Mouse model of carbon tetrachloride induced liver fibrosis: Histopathological changes and expression of CD133 and epidermal growth factor. BMC Gastroenterol. 2010;10:79.

Kamal S, Khan MA, Seth A, Cholankeril G, Gupta D, Singh U, et al. Beneficial effects of statins on the rates of hepatic fibrosis, hepatic decompensation, and mortality in chronic liver disease: a systematic review and meta-analysis. Am J Gastroenterol. 2017;112(10):1495-505.

El-Demerdash E, Abdel-Sattar SA, El-Bakly WM, Mohamed EA. Antifibrotic effects of Carvedilol and impact of liver librosis on Carvedilol pharmacokinetics in a rat model. Eur J Drug Metab Pharmacokinet. 2017;42(5):767-79.

Mirhadi K. Effect of Intraperitoneally Injection of Different Doses of Lovastatin on Pain and Inflammatory Response Induced by Formalin in Mice. Am J Animal Vet Sci. 2011;6(4):160-5.

Motawi TM, Atta HM, Sadik NA, Azzam M. The therapeutic effects of bone marrow-derived mesenchymal stem cells and Simvastatin in a rat model of liver fibrosis. Cell Biochem Biophys. 2014;68(1):111-25.

Klein S, Klo J, Schierwagen R, Rner K, Granzow M, Huss S, et al. Atorvastatin inhibits proliferation and apoptosis, but induces senescence in hepatic myofibroblasts and thereby attenuates heaptic fibrosis in rats. Lab Invest. 2012;92(10):1440-50.

Okada Y, Yamaguchi K, Nakajima T, Nishikawa T, Jo M, Mitsumoto Y, et al. Rosuvastatin ameliorates high fat and high cholesterol diet induced non-alcoholic steatohepatitis in rats. Liver International. 2013;33:301-11.

Salama SM, Abdulla MA, AlRashdi AS, Hadi AH. Mechanism of hepatoprotective effect of Boesenbergia rotunda in Thioacetamide-induced liver damage in rats. Evidence-based Complement Alternat Med. 2013;157456.

Weber LW, Boll M, Stampfl A. Hepatotoxicity and mechanism of action of haloalkanes: carbon tetrachloride as a toxicological model. Crit Rev Toxicol. 2003;33(2):105-36.

Dong S, Chen Q-L, Song Y-N, Sun Y, Wei B, Li X-Y, et al. Mechanisms of CCl4-induced liver fibrosis with combined transcriptomic and proteomic analysis. J Toxicol Sci. 2016;41(4):561-72.

Dold S, Laschke M, Lavasani S, Menger M, Jeppsson B, Thorlacius H. Simvastatin protects against cholestasis-induced liver injury. Br J Pharmacol. 2009;156(3):466-74.

La Mura V, Pasarín M, Meireles CZ, Miquel R, Rodríguez-Vilarrupla A, Hide D, et al. Effects of Simvastatin administration on rodents with lipopolysaccharide-induced liver microvascular dysfunction. Hepatology. 2013;57(3):1172-81.

Eslami L, Merat S, Malekzadeh R, Nasseri-Moghaddam S, Aramin H. Statins for non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. Cochrane Database Syst Rev. 2013;(12):CD008623.

Hyogo H, Tazuma S, Arihiro K, Iwamoto K, Nabeshima Y, Inoue M, et al. Efficacy of atorvastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia. Metabolism. 2008;57(12):1711-8.

Björnsson E, Jacobsen EL, Kalaitzakis E. Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing. J Hepatol. 2012;56(2):374-80.

de Denus S, Spinler SA, Miller K, Peterson AM. Statins and liver toxicity: a meta-analysis. Pharmacotherapy. 2004;24(5):584-91.

Ajamieh H, Farrell G, Wong HJ, Yu J, Chu E, Chen J, et al. Atorvastatin protects obese mice against hepatic ischemia-reperfusion injury by Toll-like receptor-4 suppression and endothelial nitric oxide synthase activation. J Gastroenterol Hepatol. 2012;27(8):1353-61.

Maher BM, Dhonnchu TN, Burke JP, Soo A, Wood AE, Watson RW. Statins alter neutrophil migration by modulating cellular Rho activity – a potential mechanism for statins-mediated pleiotropic effects. J Leukoc Biol. 2009;85:186-93.

Moreno M, Ramalho LN, Sancho-Bru P, Ruiz-Ortega M, Ramalho F, Abraldes JG, et al. Atorvastatin attenuates angiotensin II-induced inflammatory actions in the liver. Am J Physiol Gastrointest Liver Physiol. 2009;296(2):147-56.