Ratlarda Metotreksat ile Oluşturulan Karaciğer ve BöbrekHasarı Üzerine Eskuletin’in Etkileri

Bu çalışmada metotreksat (MTX) ile ratlarda oluşturulan karaciğer ve böbrek hasarı üzerineEskuletin’in etkisinin araştırılması amaçlandı. Çalışma Grup 1 (Kontrol grubu), Grup 2 (MTX), Grup3 (Eskuletin) ve Grup 4 (MTX+Eskuletin) olmak üzere toplam 4 gruptan oluştu. Grup 3 ve 4’dekiratlara 14 gün süre ile 100 mg/kg dozda eskuletin uygulandı. Ayrıca Grup 2 ve 4’deki ratlaradenemenin 9. gününde 20 mg/kg dozda intraperitonal olarak MTX enjekte edildi. MTX uygulamasından 5 gün sonra çalışma sonlandırıldı. Çalışma sonunda, MTX grubunda karaciğer veböbrek dokusu malondialdehit (MDA) düzeylerinin arttığı, karaciğerde redukte glutatyon (GSH)düzeyinin azaldığı, her iki dokuda glutatyon peroksidaz (GSH-Px) ve katalaz (CAT) enzimaktivitelerinin ise önemli düzeyde azaldığı ve MTX uygulamasının bu dokularda oksidatif streseneden olduğu tespit edildi. Eskuletin ile tedavi edilen gruplarda karaciğer ve böbrek dokusu MDAseviyelerinin azaldığı, GSH-Px ve CAT aktivitelerinin arttığı belirlendi. Ayrıca eskuletinuygulamasının artan serum alanin transaminaz (ALT) ve aspartat transaminaz (AST) seviyelerinide azalttığı görüldü. Histopatolojik analizlerde ise MTX’in hem karaciğer hem böbrekte hidropikdejenerasyon, yangısal hücre infiltrasyonu gibi dejeneratif ve yangısal değişikliklere sebep olduğu;eskuletin uygulamasının bu lezyonları önemli miktarda azalttığı tespit edildi. Sonuç olarakeskuletinin, antioksidan ve antiinflamatuvar etkileri ile MTX’in sebep olduğu karaciğer ve böbrekhasarını önlediği veya minimize ettiği belirlendi.

Effects of Esculetin on the Methotrexate Induced Liver and Kidney Damage in Rats

In this study, it was aimed to investigate the effect of Esculetin on liver and kidney damage inducedby methotrexate (MTX) in rats. Our study consisted of 4 groups: Group 1 (Control group), Group 2(MTX), Group 3 (Esculetin) and Group 4 (MTX+Esculetin). Groups 3 and 4 received a dose of 100mg / kg esculetin by orally during 14 days. In addition, groups 2 and 4 received MTX at a dose of20 mg / kg intraperitoneally on the 9th day of the experiment. The study was terminated 5 daysafter the MTX application. Liver and kidney tissue MDA levels increased, GSH level and CAT andGSH-Px enzyme activities significantly decreased in MTX group and MTX administration causedoxidative stress in these tissues. Esculetin administration reduced the MDA level in liver and kidneytissues and increased the CAT and GSH-Px enzyme activities. In addition, esculetin administrationdecreased serum AST, ALT. At the histopathological examination, MTX caused degenerative andinflammatory changes such as hydropic degeneration and inflammatory cell infiltration in both liverand kidney. It was determined that esculetin significantly reduced these lesions. In conclusion,esculetin can prevent or minimize MTX induced liver and kidney damage due to its antioxidant andanti-inflammatory activities.

___

  • 1. Montasser AOS, Saleh H, Ahmed-Farid OA, Saad A, Marie MS. Protective effects of balanites aegyptiaca extract, melatonin and ursodeoxycholic acid against hepatotoxicity induced by methotrexate in male rats. Asian Pac J Trop Med 2017; 10: 557-565.
  • 2. Yousefi G, Shafaatic A, Zarghic A, Foroutan SM. Pharmacokinetics and biodistribution of pegylated methotrexate after IV administration to mice. Iran J Pharm Res 2018; 17: 111-123.
  • 3. Hagner N, Joerger M. Cancer chemotherapy: Targeting folic acid synthesis. Cancer Manag Res 2010; 2: 293-301. 4. Bath RK, Brar NK, Forouhar FA, Wu GY. A review of methotrexateassociated hepatotoxicity. J Dig Dis 2014; 15: 517-524.
  • 5. Asci H, Ozmen O, Ellidag HY, et al. The impact of gallic acid on the methotrexate-induced kidney damage in rats. J Food Drug Anal 2017; 25: 890-897.
  • 6. Ali N, Rashid S, Nafees S, et al. Protective effect of chlorogenic acid against methotrexate induced oxidative stress, inflammation and apoptosis in rat liver: An experimental approach. Chem Biol Interact 2017; 272: 80- 91.
  • 7. Xu K, Cai YS, Lu SM, et al. Autophagy induction contributes to the resistance to methotrexate treatment in rheumatoid arthritis fibroblast-like synovial cells through high mobility group box chromosomal protein 1. Arthritis Res Ther 2015; 17: 1-10.
  • 8. Coleshowers CL, Oguntibeju OO, Ukpong M, Truter EJ. Effects of methotrexate on antioxidant enzyme status in a rodent model. Med Tech SA 2010; 24: 5-9.
  • 9. Wiczer T, Dotson E, Tuten A, Phillips G, Maddocks K. Evaluation of incidence and risk factors for high-dose methotrexate-induced nephrotoxicity. J Oncol Pharm Pract 2016; 22: 430-436.
  • 10. Lanse SB, Arnold GL, Gowans JD, Kaplan MM. Low incidence of hepatotoxicity associated with long‐term, low‐ dose oral methotrexate in treatment of refractory psoriasis, psoriatic arthritis, and rheumatoid arthritis. Dig Dis Sci 1985; 30: 104-109.
  • 11. Zachariae H. Liver biopsies and methotrexate: A time for reconsideration? J Am Acad Dermatol 2000; 42: 531- 534.
  • 12. Uzar E, Koyuncuoglu HR, Uz E, et al. The activities of antioxidant enzymes and the level of malondialdehyde in cerebellum of rats subjected to methotrexate: Protective effect of caffeic acid phenethyl ester. Mol Cell Biochem 2006; 291: 63-68.
  • 13. Nurgali K, Jagoe RT, Abalo R. Adverse effects of cancer chemotherapy: Anything new to improve tolerance and reduce sequelae? Front Pharmacol 2018; 9: 245.
  • 14. Payá M, Halliwell B, Hoult JRS. Interactions of a series of coumarins with reactive oxygen species: Scavenging of superoxide, hypochlorous acid and hydroxyl radicals. Biochem Pharmacol 1992; 44: 205-214.
  • 15. Witaicenis A, Seito LN, Di Stasi LC. Intestinal antiinflammatory activity of esculetin and 4-methylesculetin in the trinitrobenzenesulphonic acid model of rat colitis. Chem Biol Interact 2010; 186: 211-218.
  • 16. Tubaro A, Del Negro P, Ragazzi E, et al. Antiinflammatory and peripheral analgesic activity of esculetin in vivo. Pharmacol Res Commun 1988; 20: 83-85.
  • 17. Kuo HC, Lee HJ, Hu CC, Shun HI, Tseng TH. Enhancement of esculetin on Taxol-induced apoptosis in human hepatoma HepG2 cells. Toxicol Appl Pharmacol 2006; 210: 55-62.
  • 18. Leung KN, Leung PY, Kong LP, Leung PK. Immunomodulatory effects of esculetin (6, 7- dihydroxycoumarin) on murine lymphocytes and peritoneal macrophages. Cell Mol Immunol 2005; 2: 181- 188.
  • 19. Prabakaran D, Ashokkumar N. Antihyperglycemic effect of esculetin modulated carbohydrate metabolic enzymes activities in streptozotocin induced diabetic rats. J Funct Foods 2012; 4: 776-783.
  • 20. Kadakol A, Malek V, Goru SK, et al. Esculetin attenuates alterations in Ang II and acetylcholine mediated vascular reactivity associated with hyperinsulinemia and hyperglycemia. Biochem Biophys Res Commun 2015; 461: 342-347.
  • 21. Türk E, Güvenç M, Cellat M, et al. Zingerone protects liver and kidney tissues by preventing oxidative stress, inflammation, and apoptosis in methotrexate-treated rats Drug and Chem Toxicol 2020; 1-12.
  • 22. Placer ZA, Cushman LL, Johnson BC. Estimation of product of lipid peroxidation (malonyldialdehyde) in biochemical systems. Anal Biochem 1966; 16: 359-364.
  • 23. Sedlak J, Lindsay RH. Estimation of total, protein-bound, and nonprotein sulfhydryl groups in tissue with Ellman’s reagent. Anal Biochem 1968; 25: 192-205.
  • 24. Lawrence RA, Burk RF. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Commun 1976; 71: 952-958.
  • 25. Aebi HI. Methods of enzymatic analysis. Catalase, 1983: 673-686.
  • 26. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951; 193: 265-275.
  • 27. Güvenç M, Cellat M, Gökçek İ, et al. Nobiletin attenuates acetaminophen‐induced hepatorenal toxicity in rats. J Biochem Mol Toxicol 2020; 34: e22427.
  • 28. Özkan H, Kutlu T, Yakın A, Özsoy ŞY. Molecular, biochemical and histopathological effects of long term low and high percentage fructose consumption on liver in rats. Ankara Univ Vet Fak Derg 2021: https://doi.org/ 10.33988/auvfd.855124.
  • 29. Ohbayashi M, Kubota S, Kawase A, et al. Involvement of epithelial-mesenchymal transition in methotrexateinduced pulmonary fibrosis. J Toxicol Sci 2014; 39: 319- 330.
  • 30. Mehrzadi S, Mehrabani M, Malayeri AR, et al. Ellagic acid as a potential antioxidant, alleviates methotrexate-induced hepatotoxicity in male rats. Acta Chir Belg 2019; 119: 69- 77.
  • 31. Lin WL, Wang CJ, Tsai YY, et al. Inhibitory effect of esculetin on oxidative damage induced by t-butyl hydroperoxide in rat liver. Arch. Toxicol 2000; 74: 467- 472.
  • 32. West SG. Methotrexate hepatoxicity. Rheum Dis Clin N Am 1997; 23: 883-915.
  • 33. Dolar E. Klinik Karaciğer Hastalıkları, 1.Baskı, Ankara: Nobel&Güneş Tıp Kitabevi, 2002: 133-146.
  • 34. Guyton AC, Hall JE. Tıbbi Fizyoloji, 12. Baskı, İstanbul: Nobel Tıp Kitapevi, 2013: 937-942.
  • 35. Erdogan E, Ilgaz Y, Gurgor PN et al. Rutin ameliorates methotrexate induced hepatic injury in rats1. Acta Cir Bras 2015; 30: 778-784.
  • 36. Kevat S, Ahern M, Hall P. Hepatotoxicity of methotrexate in rheumatic diseases. Med Toxicol Adverse Drug Exp 1988; 3: 197-208.
  • 37. Mahmoud AM, Hussein OE, Hozayen WG, Abd el-Twab SM. Methotrexate hepatotoxicity is associated with oxidative stress, and down-regulation of PPARγ and Nrf2: protective effect of 18β-Glycyrrhetinic acid. Chem Biol Interact 2017; 270: 59-72.
  • 38. Kolli VK, Natarajan K, Isaac B, Selvakumar D, Abraham P. Mitochondrial dysfunction and respiratory chain defects in a rodent model of methotrexate-induced enteritis. Hum Exp Toxicol 2014; 33: 1051-1065.
  • 39. Messarah M, Boumendjel A, Chouabia A et al. Influence of thyroid dysfunction on liver lipid peroxidation and antioxidant status in experimental rats. Exp Toxicol Pathol 2010; 62: 301-310.
  • 40. Circu ML, Aw TY. Redox biology of the intestine. Free Radic Res 2011; 45: 1245-1266.
  • 41. Mohamed DI, Khairy E, Tawfek SS, Habib EK, Fetouh MA. Coenzyme Q10 attenuates lung and liver fibrosis via modulation of autophagy in methotrexate treated rat. Biomed Pharmacother 2019; 109: 892-901.
  • 42. Abdelaziz AI, Mantawy EM, Gad AM, Fawzy HM, Azab SS. Activation of pCREB/Nrf-2 signaling mediates repositioning of liraglutide as hepato-protective for methotrexate-induced liver injury (MILI). Food Chem Toxicol 2019; 132: 110719.
  • 43. Gilani AH, Janbaz KH, Shah BH. Esculetin prevents liver damage induced by paracetamol and CCl4. Pharmacol Res 1998; 37: 31-35.
  • 44. Hafez HM, Ibrahim MA, Ibrahim SA, et al. Potential protective effect of etanercept and aminoguanidine in methotrexate-induced hepatotoxicity and nephrotoxicity in rats. Eur J Pharmacol 2015; 768: 1-12.
  • 45. Famurewa AC, Aja PM, Maduagwuna EK, et al. Antioxidant and anti-inflammatory effects of virgin coconut oil supplementation abrogate acute chemotherapy oxidative nephrotoxicity induced by anticancer drug methotrexate in rats. Biomed Pharmacother 2017; 96: 905-911.
  • 46. Gönlüşen G. Tubulointersitisyel hastalıklar. In: Sarıoğlu S. (Editör). Nefropatoloji Böbrek Hastalıkları ve Böbrek Transplantasyon Patolojisi. İstanbul: Nobel Matbaacılık, 2012: 84-104.
  • 47. Prabakaran D, Ashokkumar N. Protective effect of esculetin on hyperglycemia-mediated oxidative damage in the hepatic and renal tissues of experimental diabetic rats. Biochimie 2013; 95: 366-373.
  • 48. Özen S, Akyol Ö, Iraz M, et al. Role of caffeic acid phenethyl ester, an active component of propolis, against cisplatin‐induced nephrotoxicity in rats. J Appl Toxicol 2004; 24: 27-35.
Fırat Üniversitesi Sağlık Bilimleri Veteriner Dergisi-Cover
  • ISSN: 1308-9323
  • Yayın Aralığı: Yılda 3 Sayı
  • Yayıncı: Prof.Dr. Mesut AKSAKAL
Sayıdaki Diğer Makaleler

Rutin’in Deltamethrin ile Mide Toksisitesi Geliştirilen RatlardaOksidatif Stres, Apoptoz ve İnflamasyon ParametreleriÜzerine Etkisinin Araştırılması

Mustafa İLERİTÜRK, Tuba DOĞAN, Emine SATICI

Ratlarda Metotreksat ile Oluşturulan Karaciğer ve BöbrekHasarı Üzerine Eskuletin’in Etkileri

Tuncer KUTLU, Mustafa CELLAT

İki Koyunda Bakır Zehirlenmesi Kaynaklı Patolojik Değişiklikler

Burak KARABULUT, Hatice ERÖKSÜZ, İsmet YILMAZ, Canan AKDENİZ İNCİLİ, Yesari ERÖKSÜZ, Zeynep YERLİKAYA

Veteriner Hekimliği Tarihi Yönünden Hayvan Mumyaları

Seda ÇAVUŞ ALAN, Abdullah ÖZEN

Sivas ili Manda Yetiştiricilerinin Üretim ve PazarlamaDurumu

Gökçe ÖZDEMİR

Streptococcus Pluranimalium ile Doğal Enfekte Koyunlarda Akut Faz Yanıt ve Oksidatif Hasarın Haptoglobin, Nitrik Oksit ve Malondialdehit Düzeyleri Kullanılarak Değerlendirilmesi

Oğuz MERHAN, Kadir BOZUKLUHAN, Ramazan KAMAN, Akın KIRBAŞ, Şükrü DEĞİRMENÇAY, Muhammed Sertaç EROĞLU

Van ve Yöresinde Sığır Sütlerinden İzole Edilen Koagulaz Negatif Stafilokokların Bazı Antimikrobiyal Maddelere KarşıDuyarlılığının Belirlenmesi

Özgül GÜLAYDIN, Kemal GÜRTÜRK, İsmail Hakkı EKİN, Berivan KAPLAN

Sisplatin Uygulanan Ratlarda Oluşturulan NefrotoksisitedeMelatoninin NAMPT/SIRT-1 Sinyal Yolağı Üzerine Etkisi

Ökkeş YILMAZ, Zeynep TUZCU

Yağ İkame Maddesi Olestra ve Beslenme Açısından Önemi

Ömer ÇAKMAK, Mehmet ÇALICIOĞLU

Şavak Taze Beyaz Peynirlerde Listeria monocytogenes veSalmonella spp. Varlığının Araştırılması

Gökhan Kürşad İNCİLİ, Gökçe BİLGEHAN, Müzeyyen AKGÖL, Gülsüm ÖKSÜZTEPE, Selçuk ALAN