• Elza Maria Calegari
  • Helena Cristina Endres Curso de Farmácia, Instituto de Ciências Biológicas, Universidade de Passo Fundo, Passo Fundo, Brazil
  • Eliane Dallegrave Curso de Farmácia, Instituto de Ciências Biológicas, Universidade de Passo Fundo, Passo Fundo, Brazil
  • Lucas Henrique Cendron Curso de Farmácia, Instituto de Ciências Biológicas, Universidade de Passo Fundo, Passo Fundo, Brazil
  • Charise Dallazem Bertol Curso de Farmácia, Instituto de Ciências Biológicas, Universidade de Passo Fundo, Passo Fundo, Brazil
  • Luciano Oliveira Siqueira Curso de Farmácia, Instituto de Ciências Biológicas, Universidade de Passo Fundo, Passo Fundo, Brazil
  • Luciana Grazziotin Rossato Curso de Farmácia, Instituto de Ciências Biológicas, Universidade de Passo Fundo, Passo Fundo, Brazil


Objective:  Methotrexate (MTX) is the gold standard in rheumatoid arthritis treatment; however, its continued use is related to hepatotoxicity. Thus, the aim of the present work is to evaluate the protective role of silymarin (SLM) against MTX-induced hepatotoxicity.

Methods:  Male Wistar rats were treated by gavage for 4 weeks as followed:  Control (saline solution, daily), MTX (900µg/kg, once a week and daily with saline solution), SLM (50 mg/kg, daily) and MTX+SLM (MTX 900µg/kg, once a week, SLM 50 mg/kg, daily).

Results:  MTX rats presented macro-and microscopic changes in the liver that was not counteracted by SLM. SLM was able to prevent the significant increase in lipid peroxidation observed in the hepatic tissue of MTX rats. SLM+MTX presented a decrease in the hepatic non-proteic thiols compared to control; suggesting SLM favors detoxification through glutathione conjugation. It was also seen changes in the relative mass of the spleen and lungs of MTX rats.

Conclusions:  SLM protects partially against MTX-induced hepatotoxicity.


Keywords: Hepatotoxicity, Hepato protection, Milk thistle, Silymarin, Rheumatoid arthritis


Download data is not yet available.


Weinblatt M, Kaplan H, Germain B. Methotrexate in rheumatoid arthritis. A five-year prospective multicenter study. Arthritis Rheum 1994;37:1492–8.
2. Wasko MCM, Dasgupta A, Hubert H, Fries JF, Ward MM. Propensity-adjusted association of methotrexate with overall survival in rheumatoid arthritis. Arthritis Rheum Rheum 2013;65:334–42.
3. Saag K, Gim G, Patkar N, Anuntiyo J, Finney C, Curtis J, et al. American college of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Care Res 2008;59:762–84.
4. Kevat S, Ahern M, Hall P. Hepatotoxicity of methotrexate in rheumatic diseases. Med Toxicol Adverse Drug Exper 1988;3:197–208.
5. Neuman M, Cameron R, Haber J, Katz G, Malkiewicz I, Shear N. Inducers of cytochrome P450 2E1 enhance methotrexate-induced hepatocytotoxicity. Clin Biochem 1999;32:519–36.
6. Feher J, Lengyel G. Silymarin in the prevention and treatment of liver diseases and primary liver cancer. Curr Pharm Biotech 2012;13:210–7.
7. Wellington K, Jarvis B. Silymarin: a review of its clinical properties in the management of hepatic disorders. BioDrugs 2001;15:465–89.
8. Abenavoli L, Aviello G, Capasso R, Milic N, Capasso F. Milk thistle for treatment of nonalcoholic fatty liver disease. Hepatitis Monthly 2011;11:173–7.
9. Manna S, Mukhopadhyay A, Van N, Aggarwal B. Silymarin suppresses TNF-induced activation of NF-kappa B, c-Jun N-terminal kinase, and apoptosis. J Immunol 1999;163:6800–9.
10. Flora K, Hahn M, Rosen H, Benner K. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 1998;93:139–43.
11. Rossato LG, Costa VM, Dallegrave E, Arbo M, Dinis-Oliveira RJ, Silva A, et al. Cumulative mitoxantrone-induced haematologic and hepatic adverse effects in a sub-chronic in vivo model. Basic Clin Pharmacol Toxicol 2014;114:254–62.
12. Bradford M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248–54.
13. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem 1979;95:351–8.
14. Ellman GL. Tissue sulfhydryl groups. Arch Biochem Biophys 1959;82:70–7.
15. Sharma O, Bhat T. DPPH antioxidant assay revisited. Food Chem 2009;113:1202–5.
16. Zachariae H. Liver biopsies and methotrexate: a time for reconsideration? J Am Acad Dermatol 2001;44:879–80.
17. Yeo C, Chong V, Earnest A, Yang W. Prevalence and risk factors of methotrexate hepatoxicity in Asian patients with psoriasis. World J Hepatol 2013;5:275–80.
18. Cronstein B. The mechanism of action of methotrexate. Rheum Dis Clin North Am 1997;23:739–55.
19. Ladas E, Kroll D, Oberlies N, Cheng B, Ndao D, Rheingold S, et al. A randomized, controlled, double-blind, pilot study of milk thistle for the treatment of hepatotoxicity in childhood Acute Lymphoblastic Leukemia (ALL). Cancer 2010;116:506–13.
20. Mayer K, Myers R, Lee S. Silymarin treatment of viral hepatitis: a systematic review. J Viral Hepatitis 2005;12:559–67.
21. Pradeep K, Mohan C, Gobianand K, Karthikeyan S. Silymarin modulates the oxidant-antioxidant imbalance during diethylnitrosamine induced oxidative stress in rats. Eur J Pharmacol 2007;560:110–6.
22. Rossato LG, Costa VM, de Pinho PG, Carvalho F, Bastos ML, Remião F. Structural isomerization of synephrine influences its uptake and ensuing glutathione depletion in rat-isolated cardiomyocytes. Arch Toxicol 2011;85:929–39.
23. Victorrajmohan C, Pradeep K, Karthikeyan S. Influence od silymarin administration on hepatic glutathione conjugating enzyme system in rats treated with antitubercular drugs. Drugs R D 2005;6:395–400.
24. Das S, Vasudevan D. Protective effects of silymarin, a milk thistle (Silybium marianum) derivative on ethanol-induced oxidative stress in liver. Indian J Biochem Biophys 2006;43:306–11.
25. Bressan A, Silva R, Fontenelle E, Gripp A. Imunossupressores na dermatologia. An Bras Dermatol 2010;85:9–22.
26. Miller T, Schaefer F. Changes in mouse circulating leukocyte numbers in C57BL/6 mice immunosuppressed with dexamethasone for Crypstosporidium parvum oocyst production. Vet Parasitol 2007;149:147–57.
27. Rosenow E, Myers J, SJ S, Pisani R. Drug-induced pulmonary disease. An update. Chest J 1992;102:239–50.
28. Hilliquin P, Ronoux M, Perrot S, Puéchal X, Menkès C. Occurence of pulmonary complications during methotrexate therapy in rheumatoid arthritis. Br J Rheumatol 1996;35:441–5.
350 Views | 614 Downloads
How to Cite
Calegari, E. M., H. C. Endres, E. Dallegrave, L. H. Cendron, C. D. Bertol, L. O. Siqueira, and L. G. Rossato. “SILYMARIN ELICITS PARTIAL PROTECTION AGAINST METHOTREXATE-INDUCED HEPATOTOXICITY IN WISTAR RATS”. International Journal of Pharmacy and Pharmaceutical Sciences, Vol. 7, no. 9, July 2015, pp. 462-5,
Original Article(s)