Atorvastatin mitigates cyclophosphamide-induced hepatotoxicity via suppression of oxidative stress and apoptosis in rat model

Maedeh Hamzeh , Seyed Jalal Hosseinimehr, Ali Reza Khalatbary, Hamid Reza Mohammadi, Ayat Dashti, Fereshteh Talebpour Amiri


Cyclophosphamide (CP), as a chemotherapy drug, induces hepatotoxicity through causing oxidative stress. Atorvastatin (ATV) at a low dose has antioxidant and anti-inflammatory properties. The present study was designed to investigate the protective effects of ATV against CP-induced hepatotoxicity in rat. In this experimental study, 32 rats were treated with ATV orally at a dose of 10 mg/kg for 10 consecutive days, 5 days before and 5 days after the administration of a single intraperitoneal injection of CP (150 mg/kg). The hepatoprotective effect of ATV was evaluated by measuring liver function markers, oxidative markers, histological and immunohistochemical assays. The biochemical results showed that administration of CP increased hepatic biomarkers enzymes as aspartate aminotransferase (AST), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) levels. CP increased malondialdehyde (MDA), protein carbonyl (PC) and decreased glutathione (GSH) content in rats. Moreover, administration of CP was associated with periportal leucocyte infiltration, dilation sinusoids, hepatocyte vacuolation, congestion and hemorrhage in livers of rats. CP significantly increased immunoreactivity of caspase-3 as a marker of apoptosis in liver tissue. ATV markedly mitigated liver injury through reduction in oxidative stress biomarkers, histopathological findings and apoptosis. The antioxidant and anti-apoptotic activities of ATV are main proposed mechanisms involved in its hepatoprotective effects against CP-induced hepatic injury.


Atorvastatin; Caspase-3; Cyclophosphamide; Hepatotoxicity; Oxidative stress.

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Perini P, Calabrese M, Rinaldi L, Gallo P. The safety profile of cyclophosphamide in multiple sclerosis therapy. Expert opin drug saf. 2007;6(2):183-190.

Senthilkumar S, Devaki T, Manohar BM, Babu MS. Effect of squalene on cyclophosphamide-induced toxicity. Clin Chim Acta. 2006;364(1-2):335-342.

Tripathi DN, Jena GB. Intervention of astaxanthin against cyclophosphamide-induced oxidative stress and DNA damage: a study in mice. Chem biol interact. 2009;180(3):398-406.

Sheweita SA, El-Hosseiny LS, Nashashibi MA. Protective effects of essential oils as natural antioxidants against hepatotoxicity induced by cyclophosphamide in mice. PloS One. 2016;11(11):e0165667.

Kocahan S, Dogan Z, Erdemli E, Taskin E. Protective effect of quercetin against oxidative stress-induced toxicity associated with doxorubicin and cyclophosphamide in rat kidney and liver tissue. Iran J Kidney Dis. 2017;11(2):124-131.

Tripathi D, Jena G. Astaxanthin intervention ameliorates cyclophosphamide-induced oxidative stress, DNA damage and early hepatocarcinogenesis in rat: role of Nrf2, p53, p38 and phase-II enzymes. Mutat Res. 2010;696(1):69-80.

Wei X, Su F, Su X, Hu T, Hu S. Stereospecific antioxidant effects of ginsenoside Rg3 on oxidative stress induced by cyclophosphamide in mice. Fitoterapia. 2012;83(4):636-642.

Schrott HG, Knapp H, Davila M, Shurzinske L, Black D. Effect of atorvastatin on blood lipid levels in the first 2 weeks of treatment: a randomized, placebo-controlled study. Am Heart J. 2000;140(2):249-252.

Zhou Q, Liao JK. Pleiotropic effects of statins. Basic research and clinical perspectives. Circ J. 2010;74(5):818-826.

Parlakgumus HA, Bolat FA, Kilicdag EB, Simsek E, Parlakgumus A. Atorvastatin for ovarian torsion: effects on follicle counts, AMH, and VEGF expression. Eur J Obstet Gynecol Reprod Biol. 2014;175:186-190.

Ozacmak VH, Sayan H, Igdem AA, Cetin A, Ozacmak ID. Attenuation of contractile dysfunction by atorvastatin after intestinal ischemia reperfusion injury in rats. Eur J pharmacol. 2007;562(1-2): 138-147.

Gottmann U, Brinkkoetter PT, Hoeger S, Gutermann K, Coutinho ZM, Ruf T, et al. Atorvastatin donor pretreatment prevents ischemia/reperfusion injury in renal transplantation in rats: possible role for aldose-reductase inhibition. Transplantation. 2007;84(6):755-762.

Naeimi RA, Talebpour Amiri F, Khalatbary AR, Ghasemi A, Zargari M, Ghesemi M, et al. Atorvastatin mitigates testicular injuries induced by ionizing radiation in mice. Reprod Toxicol. 2017;72:115-121.

Hamzeh M, Talebpour Amiri F, Karimpour Malekshah A, Yaghubi Beklar S, Hosseinimehr SJ. Protective effect of atorvastatin against cardiotoxicity and hematotoxicity induced by cyclophosphamide in rat. J Mazandaran Univ Med Sci. 2017;27(151):1-11.

Carrascosa MF, Salcines-Caviedes JR, Lucena MI, Andrade RJ. Acute liver failure following atorvastatin dose escalation: Is there a threshold dose for idiosyncratic hepatotoxicity? J Hepatol. 2015;62(3):751-752.

Ajamieh H, Farrell GC, McCuskey RS, Yu J, Chu E, Wong HJ, et al. Acute atorvastatin is hepatoprotective against ischaemia‐reperfusion injury in mice by modulating eNOS and microparticle formation. Liver Int. 2015;35(9): 2174-2186.

Zamani E, Mohammadbagheri M, Fallah M, Shaki F. Atorvastatin attenuates ethanol-induced hepatotoxicity via antioxidant and anti-inflammatory mechanisms. Res pharm sci. 2017;12(4):315-321.

Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF. Sex differences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol. 2004;44:499-523.

Massafra C, Gioia D, De Felice C, Picciolini E, De Leo V, Bonifazi M, et al. Effects of estrogens and androgens on erythrocyte antioxidant superoxide dismutase, catalase and glutathione peroxidase activities during the menstrual cycle. Journal of Endocrinology. 2000;167(3):447-452.

El-Moselhy MA, El-Sheikh AA. Protective mechanisms of atorvastatin against doxorubicin-induced hepato-renal toxicity. Biomed Pharmacother. 2014;68(1):101-110.

Fouad AA, Albuali WH, Jresat I. Protective effect of hesperidin against cyclophosphamide hepatotoxicity in rats. Int J Biol Food Vet Agric Eng. 2014;8(7):722-5.

Radu M, Munteanu MC, Petrache S, Serban AI, Dinu D, Hermenean A, et al. Depletion of intracellular glutathione and increased lipid peroxidation mediate cytotoxicity of hematite nanoparticles in MRC-5 cells. Acta Biochim Pol. 2010;57(3):355-360.

Fathi H, Ebrahimzadeh MA, Ziar A, Mohammadi H. Oxidative damage induced by retching; antiemetic and neuroprotective role of Sambucus ebulus L. Cell Biol Toxico. 2015;31(4-5):231-239.

Ghazi‐Khansari M, Mohammadi‐Bardbori A, Hosseini MJ. Using janus green B to study paraquat toxicity in rat liver mitochondria. Ann N Y Acad Sci. 2006;1090(1):98-107.

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):10158-10165.

Talebpour Amiri F, Hamzeh M, Naeim RA, Ghasemi A, Hosseinimehr SJ. Radioprotective effect of atorvastatin against ionizing radiation-induced nephrotoxicity in mice. Int J Radiat Biol. 2018;94(2):106-113.

McDonald GB, Slattery JT, Bouvier ME, Ren S, Batchelder AL, Kalhorn TF, et al. Cyclophosphamide metabolism, liver toxicity, and mortality following hematopoietic stem cell transplantation. Blood. 2003;101(5):2043-2048.

Ghobadi E, Moloudizargari M, Asghari MH, Abdollahi M. The mechanisms of cyclophosphamide-induced testicular toxicity and the protective agents. Expert Opin Drug Metab Toxicol. 2017;13(5):525-536.

Mahmoud AM. Hesperidin protects against cyclophosphamide-induced hepatotoxicity by upregulation of PPARγ and abrogation of oxidative stress and inflammation. Can J Physiol Pharmacol. 2014;92(9):717-724.

Aksu E, Kandemir FM, Özkaraca M, Ömür AD, Küçükler S, Çomaklı S. Rutin ameliorates cisplatin‐induced reproductive damage via suppression of oxidative stress and apoptosis in adult male rats. Andrologia. 2017;49(1). DOI: 10.1111/and.12593.

Cuce G, Çetinkaya S, Koc T, Esen HH, Limandal C, Balcı T, et al. Chemoprotective effect of vitamin E in cyclophosphamide-induced hepatotoxicity in rats. Chem Biol Interact. 2015;232:7-11.

El-Kholy AA, Elkablawy MA, El-Agamy DS. Lutein mitigates cyclophosphamide induced lung and liver injury via NF-κB/MAPK dependent mechanism. Biomed Pharmacother. 2017;92: 519-527.

Wassmann S, Laufs U, Müller K, Konkol C, Ahlbory K, Bäumer AT, et al. Cellular antioxidant effects of atorvastatin in vitro and in vivo. Arterioscler Thromb Vasc Biol. 2002;22(2): 300-305.

Elewa HF, Kozak A, El-Remessy AB, Frye RF, Johnson MH, Ergul A, et al. Early atorvastatin reduces hemorrhage after acute cerebral ischemia in diabetic rats. J Pharmacol Exp Ther. 2009;330(2):532-540.

Hosseinimehr SJ, Izakmehri M, Ghasemi A. In vitro protective effect of atorvastatin against ionizing radiation induced genotoxicity in human lymphocytes. Cell Mol Biol (Noisy-le-grand). 2015;61(1):68-71.

Clarke AT, Johnson PC, Hall GC, Ford I, Mills PR. High dose atorvastatin associated with increased risk of significant hepatotoxicity in comparison to simvastatin in UK GPRD cohort. PloS One. 2016;11(3):e0151587.

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):1353-1361.

Kocak FE, Kucuk A, Ozyigit F, Tosun M, Kocak C, Kocak A, et al. Protective effects of simvastatin administered in the experimental hepatic ischemia-reperfusion injury rat model. J Surg Res. 2015;199(2):393-401.

Wiggers JK, van Golen RF, Verheij J, Dekker AM, van Gulik TM, Heger M. Atorvastatin does not protect against ischemia-reperfusion damage in cholestatic rat livers. BMC Surg. 2017;17(1):35.

Selvakumar E, Prahalathan C, Mythili Y, Varalakshmi P. Mitigation of oxidative stress in cyclophosphamide-challenged hepatic tissue by DL-alpha-lipoic acid. Mol Cell Biochem. 2005; 272(1-2):179-185.

Frew JW, Davatchi CC, Murrell DF. Cyclophosphamide in autoimmune blistering diseases: safety, efficacy and evidence base. Blistering Diseases: Springer. 2015;507-13.

Hussein MR. Apoptosis in the ovary: molecular mechanisms. Hum Reprod Update. 2005;11(2): 162-177.

Shi L, Liu Y, Tan D, Yan T, Song D, Hou M, et al. Blueberry anthocyanins ameliorate cyclophosphamide-induced liver damage in rats by reducing inflammation and apoptosis. J Funct Foods. 2014;11:71-81.

Bao XM, Wu CF, Lu GP. Atorvastatin inhibits homocysteine-induced oxidative stress and apoptosis in endothelial progenitor cells involving Nox4 and p38MAPK. Atherosclerosis. 2010;210(1):114-121.


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