Ratlarda Siklofosfamid ile İndüklenen Hepatotoksisite Üzerine Kuersetinin Etkileri

Yıl 2019, Cilt: 46 Sayı: 1, 41 - 50, 03.03.2019

Semin Gedikli Emin Şengül

https://doi.org/10.5798/dicletip.534825

Cited By: 3

Öz

Amaç: Siklofosfamid (CYP), karaciğer ve akciğer gibi birçok
organda toksisiteye neden olur. Pek çok çalışmada bazı antioksidanların CYP'nin
yan etkilerine karşı koruyucu etkileri olduğu gösterilmiştir. Bu çalışmada,
kuersetinin histolojik ve biyokimyasal yöntemler kullanılarak sıçanlarda CYP
ile indüklenen hepatotoksisite üzerindeki koruyucu etkisinin araştırılması
amaçlanmıştır.

Yöntemler: Otuz Sprague-Dawley erkek sıçan 5 gruba ayrıldı.
Kontrol grubuna 7 gün boyunca intragastrik olarak mısıryağı verildi. CYP
grubuna 7 gün intragastrik olarak mısır yağı verildi ve 7. günde
intraperitoneal olarak CYP (200 mg/kg) uygulandı. 7 gün boyunca Q50+CYP ve
Q100+CYP gruplarına sırasıyla kuersetin verildi ve 7. günde tek doz CYP (200
mg/kg) uygulandı. Q100 grubuna günde 100 mg/kg dozda kuersetin verildi. 8.
günde biyokimyasal ve histopatolojik incelemeler için kan örnekleri ve
karaciğer dokuları alındı.

Bulgular: MDA seviyesinin kontrol grubu ile
karşılaştırıldığında CYP grubunda belirgin olarak yüksek olduğunu ve kuersetin
uygulaması ile azaldığını tespit ettik. SOD ve GSH düzeyleri CYP grubunda
kontrol, Q50+CYP, Q100+CYP ve Q100 gruplarına göre azalmıştı. Histolojik
analizlerde CYP grubunda sinüsoidal dilatasyon, mononükleer hücre infiltrasyonu
ve vasküler konjesyon gözlenirken, bu dejeneratif değişikliklerin kuersetin
uygulaması ile azaldığı tespit edildi. TUNEL yönteminde, CYP grubunda kontrol
grubuna kıyasla fazla sayıda TUNEL pozitif hepatosit tespit edildi. Ayrıca Bax
ve Caspase-3 immunpozitivitesi açısından CYP grubunda diğer gruplara oranla
imünpozitiflik fazla iken, Bcl-2 immunpozitivitesi CYP grubunda diğer
gruplardan daha düşüktü.

Sonuç: Elde ettiğimiz sonuçlar, kuersetinin siklofosfamidle
indüklenen hepatotoksisite üzerinde koruyucu etkiye sahip olduğunu
göstermektedir.

Anahtar Kelimeler

Siklofosfamid, Kuersetin, Karaciğer

Kaynakça

• 1. Nafees S, Rashid S, Ali N, et al. Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: role of NFkappaB/MAPK pathway. Chem Biol Interact 2015; 231:98-107.
• 2. Abd El Tawab AM, Shahin NN, AbdelMohsen MM. Protective effect of Satureja montana extract on cyclophosphamide-induced testicular injury in rats. Chem Biol Interact 2014; 224:196-205.
• 3. Xie R, Chen L, Wu H, et al. GnRH Antagonist Improves Pubertal Cyclophosphamide-Induced Long-Term Testicular Injury in Adult Rats. Int J Endocrinol 2018; 2018:4272575.
• 4. Zarei M, Shivanandappa T. Amelioration of cyclophosphamide-induced hepatotoxicity by the root extract of Decalepis hamiltonii in mice. Food Chem Toxicol2013; 57: 179-84.
• 5. Abraham P, Sugumar E. Increased glutathione levels and activity of PON1 (phenyl acetate esterase) in the liver of rats after a single dose of cyclophosphamide: A defense mechanism? Experimental and Toxicologic Pathology 2008; 59: 301-6.
• 6. Bhattacharjee A, Basu A, Biswas J, et al. Nano-Se attenuates cyclophosphamide-induced pulmonary injury through modulation of oxidative stress and DNA damage in Swiss albino mice. Mol Cell Biochem 2015; 405: 243-56.
• 7. Shulman HM, McDonald GB, Matthews D, et al. An analysis of hepatic venocclusive disease and centrilobular hepatic degeneration following bone marrow transplantation. Gastroenterology 1980; 79: 1178-91.
• 8. Bacon AM, Rosenberg SA. Cyclophosphamide hepatotoxicity in a patient with systemic lupus erythematosus. Ann Intern Med 1982; 97: 62-3.
• 9. Snover DC, Weisdorf S, Bloomer J, et al. Nodular regenerative hyperplasia of the liver following bone marrow transplantation. Hepatology 1989; 9: 443-8.
• 10. Sherif IO. The effect of natural antioxidants in cyclophosphamide-induced hepatotoxicity: Role of Nrf2/HO-1 pathway. Int Immunopharmacol 2018; 61:29-36.
• 11. Sladek NE. Metabolism of cyclophosphamide by rat hepatic microsomes. Cancer Res 1971; 31: 901-8.
• 12. Haque R, Bin-Hafeez B, Parvez S, et al. Aqueous extract of walnut (Juglans regia L.) protects mice against cyclophosphamide-induced biochemical toxicity. Hum Exp Toxicol 2003; 22: 473-80.
• 13. Manda K, Bhatia AL. Prophylactic action of melatonin against cyclophosphamide-induced oxidative stress in mice. Cell Biol Toxicol 2003; 19: 367-72.
• 14. Stankiewicz A, Skrzydlewska E, Makiela M. Effects of amifostine on liver oxidative stress caused by cyclophosphamide administration to rats. Drug Metabol Drug Interact 2002; 19:67-82.
• 15. Hamzeh M, Hosseinimehr SJ, Khalatbary AR, et al. Atorvastatin mitigates cyclophosphamide-induced hepatotoxicity via suppression of oxidative stress and apoptosis in rat model. Res Pharm Sci 2018; 13: 440-9.
• 16. Horton ND, Mamiya BM, Kehrer JP. Relationships between cell density, glutathione and proliferation of A549 human lung adenocarcinoma cells treated with acrolein. Toxicology 1997; 122: 111-22.
• 17. Mohammad MK, Avila D, Zhang J, et al. Acrolein cytotoxicity in hepatocytes involves endoplasmic reticulum stress, mitochondrial dysfunction and oxidative stress. Toxicol Appl Pharmacol 2012; 265:73-82.
• 18. Pratheeshkumar P, Kuttan G. Ameliorative action of Vernonia cinerea L. on cyclophosphamide-induced immunosuppression and oxidative stress in mice. Inflammopharmacology 2010; 18:197-207.
• 19. Tripathi DN, Jena GB. Intervention of astaxanthin against cyclophosphamide-induced oxidative stress and DNA damage: a study in mice. Chem Biol Interact 2009; 180:398-406.
• 20. Patra K, Bose S, Sarkar S, et al. Amelioration of cyclophosphamide induced myelosuppression and oxidative stress by cinnamic acid. Chem Biol Interact 2012; 195: 231-9.
• 21. Wei X, Su F, Su X, et al. Stereospecific antioxidant effects of ginsenoside Rg3 on oxidative stress induced by cyclophosphamide in mice. Fitoterapia 2012; 83: 636-42.
• 22. Gibellini L, Pinti M, Nasi M, et al. Quercetin and cancer chemoprevention. Evid Based Complement Alternat Med 2011; 2011:591356.
• 23. Chen KC, Hsu WH, Ho JY, et al. Flavonoids Luteolin and Quercetin Inhibit RPS19 and contributes to metastasis of cancer cells through c-Myc reduction. J Food Drug Anal 2018; 26: 1180-91.
• 24. Kahraman A, Erkasap N, Koken T, et al. The antioxidative and antihistaminic properties of quercetin in ethanol-induced gastric lesions. Toxicology 2003; 183: 133-42.
• 25. Olayinka ET, Ore A, Ola OS, et al. Protective effect of quercetin on melphalan-induced oxidative stress and impaired renal and hepatic functions in rat. Chemother Res Pract 2014; 2014:936526.
• 26. Ong CS, Tran E, Nguyen TT, et al. Quercetin-induced growth inhibition and cell death in nasopharyngeal carcinoma cells are associated with increase in Bad and hypophosphorylated retinoblastoma expressions. Oncol Rep 2004; 11:727-33.
• 27. Seufi AM, Ibrahim SS, Elmaghraby TK, et al. Preventive effect of the flavonoid, quercetin, on hepatic cancer in rats via oxidant/antioxidant activity: molecular and histological evidences. J Exp Clin Cancer Res 2009; 28:80.
• 28. Kumar Mishra S, Singh P, Rath SK. Protective effect of quercetin on chloroquine-induced oxidative stress and hepatotoxicity in mice. Malar Res Treat 2013; 2013:141734.
• 29. Dong YS, Wang JL, Feng DY, et al. Protective effect of quercetin against oxidative stress and brain edema in an experimental rat model of subarachnoid hemorrhage. Int J Med Sci 2014; 11: 282-90.
• 30. Tripathi DN, Jena GB. Astaxanthin intervention ameliorates cyclophosphamide-induced oxidative stress, DNA damage and early hepatocarcinogenesis in rat: role of Nrf2, p53, p38 and phase-II enzymes. Mutat Res 2010; 696:69-80.
• 31. Habibi E, Shokrzadeh M, Ahmadi A, et al. Pulmonoprotective Action of Zataria multiflora Ethanolic Extract on Cyclophosphamide-Induced Oxidative Lung Toxicity in Mice. Chin J Integr Med 2018.
• 32. Kehrer JP, Biswal SS. The molecular effects of acrolein. Toxicol Sci 2000; 57:6-15.
• 33. Oyagbemi AA, Omobowale OT, Asenuga ER, et al. Cyclophosphamide-induced Hepatotoxicity in Wistar Rats: The Modulatory Role of Gallic Acid as a Hepatoprotective and Chemopreventive Phytochemical. Int J Prev Med 2016; 7:51.
• 34. Tabakoğlu E DR. Veteriner Hekimlikte Oksidatif Stres ve Bazı Önemli Hastalıklarda Oksidatif Stresin Etkileri. AVKAE Derg 2013; 3:69-75.
• 35. Cavdaroğlu BK, N. Başkol, G. Demir, H. Postmenopozal osteoporozlu hastalarda proteinler ve lipidlerdeki oksidatif stresin değerlendirilmesi. Dicle Tıp Dergisi 2014; 41:71-77.
• 36. Guo TZ, Wei T, Huang TT, et al. Oxidative Stress Contributes to Fracture/Cast-Induced Inflammation and Pain in a Rat Model of Complex Regional Pain Syndrome. J Pain 2018; 19: 1147-56.
• 37. Sheweita SA. Drug-metabolizing enzymes: mechanisms and functions. Curr Drug Metab 2000; 1: 107-32.
• 38. Townsend DM, Tew KD, Tapiero H. The importance of glutathione in human disease. Biomed Pharmacother 2003; 57: 145-55.
• 39. Murray GI, Burke MD, Ewen SW. Glutathione localisation in benign and malignant human breast lesions. Br J Cancer 1987; 55: 605-9.
• 40. Cui H, Li T, Wang L, et al. Dioscorea bulbifera polysaccharide and cyclophosphamide combination enhances anti-cervical cancer effect and attenuates immunosuppression and oxidative stress in mice. Sci Rep 2016; 5:19185.
• 41. Kanter M, Tuncer I, Erboga M, et al. The effects of quercetin on liver regeneration after liver resection in rats. Folia Morphol (Warsz) 2016; 75: 179-87.
• 42. de David C, Rodrigues G, Bona S, et al. Role of quercetin in preventing thioacetamide-induced liver injury in rats. Toxicol Pathol 2011; 39: 949-57.
• 43. Santra A, Chowdhury A, Chaudhuri S, et al. Oxidative stress in gastric mucosa in Helicobacter pylori infection. Indian J Gastroenterol 2000; 19: 21-3.
• 44. Tripathi P, Patel RK, Tripathi R, et al. Investigation of antigenotoxic potential of Syzygium cumini extract (SCE) on cyclophosphamide-induced genotoxicity and oxidative stress in mice. Drug Chem Toxicol 2013; 36:396-402.
• 45. Mahmoud AM, Al Dera HS. 18beta-Glycyrrhetinic acid exerts protective effects against cyclophosphamide-induced hepatotoxicity: potential role of PPARgamma and Nrf2 upregulation. Genes Nutr 2015; 10:41.
• 46. Li X, Li B, Jia Y. The Hepatoprotective Effect of Haoqin Qingdan Decoction against Liver Injury Induced by a Chemotherapeutic Drug Cyclophosphamide. Evid Based Complement Alternat Med 2015; 2015:978219.
• 47. Mukherjee S, Ghosh S, Choudhury S, et al. Pomegranate reverses methotrexate-induced oxidative stress and apoptosis in hepatocytes by modulating Nrf2-NF-kappaB pathways. J Nutr Biochem 2013; 24: 2040-50.
• 48. El-Agamy DS, Abo-Haded HM, Elkablawy MA. Cardioprotective effects of sitagliptin against doxorubicin-induced cardiotoxicity in rats. Exp Biol Med (Maywood) 2016; 241: 1577-87.
• 49. Marques C, Mega C, Goncalves A, et al. Sitagliptin prevents inflammation and apoptotic cell death in the kidney of type 2 diabetic animals. Mediators Inflamm 2014; 2014:538737.
• 50. Saandeep K, Vikram A, Tripathi DN, et al. Influence of hyperglycaemia on chemical-induced toxicity: study with cyclophosphamide in rat. Basic Clin Pharmacol Toxicol 2009; 105: 236-42.