Published: 2019-03-23

Evaluation and comparison of the hepatoprotective effects of trimetazidine and lovastatin against doxorubicin-induced hepatotoxicity

Abeera Sikandar, Kulsoom Farhat, Amir Hamza


Background: The dosage of highly efficacious anti-cancer drug doxorubicin (DOX) is often constrained as limited data exists on its hepatotoxic potential. The present study not only evaluated the extent of its hepatotoxicity but also aimed at curtailing it, by administration of two drugs i.e. trimetazidine and lovastatin, both of which are otherwise known for their cardioprotective benefits.

Methods: The study was a lab-based randomized controlled study on mice. Acute toxicity was introduced with DOX injected intraperitoneally at a dose of 10 mg/kg and it was protected by oral administration of trimetazidine and lovastatin, both in a dose of 10 mg/kg. The protective drugs were both given for five and ten consecutive days in short and long term study designs whereby DOX was administered on the third and eighth days of the respective studies.

Results: Doxorubicin administration caused significant hepatotoxicity reflected by markedly raised biomarkers (serum alanine aminotransferase and aspartate aminotransferase) and mild inflammation of liver parenchyma with a score of 4 as per Ishak grading scale. The changes were significantly attenuated by both the protective drugs in the ten days study design. However, in the five days study, lovastatin exhibited more significant hepatoprotection than trimetazidine.

Conclusions: Pretreatment with two commonly available, cost effective and safe drugs can effectively prevent a potentially life-threatening adverse effect of DOX. This approach might prove very convenient for the health care providers as well as for the patients without burdening the economics.


Alanine aminotransferase, Aspartate aminotransferase, Doxorubicin, Hepatotoxicity, Lovastatin, Trimetazidine

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Harake D, Franco VI, Henkel JM, Miller TL, Lipshultz SE. Cardiotoxicity in childhood cancer survivors: strategies for prevention and management. Future Cardiol. 2012 Jul;8(4):647-70.

Salouege I, Ali RB, Saïd DB, Elkadri N, Kourda N, Lakhal M, et al. Means of evaluation and protection from doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. J Cancer Res Therapeut. 2014 Apr 1;10(2):274.

Nagai K, Oda A, Konishi H. Theanine prevents doxorubicin-induced acute hepatotoxicity by reducing intrinsic apoptotic response. Food Chem Toxicol. 2015;78:147-52.

Hozayen WG, Seif HSA, Amin S. Protective Effects of Ruitn and / or Hesperidin Against Doxorubicin-Induced Hepatotoxicity. Int J Clin Nutr. 2014;2(1):11-7.

Zhao X, Zhang J, Tong N, Chen Y, Luo Y. Protective effects of berberine on Doxorubicin-induced hepatotoxicity in mice. Biol Pharm Bull. 2012;35(5):796-800.

Damodar G, Smitha T, Gopinath S, Vijayakumar S, Rao Y. An evaluation of hepatotoxicity in breast cancer patients receiving injection Doxorubicin. Ann Med Health Sci Res. 2014 Jan;4(1):74-9.

Al-zubaidy AA, Khattab YI. The Possible Protective Effect of Pentoxifylline against Doxorubicin-Induced Hepatotoxicity Rabbits. 2014;2(9).

Thatishetty AV, Agresti N, O'Brien CB. Chemotherapy-induced hepatotoxicity. Clin Liver Dis. 2013 Nov 1;17(4):671-86.

Morris CA, El-Hiti GA, Weeks I, Woodhead S, Smith K, Kille P. Quantitative analysis of gene expression changes in response to genotoxic compounds. Toxicol Vitro. 2017 Mar 1;39:15-28.

Dézsi CA. Trimetazidine in Practice: Review of the Clinical and Experimental Evidence. Am J Ther. 2013;30(3):e871-9.

Tsioufis K, Andrikopoulos G, Manolis A. Trimetazidine and Cardioprotection. Angiology. 2015;66(3):204-10.

Mate V, Pandit V, Wani D, Dhande P. Role of trimetazidine in carbon tetrachloride induced liver damage in rats. Int J Basic Clin Pharmacol. 2014;3(1):164.

Ateyya H, Yosef H, Nader MA. Ameliorative effect of trimetazidine on cisplatin-induced hepatotoxicity in rats. Canadian J Physiol Pharmacol. 2015 Aug 19;94(2):225-30.

Boussaid AM, Selmi R, Bejaoui M, AYED KH, Zaouali MA, Abdennebi HB. Effectiveness of a single versus repeated administration of trimetazidine in the protection against warm ischemia/reperfusion injury of rat liver. Turkish J Med Sci. 2016 Jun 23;46(4):1258-64.

Rohilla A, Rohilla S, Kumar A, Khan MU, Deep A. Pleiotropic effects of statins: a boulevard to cardioprotection. Arabian J Chem. 2016 Sep 1;9:S21-7.

Henninger C, Ohlig J, Bopp A, Wartlick F, Merx M, Fritz G. Targeting of RAC1-signaling for the prevention of anthracycline-induced cardio-and hepatotoxicity. Support Care Cancer. 2014;22(1):S161.

Kumar S, Srivastava N, Gomes J. The effect of lovastatin on oxidative stress and antioxidant enzymes in hydrogen peroxide intoxicated rat. Food Chem Toxicol. 2011;49(4):898-902.

Jiang P, Mukthavaram R, Chao Y, Nomura N, Bharati IS, Fogal V, et al. In vitro and in vivo anticancer effects of mevalonate pathway modulation on human cancer cells. Br J Cancer. 2014;111(8):1562-71.

Henninger C, Huelsenbeck J, Huelsenbeck S, Grösch S, Schad A, Lackner KJ, et al. The lipid lowering drug lovastatin protects against doxorubicin-induced hepatotoxicity. Toxicol Applied Pharmacol. 2012 May 15;261(1):66-73.

Huelsenbeck J, Henninger C, Schad A, Lackner KJ, Kaina B, Fritz G. Inhibition of Rac1 signaling by lovastatin protects against anthracycline-induced cardiac toxicity. Cell Death Dis. 2011;2(8):e190.

Bopp A, Wartlick F, Henninger C, Kaina B, Fritz G. Rac1 modulates acute and subacute genotoxin-induced hepatic stress responses, fibrosis and liver aging. Cell Death Dis. 2013 Mar;4(3):e558.

Grigorian A, O’Brien CB. Hepatotoxicity Secondary to Chemotherapy. J Clin Transl Hepatol. 2014;2(2):95-106.

Desai VG, Herman EH, Moland CL, Branham WS, Lewis SM, Davis KJ, et al. Development of doxorubicin-induced chronic cardiotoxicity in the B6C3F1 mouse model. Toxicol Appl Pharmacol. 2013 Jan 1;266(1):109-21.

Octavia Y, Tocchetti CG, Gabrielson KL, Janssens S, Crijns HJ, Moens AL. Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies. J Mol Cell Cardiol. 2012;52(6):1213-25.

2Kalender Y, Yel M, Kalender S. Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats. Toxicology. 2005;209(1):39-45.

Tallarico D, Rizzo V, Maio F di, Petretto F, Bianco G, Placanica G, et al. Myocardial Cytoprotection by Trimetazidine Against Anthracycline-Induced Cardiotoxicity in Anticancer Chemotherapy. Angiology. 2003;54(2):219–27.

Osmak M. Statins and cancer: Current and future prospects. Cancer Lett. 2012;324(1):1-12.

Ramanjaneyulu SV, Trivedi PP, Kushwaha S, Vikram A, Jena GB. Protective role of atorvastatin against doxorubicin-induced cardiotoxicity and testicular toxicity in mice. J Physiol Biochem. 2013 Sep 1;69(3):513-25.

Jose J. Statins and its hepatic effects: Newer data, implications, and changing recommendations. J Pharmacy Bioallied Sci. 2016 Jan;8(1):23.

30. Sikka P, Saxena KK, Kapoor S. Statin Hepatotoxicity: Is it a Real Concern? Heart Views. 2011;12(3):104-6.