TY  - JOUR
T1  - Can Leflunomide prevent Methotrexate induced liver toxicity?
TT  - Leflunomid Methotrexat'a bağlı karaciğer toksisitesini önleyebilir mi?
AU  - Kutluana, Ufuk
AU  - Oruç, Nevin
AU  - Dinçer Tekekoğlu, Selma
AU  - Çallı Demirkan, Neşe
AU  - Akdağ, Beyza
AU  - Yılmaz, Mustafa
AU  - Yönetçi, Nadir
AU  - Özütemiz, Ömer
PY  - 2018
DA  - September
Y2  - 2018
DO  - 10.31362/patd.451731
JF  - Pamukkale Medical Journal
JO  - Pam Tıp Derg
PB  - Pamukkale University
WT  - DergiPark
SN  - 1308-0865
SP  - 321
EP  - 327
VL  - 11
IS  - 3
LA  - en
AB  - INTRODUCTION: Long-term clinical use of Methotrexate is to connect with araised risk of liver injury and fibrosis. Leflunomide is a is adisease-modifying drug. Leflunomide has a powerful inhibitory effect on nuclearfactor kappa B activation. Leflunomide also presents antioxidant activity. Inthis experimental study, we aimed to investigate the effects of Leflunomidetreatment on Methotrexate -induced hepatotoxicity.METHODS: Thirty-nine rats were divided into 4 groups. A single dose of 20mg/kgMethotrexate was injected intraperitoneally for Methotrexate-inducedhepatotoxicity. After induction, Leflunomide (10 mg/kg) was administered intothe stomach for consecutive 5 days. Then, serum samples and homogenated livertissues were collected for analyzed serum alanine aminotransferase, alkalinephosphatase, superoxide dismutase activity, myeloperoxidase activity,glutathione levels and assessment of histopathology. RESULTS: Leflunomide treatment significantly ameliorated total histopathologicscore according to semiquantitative scale compared to the untreated group,(Pathological score 1.1+0.7 versus 5.1+2 respectively, p<0,01). Leflunomidetreatment significantly ameliorated Kuppfer cell activation. (Elevation of theactivated Kupffer cells score were 0.2+0.6 and 2.5+1.01 respectively, p =0.001). The serum alanine aminotransferase, alkaline phosphatase levels werelower and glutathione levels, myeloperoxidase activity, and superoxidedismutase activity were similar between Leflunomide treated and untreatedMethotrexate toxicity groups. DISCUSSION AND CONCLUSION: Leflunomide treatment ameliorated Methotrexateinduced liver toxicity in an experimental model.
KW  - Leflunomide
KW  - methotrexate
KW  - liver toxicity
N2  - GİRİŞ ve AMAÇ: Uzun dönem Methotrexat kullanımı artmış karaciğer hasarı vefibrozis riski ile ilişkilidir. Leflunomid hastalık modifiye edici bir ilaçtır.Leflunomid nükleer faktör kappa B aktivasyonunun güçlü bir inhibitörüdür. Aynızamanda anti-oksidan aktivitesi de vardır. Bu deneysel çalışmada Methotrexat'ınneden olduğu karaciğer toksisitesinde Leflunomid tedavisinin etkinliğiaraştırılmıştır. YÖNTEM ve GEREÇLER: 39 rat 4 gruba ayrılmıştır. Methotrexat'a bağlı karaciğertoksisitesi tek doz 20mg/kg Methotrexat'ın periton içine injeksiyonu ileoluşturulmuştur. Ardından Leflunomid 5 gün boyunca 10 mg/kg dozda verilmiştir.Ardından serum örnekleri ve homojenize karaciğer örnekleri toplanmıştır. Serumalanin aminotransferaz, alkalin fosfataz, superoxide dismutaz, myeloperoxidazaktivitesi, glutatyon düzeyleri çalışılmış ve histopatolojik değerlendirmeyapılmıştır. BULGULAR: Leflunomid tedavisi tedavi almayan gruba göre karaciğersemikantitatif skalaya bağlı histopatolojik değerlendirmede anlamlı düzelmesağlamıştır (Patolojik skor 1.1+0.7 ve 5.1+2, p<0,01). Leflunomid tedavisiKuppfer hücre aktivasyonunu anlamlı derecede iyileştirmiştir. (Aktive Kuppferhücre skorunda yükselme 0.2+0.6 ve 2.5+1.01, p = 0.001). Leflunomid tedavisialan grupta Methotrexat toksisite grubuna göre serum alanin aminotransferaz,alkalin fosfataz düzeyleri düşük, glutatyon seviyesi, superoxide dismutaz vemyeloperoxidaz aktivitesi benzer bulunmuştur. TARTIŞMA ve SONUÇ: Bu deneysel modelde Leflunomid tedavisi Methotrexat'a bağlıkaraciğer toksisitesini iyileştirmektedir. 
CR  - References
CR  - 1.Feagan BG, Alfadhli A. Methotrexate in inflammatory bowel disease. Gastroenterol Clin North Am 2004;33:407-420
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 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
CR  - 9. Özturk E, Demirbilek S, BegecZ, et al. Does leflunomide attenuate the sepsis-induced acute lung injury? Pediatr Surg Int 2008;24:899-905
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 13. Akerboom TP, Sies H. Assay of glutathione, glutathione disulfide and glutathione mixed disulfides in biological samples. Methods Enzymol 1981;77:373-382.
CR  - 14. Hillegass LM, Griswold DE, Brickson B, Albrightson WC, Assessment of myeloperoxidase activity in whole rat kidney. J Pharmacol Methods 1990;24:285-295.
CR  - 15. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1988;34:497-500.
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 21. Kobayashi K, Terada C, Tsukamoto I. Methotrexate-induced apoptosis in hepatocytes after partial hepatectomy. Eur J Pharmacol 2002;438:19-24.
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 28. Hall PD, Jenner MA, Ahern MJ. Hepatotoxicity in a rat model caused by orally administered methotrexate. Hepatology 1991;14:906-910.
CR  - 29. Mackay IR. Hepatoimmunology: A perspective. Immunol. Cell Biol 2002;80:36-44.
CR  - 30. Muriel P. NF-kappaB in liver diseases: a target for drug therapy. J Appl Toxicol 2009;29:91-100.
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 34. Muriel P, Mourelle M. Prevention by silymarin of membrane alterations in acute CC14 liver damage. J Appl Toxicol 1990;10:275-279.
CR  - 35. Muriel P, Rivera-Espinoza Y. Beneficial drugs for liver diseases. J Appl Toxicol 2008;28:93-103.
CR  - 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.
CR  - 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.
CR  - 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.
CR  - 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.
UR  - https://doi.org/10.31362/patd.451731
L1  - https://dergipark.org.tr/en/download/article-file/520758
L1  - https://dergipark.org.tr/en/download/article-file/544625
ER  -