Effect of leflunomide on methotrexate-induced oxidative small intestinal injury in rats

Öz

Background and Aims: The aim of this study was to investigate the effects of leflunomide treatment in methotrexate-induced oxidative small intestinal injury in rats. Materials and Methods: Forty rats were randomly divided into 4 groups. Methotrexate-induced intestinal injury was induced by single dose intraperitoneal injection of 20 mg/kg methotrexate. After induction, leflunomide (10 mg/kg/day) was administered intragastrically for 5 consecutive days. On the sixth day, homogenized small intestine tissues were examined for superoxide dismutase activity, myeloperoxidase activity, and glutathione and malondialdehyde levels. Results: Leflunomide treatment significantly decreased tissue myeloperoxidase activity and malondialdehyde levels (3.4±0.7, 1.9±0.4, p

Anahtar Kelimeler

• Leflunomide, methotrexate, intestinal injury

Ratlarda metotreksata bağlı oksidatif intestinal hasarda leflunomidinin koruyucu etkisinin araştırılması

Öz

Giriş ve Amaç: Bu çalışmanın amacı metotreksata bağlı oksidatif ince barsak hasarında leflunomid tedavisinin etkisini araştırmaktır. Gereç ve Yöntem: 40 adet rat randomize olarak dört gruba ayrılmıştır. Metotreksata bağlı ince barsak hasarı 20 mg/kg metotreksatın tek doz intraperitoneal injeksiyonu ile oluşturulmuştur. İndüksiyon sonrası leflunomid 10 mg/kg/gün dozunda intra gastrik olarak 5 gün boyunca verilmiştir. İnce barsak dokuları, 6. gün superoksit dismutaz aktivitesi, myeloperoksidaz aktivitesi, glutatyon ve malondialdehit düzeylerinin ölçümü için homojenize edilmiştir. Bulgular: Leflunomid tedavisi doku myeloperoksidaz aktivitesi ve malondialdehit düzeylerini anlamlı ölçüde azaltmıştır (Sırasıyla 3.4±0.7, 1.9±0,4 p < 0.05 ve 231±199, 94±80 p < 0.05). Leflunomid tedavisi doku glutatyon düzeyleri ve süperoksit dizsmutaz aktivitesindeki azalmayı anlamlı ölçüde iyileştirmiştir (Sırasıyla 21±0.5, 25±3 p < 0.05 ve 22±0.6, 25±2 p < 0.05). Sonuç: Leflunomid tedavisi metotreksata bağlı ince barsak hasarındaki oksidatif parametreleri düzeltmektedir.

Anahtar Kelimeler

• Leflunomid, metotreksat, intestinal hasar

Kaynakça

1. Schilsky RL. Methotrexate: An effective agent for treating cancer and building careers. The polyglutamate era. Stem Cells 1996; 14: 29-32.
2. Naldi L, Griffiths CE. Traditional therapies in the management of moderate to severe chronic plaque psoriasis: an assessment of the benefits and risks. Br J Dermatol 2005;152: 597-615.
3. Wu JJ, Schiff KR. Sarcoidosis. Am Fam Physician 2004; 70: 312-22.
4. Feagan BG, Alfadhli A. Methotrexate in inflammatory bowel disease. Gastroenterol Clin North Am 2004; 33: 407-20.
5. Langford CA. Management of systemic vasculitis. Best Pract Res Clin Rheumatol 2001; 15: 281-97.
6. Friis H, Andreasen PB. Drug-induced hepatic injury: an analysis of 1,100 cases reported to the Danish Committee on Adverse Drug Reactions between 1978 and 1987. J Intern Med 1992; 232: 1338.
7. Nagakubo J, Tomimatsu T, Kitajima M, et al. Characteristics of transport of fluoresceinated methotrexate in rat small intestine. Life Sci 2001; 69: 739-47.
8. Gibson RJ, Bowen JM, Cummins AG, Keefe DM. Relationship between dose of methotrexate, apoptosis, p53/p21 expression and intestinal crypt proliferation in the rat. Clin Exp Med 2005; 4: 18895.

9. Gao F, Horie T. A synthetic analog of prostaglandin E1 prevents the production of reactive oxygen species in the intestinal mucosa of methotrexate treated rats. Life Sci 2002; 71: 1091-9.
10. Cody V, Luft JR, Pangborn W, et al. Understanding the role of Leu22 variants in methotrexate resistance: comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate reductase ternary crystal complexes with methotrexate and NADPH. Acta Crystallogr D Biol Crystallogr 2005; 61: 147-55.
11. ter Borg EJ, Seldenrijk CA, Timmer R. Liver cirrhosis due to methotrexate in a patient with rheumatoid arthritis. Neth J Med 1996; 49: 244-6.
12. van't Land B, Blijlevens NM, Marteijn J, et al. Role of curcumin and the inhibition of NF-kappaB in the onset of chemotherapy-induced mucosal barrier injury. Leukemia 2004; 18: 276-84
13. Manna SK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF- dependent nuclear factor-kappaB activation and gene expression. J Immunol 1999; 162: 2095-102.
14. Yao HW, Li J, Jin Y, et al. Effect of leflunomide on immunological liver injury in mice. World J Gastroenterol 2003; 9: 320-3.
15. Jahovic1 N, Sener G, Çevik H, et al. Amelioration of methotrexateinduced enteritis by melatonin in rats. Cell Biochem Funct 2004; 22: 169-78.
16. Yao HW, Li J, Chen JQ, Xu SY. Inhibitory effect of leflunomid on hepatic fibrosis induced by CCl4 in rats. Acta Pharmacol Sin 2004; 25: 915-20.
17. Naito Y, Yoshikawa T, Matsuyama K, et al. Neutrophils, lipid peroxidation, and nitric oxide in gastric reperfusion injury in rats. Free Radic Biol Med 1998; 24: 494-502.
18. Akerboom TP, Sies H. Assay of glutathione, glutathione disulfide and glutathione mixed disulfides in biological samples. Meth Enzymol 1981; 77: 373-82.
19. Yagi K. Lipid peroxides in hepatic, gastrointestinal, and pancreatic diseases. Adv Exp Med Biol 1994; 366: 165-9.
20. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1998; 34: 497-500.
21. Siegers CP, Riemann D, Thies E, Younes M. Glutathione and GSH dependent enzymes in the gastrointestinal mucosa of the rat. Cancer Lett 1988; 40: 71-6.
22. Jubeh TT, Antler S, Haupt S, et al. Local prevention of oxidative stress in the intestinal epithelium of the rat by adhesive liposomes of superoxide dismutase and tempamine. Mol Pharm 2005; 2: 211.
23. Ciralik H, Bulbuloglu E, Cetinkaya A, et al. Effects of N-acetylcysteine on methotrexate-induced small intestinal damage in rats. Mt Sinai J Med 2006; 73: 1086-92.
24. Zimmerman BJ, Granger N. Reperfusion injury. Surg Clin North Am 1992; 72: 65-83.
25. Bartlett RR, Anagnostopulos H, Zielinski T, et al. Effects of leflunomid on immune responses and models of inflammation. Springer Semin Immunopathol 1993; 14: 381-94.
26. Karin M, Lin A. NF-kappaB at the crossroads of life and death. Nat Immunol 2002; 3: 221-7.
27. Taminiau J, Gall DG, Hamilton JR. Response of the rat small-intestine epithelium to methotrexate. Gut 1980; 21: 486-92