Leflunomid Methotrexat'a bağlı karaciğer toksisitesini önleyebilir mi?

Öz

GİRİŞ ve AMAÇ: Uzun dönem Methotrexat kullanımı artmış karaciğer hasarı ve fibrozis riski ile ilişkilidir. Leflunomid hastalık modifiye edici bir ilaçtır. Leflunomid nükleer faktör kappa B aktivasyonunun güçlü bir inhibitörüdür. Aynı zamanda anti-oksidan aktivitesi de vardır. Bu deneysel çalışmada Methotrexat'ın neden olduğu karaciğer toksisitesinde Leflunomid tedavisinin etkinliği araştırılmıştır.
YÖNTEM ve GEREÇLER: 39 rat 4 gruba ayrılmıştır. Methotrexat'a bağlı karaciğer toksisitesi tek doz 20mg/kg Methotrexat'ın periton içine injeksiyonu ile oluşturulmuştur. Ardından Leflunomid 5 gün boyunca 10 mg/kg dozda verilmiştir. Ardından serum örnekleri ve homojenize karaciğer örnekleri toplanmıştır. Serum alanin aminotransferaz, alkalin fosfataz, superoxide dismutaz, myeloperoxidaz aktivitesi, glutatyon düzeyleri çalışılmış ve histopatolojik değerlendirme yapılmıştır.
BULGULAR: Leflunomid tedavisi tedavi almayan gruba göre karaciğer semikantitatif skalaya bağlı histopatolojik değerlendirmede anlamlı düzelme sağlamıştır (Patolojik skor 1.1+0.7 ve 5.1+2, p<0,01). Leflunomid tedavisi Kuppfer hücre aktivasyonunu anlamlı derecede iyileştirmiştir. (Aktive Kuppfer hücre skorunda yükselme 0.2+0.6 ve 2.5+1.01, p = 0.001). Leflunomid tedavisi alan grupta Methotrexat toksisite grubuna göre serum alanin aminotransferaz, alkalin fosfataz düzeyleri düşük, glutatyon seviyesi, superoxide dismutaz ve myeloperoxidaz aktivitesi benzer bulunmuştur.
TARTIŞMA ve SONUÇ: Bu deneysel modelde Leflunomid tedavisi Methotrexat'a bağlı karaciğer toksisitesini iyileştirmektedir. 

Anahtar Kelimeler

• Leflunomid,methotrexat,karaciğer toksisitesi

Can Leflunomide prevent Methotrexate induced liver toxicity?

Abstract

INTRODUCTION: Long-term clinical use of Methotrexate is to connect with a raised risk of liver injury and fibrosis. Leflunomide is a is a disease-modifying drug. Leflunomide has a powerful inhibitory effect on nuclear factor kappa B activation. Leflunomide also presents antioxidant activity. In this experimental study, we aimed to investigate the effects of Leflunomide treatment on Methotrexate -induced hepatotoxicity.
METHODS: Thirty-nine rats were divided into 4 groups. A single dose of 20mg/kg Methotrexate was injected intraperitoneally for Methotrexate-induced hepatotoxicity. After induction, Leflunomide (10 mg/kg) was administered into the stomach for consecutive 5 days. Then, serum samples and homogenated liver tissues were collected for analyzed serum alanine aminotransferase, alkaline phosphatase, superoxide dismutase activity, myeloperoxidase activity, glutathione levels and assessment of histopathology.
RESULTS: Leflunomide treatment significantly ameliorated total histopathologic score according to semiquantitative scale compared to the untreated group, (Pathological score 1.1+0.7 versus 5.1+2 respectively, p<0,01). Leflunomide treatment significantly ameliorated Kuppfer cell activation. (Elevation of the activated Kupffer cells score were 0.2+0.6 and 2.5+1.01 respectively, p = 0.001). The serum alanine aminotransferase, alkaline phosphatase levels were lower and glutathione levels, myeloperoxidase activity, and superoxide dismutase activity were similar between Leflunomide treated and untreated Methotrexate toxicity groups.
DISCUSSION AND CONCLUSION: Leflunomide treatment ameliorated Methotrexate induced liver toxicity in an experimental model.

Keywords

• Leflunomide,methotrexate,liver toxicity

Kaynakça

1. References
2. 1.Feagan BG, Alfadhli A. Methotrexate in inflammatory bowel disease. Gastroenterol Clin North Am 2004;33:407-420
3. 2. Richard S, Guerret S, Gerard F, Tebib JG, Vignon E. Hepatic fibrosis in rheumatoid arthritis patients treated with methotrexate: application of a new semi-quantitative scoring system. Rheumatology (Oxford)2000;39:50-54.
4. 3. Beyeler C, Reichen J, Thomann SR, Lauterburg BH, Gerber NJ. Quantitative liver function in patients with rheumatoid arthritis treated with low dose methotrexate: A longitudinal study. Br J Rheumatol 1997;36:338-344.
5. 4. Boffa MJ, Chalmers RJ, Haboubi NY, Shomaf M, Mitchell DM. Sequential liver biopsies during long-term methotrexate treatment for psoriasis: A reappraisal. Br J Dermatol 1995;133:774-778.
6. 5. Neuman MG, Cameron RG, Haber JA, Katz GG, Malkiewicz IM, Shear NH. Inducers of cytochrome P450 2E1 enhance methotrexate induced hepatotoxicity. Clin Biochem 1999;32:519-536.
7. 6. Mladenovıc V, Domljan Z, Rozman B et al. Safety and effectiveness of leflunomide in the treatment of patients with active rheumatoid arthritis. Results of a randomized, placebo-controlled, phase II study. Arthritis Rheum 1995;38:1595-1603.
8. 7. MannaSK, Aggarwal BB. Immunosuppressive leflunomide metabolite (A77 1726) blocks TNF-dependent nuclear factor-kappa B activation and gene expression. J Immunol. 1999;162:2095-2102.

9. 8. Bartlett RR, Anagnostopulos H, Zıelınskı T, Mattar T, Schleyerbach R. Effects of leflunomide on immune responses and models of inflammation. Springer Semin Immunopathol 1993;14:381-394
10. 9. Özturk E, Demirbilek S, BegecZ, et al. Does leflunomide attenuate the sepsis-induced acute lung injury? Pediatr Surg Int 2008;24:899-905
11. 10. Manna SK, Mukhopadhyay A, Aggarwal BB. Leflunomide suppresses TNF-induced cellular responses: effects on NF-kappa B, activator protein-1, c-Jun N-terminal protein kinase, and apoptosis. J Immunol. 2000;165:5962-5969.
12. 11.Yao HW, Li J, Chen JQ, Xu SY. Inhibitory effect of leflunomide on hepatic fibrosis induced by CCl4 in rats. Acta Pharmacol Sin 2004;25:915-920.
13. 12. Uraz S, Tahan V, Aygun C, et al. Role of ursodeoxycholic acid in prevention of methotrexate-induced liver toxicity. Dig Dis Sci 2008;53:1071-1077.
14. 13. Akerboom TP, Sies H. Assay of glutathione, glutathione disulfide and glutathione mixed disulfides in biological samples. Methods Enzymol 1981;77:373-382.
15. 14. Hillegass LM, Griswold DE, Brickson B, Albrightson WC, Assessment of myeloperoxidase activity in whole rat kidney. J Pharmacol Methods 1990;24:285-295.
16. 15. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1988;34:497-500.
17. 16. Demling R, Lalonde C, Knox J, Youn Y, Zhu D, Daryani R. Fluid resuscitation with deferoxamine prevents systemic burn induced oxidant injury. J Trauma 1991;31:538-543.
18. 17. Sener G, Toklu H, Kapucu C, et al. Melatonin protects against oxidative organ injury in a rat model of sepsis. Surg Today 2005;35:52-59. 18. Roenigk HH, Auerbach R, Weinstein GD. Use of methotrexate in psoriasis. Arch Dermatol 1972;105:363-365.
19. 19. Alves JA, Fialho SC, Morato EF, et al. Liver toxicity is rare in rheumatoid arthritis patients using combination therapy with leflunomide and methotrexate. Rev Bras Reumatol. 2011;51:141-144.
20. 20. Borg EJ, Seldenrijk CA, Timmer R. Liver cirrhosis due to methotrexate in a patient with rheumatoid arthritis. Neth J Med 1996;49:244-246.
21. 21. Kobayashi K, Terada C, Tsukamoto I. Methotrexate-induced apoptosis in hepatocytes after partial hepatectomy. Eur J Pharmacol 2002;438:19-24.
22. 22. Cetinkaya A, Bulbuloglu E, Kurutas EB, Kantarceken B. N-acetylcysteine ameliorates methotrexate-induced oxidative liver damage in rats. Med Sci Monit 2006;12:274-278.
23. 23. Cetin A, Kaynar L, Kocyigit I. et al. Role of grape seed extract on methotrexate induced oxidative stress in rat liver. Am J Chin Med 2008;36:861-872.
24. 24. Jahovic N, Cevik H, Sehirli AO, Yeğen BC, Sener G. Melatonin prevents methotrexate-induced hepatorenal oxidative injury in rats. J Pineal Res 2003;34:282-287.
25. 25. Karaman A, Iraz M, Kirimlioglu H, Karadag N, Tas E, Fadillioglu E. Hepatic damage in biliary-obstructed rats is ameliorated by leflunomide treatment. Pediatr Surg Int 2006;229:701-708.
26. 26. Imose M, Nagaki M, Kimura K, et al. Leflunomide protects from T-cell-mediated liver injury in mice through Iinhibition of nuclear factor kappaB. Hepatology 2004;40:1160-1169.
27. 27. Latchoumycandane C, Seah QM, Tan RC, Sattabongkot J, Beerheide W, Boelsterli UA. Leflunomide or A77 1726 protect from acetaminophen-induced cell injury through inhibition of JNK-mediated mitochondrial permeability transition in immortalized human hepatocytes. Toxicol Apol Parmacol 2006;217:125-133.
28. 28. Hall PD, Jenner MA, Ahern MJ. Hepatotoxicity in a rat model caused by orally administered methotrexate. Hepatology 1991;14:906-910.
29. 29. Mackay IR. Hepatoimmunology: A perspective. Immunol. Cell Biol 2002;80:36-44.
30. 30. Muriel P. NF-kappaB in liver diseases: a target for drug therapy. J Appl Toxicol 2009;29:91-100.
31. 31. Perez-Alvarez V, Bobadilla RA, Muriel P. Structure-hepatoprotective activity relationship of 3,4-dihydroxycinnamic acid (caffeic acid) derivatives. J Appl Toxicol 2001;21:527-531.
32. 32. Bruck R, Schey R, Aeed H, Hochman A, Genina O, Pines M. A protective effect of pyrrolidine dithiocarbamate in a rat model of liver cirrhosis. Liver Int 2004;24:169-176.
33. 33. Chávez E, Reyes-Gordillo KR, Segovia J, et al. Resveratrol prevents fibrosis, NF-kappaB activation and TGF-beta increases induced by chronic CCl4 treatment in rats. J Appl Toxicol 2008;28:35-43.
34. 34. Muriel P, Mourelle M. Prevention by silymarin of membrane alterations in acute CC14 liver damage. J Appl Toxicol 1990;10:275-279.
35. 35. Muriel P, Rivera-Espinoza Y. Beneficial drugs for liver diseases. J Appl Toxicol 2008;28:93-103.
36. 36. Khafaga AF, El-Sayed YS. Spirulina ameliorates methotrexate hepatotoxicity via antioxidant, immune stimulation, and proinflammatory cytokines and apoptotic proteins modulation.Life Sci 2018;196:9-17.
37. 37. Mehrzadi S, Fatemi I, Esmaeilizadeh M. Ghaznavi H, Kalantar H, Goudarzi M. Hepatoprotective effect of berberine against methotrexate induced liver toxicity in rats. Biomed Pharmacother 2018;97:233-239.
38. 38.Bilasy SE, Essawy SS, Mandour MF, Ali EA, Zaitone SA. Myelosuppressive and hepatotoxic potential of leflunomide and methotrexate combination in a rat model of rheumatoid arthritis. Pharmacol Rep 2015;67:102-114.
39. 39. Curtis JR, Beukelman T, Onofrei A, et al. Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide. Ann Rheum Dis 2010;69:43-47.