Silymarin attenuates mycophenolate mofetil-induced duodenal disorders in rats

Document Type : Original Research Article


1 Department of Pharmacology & Toxicology, Faculty of Veterinary Medicine, Urmia University, Urmia, I. R. Iran

2 Department of Pathology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran, I. R. Iran


Objective: The protective effect of silymarin (SMN) on mycophenolate mofetil (MMF)–induced duodenal disorders was investigated.
Materials and Methods: Forty-two Wistar rats were assigned to seven groups including control and test groups. The control animals received saline and the test animals were treated with MMF (30 mg/kg, orally) and saline, MMF and SMN (25, 50, and 100 mg/kg, orally), MMF and Celecoxib (CLX, 50 mg/kg, orally), and MMF and SMN plus CLX for 14 consecutive days. The antioxidant status and myeloperoxidase activity were determined and the histopathological examinations on duodenal section also were performed.
Results: Biochemical analyses revealed that SMN and CLX individually and in combination therapy could reduce the MMF-increased nitric oxide (NO) content, myeloperoxidase (MPA) activity, and malondialdehyde (MDA) level, while the MMF-reduced level of total thiol molecules (TTM) was increased significantly (p<0.05) by given compounds. Concurrent administration of SMN and CLX resulted in a synergistic effect on the reduction of MDA level and MPO activity. SMN and CLX were able to improve the MMF-induced histopathological damages including the villus atrophy and inflammatory cells infiltration.
Conclusion: Our data suggest that the MMF-induced duodenal disorders may attribute to the elevated NO and MDA levels and myeloperoxidase activity that resulted in pathological injuries. Moreover, the biochemical alterations and histopathological injuries due to MMF administration were reduced by SMN alone or in combination with CLX indicating its protective effect.


Main Subjects

Abou-Samra M, Sanda –Chedea V, Economou A, Calokerinos A, Kefalas P. 2011.    Antioxidant/pro-oxidant properties of model phenolic compounds: Part I. Studies on equimolar mixtures by chemiluminescence and cyclic voltammetry. Food Chem, 125: 622-629.
Allison AC, Eugui EM. 2000. Mycophenolate mofetil and its mechanisms of action.  Immunopharmacol, 47: 85-118.

Ashkavand Z, Malekinejad H, Amniattalab A, Rezaei-Golmisheh A, Vishwanath BS. 2012. Silymarin potentiates the anti-inflammatory effects of Celecoxib on chemically induced osteoarthritis in rats. Phytomedicine, 19: 1200-1205.

Behrend M. 2001. Adverse gastrointestinal effects of mycophenolate mofetil: Aetiology, incidence and management. Drug Saf, 24: 645-663.
Cuzzocrea S, Ianaro A, Wayman NS, Mazzon E, Pisano B, Dugo L, Serraino I, Di Paola R, Chatterjee PK, Di Rosa M, Caputi AP, Thiemermann C. 2003. The cyclopentenone prostaglandine 15-deoxy-delta (12, 14)-PGJ2 attenuates development of colon injury caused by dinitrobenzene sulphonic acid in the rat. Br J Pharmacol, 138: 678-688.
El-Lakkany NM, Hammam OA, El-Maadawy WH, Badawy AA, Ain-Shoka AA, Ebeid FA. 2012. Anti-inflammatory/anti-fibrotic effects of the hepatoprotective silymarin and the schistosomicide praziquantel against Schistosoma mansoni-induced liver fibrosis. Parasit  Vectors, 5: 9 
Fernandes PD, Landgraf RG, Britto LR, Jancar S. 2007. Production of nitric oxide by airways neutrophils in the initial phase of murine asthma. Int Immunopharmacol, 7: 96-102.
Flora K, Hahn M, Rosen H, Benner K. 1998. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol, 93: 139-143.
Gozdowska J, Urbanowicz A. 2009. Safety and tolerance of sodium mycophenolate in patients after renal transplantation--an observational study. Transplant Proc, 41: 3016-8.
Green LC, Wagner AD, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. 1982. Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem, 126: 131-138.
Herrero JL, Benlloch S, Bernardos A, Bilbao I, Castells L, Castroagudin JF, Gonzalez L, Irastorza I, Navasa M, Otero A, Pons JA, Rimola A, Suarez F, Casanovas T, Otero E, Rodriguez M, Serrano T, Otero S, Lopez I, Miras M, Prieto M. 2007. Gastrointestinal complications in liver transplant recipients: MITOS study. Transplant Proc, 39: 2311-2313.
Huang TC, Lu KT, Wo YY, Wu YJ, Yang YL. 2011. Resveratrol protects rats from Aβ-induced neurotoxicity by the reduction of iNOS expression and lipid peroxidation. PLoS One, 6: e29102.
Kiruthiga PV, Shafreen RB, Pandian SK, Arun S, Govindu S, Devi KP. 2007. Protective effect of silymarin on erythrocyte haemolysate against benzo(a)pyrene and exogenous reactive oxygen species (H2O2) induced oxidative stress. Chemosphere, 68: 1511-1518.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. 1951. Protein measurement with the Folin phenol reagent. J Biol Chem, 193: 265-275.
Malekinejad H, Cheraghi H, Alizadeh A, Khadem-Ansari MH, Tehrani AA, Varasteh S. 2011. Nitric oxide and acute phase proteins are involved in pathogenesis of mycophenolate mofetil–induced gastrointestinal disorders in rats. Transplant Proc, 43: 2741-2746.
Malekinejad H, Rahmani F, Valivande-Azar S, Taheri-Broujerdi M, Bazargani-Gilani B. 2012. Long-term administration of Silymarin augments proinflammatory mediators in the hippocampus of rats: Evidence for antioxidant and pro-oxidant effects. Hum Exp Toxicol, 31: 921-930.
Moreau JF, Bouchet PL, Molimard M, Pinson B, Couzi L, Merville P, Mahfouf W, Chaigne-Delalande SB, Guidicelli G. 2008. The immunosuppressor mycophenolic acid kills activated lymphocytes by inducing a nonclassical actin-dependent necrotic signal. J Immunol, 181: 7630-7638.
Nguyen T, Park JY, Scudiere JR, Montgomery E. 2009. Mycophenolic acid (cellcept and myofortic) induced injury of the upper GI tract. Am J Surg Pathol, 33: 1355-1363.
Niehaus WG, Samuelsson JRB. 1968. Formation of malonaldehyde from phospholipid arachidonate during microsomal lipid peroxidation. Eur J Biochem, 6: 126-130.
Parfitt JR, Jayakumar S, Driman DK. 2008. Mycophenolate mofetil-related gastrointestinal mucosal injury: Variable injury patterns, including graft-versus-host disease-like changes. Am J Surg Pathol, 32: 1367-1372.
Patel JD, Krupka T, Anderson JM. 2007. iNOS-mediated generation of reactive oxygen and nitrogen species by biomaterial-adherent neutrophils. J Biomed Mater Res, 80: 381-90.
Phatak UP, Seo-Mayer P, Jain D, Selbst M, Husain S, Pashankar DS. 2009. Mycophenolate mofetil-induced colitis in children. J Clin Gastroenterol, 43: 967-969.
Ponticelli C, Passerini P. 2005. Gastrointestinal complications in renal transplant recipients. Transpl Int, 18: 643-650.
Ranjbar A, Khorami S, Safarabadi M, Shahmoradi A, Malekirad AA, Vakilian K, Mandegary A, Abdollahi M. 2006. Antioxidant activity of Iranian Echium amoenum fisch & C.A. Mey flower decoction in humans: A cross-sectional before/after clinical trial. Evid Based Complement Alternat Med, 3: 469- 473.
Renes IB, Verburg M, Van Nispen DJPM, Bu¨ ller HA, Dekker J, Einerhand AW. 2002. Distinct epithelial responses in experimental colitis: implications for ion uptake and mucosal protection. Am J Physiol
     Gastrointest Liver Physiol, 283: G169-179.
Sánchez de Medina F, Martínez-Augustin O, González R, Ballester I, Nieto A, Gálvez J, Zarzuelo A. 2004. Induction of alkaline phosphatase in the inflamed intestine: A novel pharmacological target for inflammatory bowel disease. Biochem Pharmacol, 68: 2317-2326.
Telkes G, Peter A, Tulassay Z, Asderakis A. 2011. High frequency of ulcers, not associated with Helicobacter pylori, in the stomach in the first year after kidney transplantation. Nephrol Dial Transplant, 26: 727-732.
Turgut F, Bayrak O, Catal F, Bayrak R, Atmaca AF, Koc A, Akbas A, Akcay A, Unal D. 2008. Antioxidant and protective effects of silymarin on ischemia and reperfusion injury in the kidney tissues of rats. Int Urol Nephrol, 40: 453-460.
Watanabe M, Yuzawa K, Homma M, Ohkohchi N. 2006. Establishment of an animal model with side effects induced by mycophenolate mofetil and pharmacological analysis of them.Transplant Proc, 38: 3323-3326.