Ratlarda 5-Fluorouracil ile İndüklenen Akciğer Toksisitesi Üzerine Naringinin Koruyucu Etkileri

Abstract

Mevcut çalışmanın amacı; kemoterapötik olarak kullanılan 5-FU’nun akciğerlerde oluşturduğu hasara karşı doğal flavonoidlerden olan naringinin koruyucu etkilerini araştırmaktır. Çalışmada 200-250 g ağırlığında, 30 adet Sprague Dawley cinsi erkek rat kullanıldı. Ratlar rastgele seçilerek Kontrol grubu, 5-FU grubu ve NA+5-FU grubu olarak ayrıldı. 5-Fluorouracilin akciğer dokularında interstisyel fibrozis ve konjesyona, alveoller arası septumda yangısal hücre infiltrasyonuna bağlı kalınlaşma, peribronşiyal lenfoid doku hiperplazisi ile birlikte bronşiyollerde epitelyal hücre dökülmelerine neden olduğu gözlendi. Naringin uygulamasının ise akciğerdeki histopatolojik bulguları hafiflettiği ve normal akciğer doku histolojisine yaklaştırdığı gözlendi. 5-Fluorouracil uygulamasının akciğerlerdeki Bax immünpozitifliğini artırırken, Bcl-2 immünpozitifliğini azalttığı, naringin uygulamasının ise kontrol grubuna benzer şekilde Bax immünpozitifliğini azaltıp, Bcl-2 immünpozitifliğini artırdığı belirlendi. Akciğer dokularında kontrole kıyasla TBARS ve NO düzeylerinin 5-FU uygulaması ile anlamlı şekilde arttığı, GSH düzeyinin ise anlamlı şekilde azaldığı, naringin uygulanan grupta ise bu parametrelerin kontrol grubundaki düzeylere yaklaştığı tespit edildi. Tüm bu bulgular naringin uygulamasının, 5-FU kaynaklı akciğer hasarında faydalı etkiler gösterebileceğini düşündürmektedir.

Keywords

• 5-Fluorouracil
• Akciğer
• Naringin
• Oksidatif Stres

Protective Effects of Naringin on Lung Toxicity Induced by 5-Fluorouracil in Rats

Abstract

The current study aims to investigate the protective effects of naringin, one of the natural flavonoids, against in the lungs damage caused by 5-FU, which is used chemotherapeutically. Thirty Sprague Dawley male rats weighing 200-250 g were used in the study. The rats were randomly selected and divided into the control group, the 5-FU group and the NA+5-FU group. It was observed that 5-FU caused interstitial fibrosis and congestion in the lung tissues, thickening due to inflammatory cell infiltration in the inter-alveolar septum, peribronchial lymphoid tissue hyperplasia and epithelial cell shedding in the bronchioles. It was observed that naringin application alleviated the histopathological findings in the lung and brought it closer to normal lung tissue histology. It was determined that 5-FU administration increased Bax immunopositivity in the lungs, decreased Bcl-2 immunopositivity, and naringin administration decreased Bax immunopositivity and increased Bcl-2 immunopositivity, similar to the control group. It was found that TBARS and NO levels increased significantly with 5-FU administration, GSH level decreased significantly in the lung tissues compared to the control group, and these parameters approached the levels in the control group in the naringin group. All these findings suggest that naringin administration may have beneficial effects on 5-FU-induced lung injury.

Keywords

• 5-Fluorouracil
• Lung
• Naringin
• Oxidative Stress

References

1. Abdel-Hamid NM, Fawzy MA, El-Moselhy MA. Evaluation of hepatoprotective and anticancer properties of aqueous olive leaf extract in chemically induced hepatocellular carcinoma in rats. Am. J. Med. Med. Sci. 2011; 1(1):15–22.
2. Al-Hamdany MZ, Al-Hubaity AY. Protective effects of N-acetylcysteine against 5-fluorouracil-induced pulmonary toxicity in albino rats. Iraqi J. Med. Sci. 2014a; 12(2):139–149.
3. Al-Hamdany MZ, Al-Hubaity AY. The structural changes of the rat’s lung induced by intraperitoneal injection of 5-fluorouracil. J Pak Med Assoc. 2014b; 64:734–738.
4. Al-Jawaly NK, Al-Sadi H. Histopathological Study of Lung, Testis, and Urinary Bladder of Mice Treated with 5-Fluorouracil. Rafidain J. Sci. 2017; 26(1):9–16.
5. Alvarez-Cabellos R, Garcia-Carbonero R, Garcia-Lacalle C, Gomez P, Tercero A, Sanchez D, Paz-Ares L. Fluorouracil-based chemotherapy in patients with gastrointestinal malignancies: influence of nutritional folate status on toxicity. J. Chemother. 2007; 19(6):744–749.
6. Bhandari A, Bhandari V. Bronchopulmonary dysplasia: an update. Indian J. Pediatr. 2007; 74(1):73–77.
7. Chen Y, Nie Y, Luo Y, Lin F, Zheng Y, Cheng G, Wu H, Zhang K, Su W, Shen J. Protective effects of naringin against paraquat-induced acute lung injury and pulmonary fibrosis in mice. Food Chem. Toxicol. 2013; 58:133–140.
8. Choi J-S, Piao Y-J, Kang KW. Effects of quercetin on the bioavailability of doxorubicin in rats: role of CYP3A4 and P-gp inhibition by quercetin. Arch. Pharm. Res. 2011; 34(4):607–613.

9. Chtourou Y, Slima A Ben, Makni M, Gdoura R, Fetoui H. Naringenin protects cardiac hypercholesterolemia-induced oxidative stress and subsequent necroptosis in rats. Pharmacol. Reports. 2015; 67(6):1090–1097.
10. Coşkun G, Özgür H. Apoptoz ve nekrozun moleküler mekanizması. Arşiv Kaynak Tarama Derg. 2011; 20(3):45–58.
11. Cui J, Wang G, Kandhare AD, Mukherjee-Kandhare AA, Bodhankar SL. Neuroprotective effect of naringin, a flavone glycoside in quinolinic acid-induced neurotoxicity: possible role of PPAR-γ, Bax/Bcl-2, and caspase-3. Food Chem. Toxicol. 2018; 121:95–108.
12. Dani C, Cecchi A, Bertini G. Role of oxidative stress as physiopathologic factor in the preterm infant. Minerva Pediatr. 2004; 56(4):381–94.
13. El-Sayyad HI, Ismail MF, Shalaby FM, Abou-El-Magd RF, Gaur RL, Fernando A, Raj MHG, Ouhtit A. Histopathological effects of cisplatin, doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats. Int. J. Biol. Sci. 2009; 5(5):466.
14. Eren H, Aydin HR, Tumkaya L, Kazaz IO, Kalkan Y, Kazaz SN, Mercantepe T, Horsanali MO, Yilmaz A. Whortleberry protects kidney against the cisplatin-induced nephrotoxicity: an experimental study. Ren. Fail. 2018; 40(1):466–474.
15. Eskandari MR, Moghaddam F, Shahraki J, Pourahmad J. A comparison of cardiomyocyte cytotoxic mechanisms for 5-fluorouracil and its pro-drug capecitabine. Xenobiotica. 2015; 45(1):79–87.
16. Famurewa AC, Asogwa NT, Aja PM, Akunna GG, Awoke JN, Ekeleme-Egedigwe CA, Maduagwuna EK, Folawiyo AM, Besong EE, Ekpono EU. Moringa oleifera seed oil modulates redox imbalance and iNOS/NF-κB/caspase-3 signaling pathway to exert antioxidant, anti-inflammatory and antiapoptotic mechanisms against anticancer drug 5-fluorouracil-induced nephrotoxicity in rats. South African J. Bot. 2019; 127:96–103.
17. Formica J V, Regelson W. Review of the biology of quercetin and related bioflavonoids. Food Chem. Toxicol.. 1995; 33(12):1061–1080.
18. Gan Y, Ai G, Wu J, Luo H, Chen L, Huang Q, Wu X, Xu N, Li M, Su Z. Patchouli oil ameliorates 5-fluorouracil-induced intestinal mucositis in rats via protecting intestinal barrier and regulating water transport. J. Ethnopharmacol. 2020; 250:112519.
19. Gawish S, Omar N, Sarhan N. Histological and ultrastructural study of 5-fluorouracil induced small intestinal mucosal damage in rats. Asian J Cell Biol. 2013; 8(1):1–21.
20. Gelen V, Şengül E, Gedikli S, Atila G, Uslu H, Makav M. The protective effect of rutin and quercetin on 5-FU-induced hepatotoxicity in rats. Asian Pac. J. Trop. Biomed. 2017; 7(7):647-653.
21. Gelen V, Şengül E, Yıldırım S, Atila G. The protective effects of naringin against 5-fluorouracil-induced hepatotoxicity and nephrotoxicity in rats. Iran. J. Basic Med. Sci. 2018; 21(4):404-410.
22. Gien J, Kinsella JP. Pathogenesis and treatment of bronchopulmonary dysplasia. Curr. Opin. Pediatr. 2011; 23(3):305-313.
23. Giri SN, Biring I, Nguyen T, Wang Q, Hyde DM. Abrogation of bleomycin-induced lung fibrosis by nitric oxide synthase inhibitor, aminoguanidine in mice. Nitric Oxide. 2002; 7(2):109–118.
24. Grande NR, Peão MND, de Sá CM, Águas AP. Lung fibrosis induced by bleomycin: structural changes and overview of recent advances. Scanning Microsc. 1998; 12(3):487–494.
25. Han R, Yang YM, Dietrich J, Luebke A, Mayer-Pröschel M, Noble M. Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. J. Biol. 2008; 7(4):12.
26. Hay J, Shahzeidi S, Laurent G. Mechanisms of bleomycin-induced lung damage. Arch. Toxicol. 1991; 65(2):81–94.
27. Hermenean A, Ardelean A, Stan M, Hadaruga N, Mihali C-V, Costache M, Dinischiotu A. Antioxidant and hepatoprotective effects of naringenin and its β-cyclodextrin formulation in mice intoxicated with carbon tetrachloride: a comparative study. J. Med. Food. 2014; 17(6):670–677.
28. Jung G, Hennings G, Pfeifer M, Bessler WG. Interaction of metal-complexing compounds with lymphocytes and lymphoid cell lines. Mol. Pharmacol. 1983; 23(3):698–702.
29. Juranek I, Bezek S. Controversy of free radical hypothesis: reactive oxygen species-cause or consequence of tissue injury? Gen. Physiol. Biophys. 2005; 24(3):263-278.
30. Küçükler S, Özdemir S, Çomaklı S, Kandemir F. Ratlarda İzoniazid Kaynaklı Akciğer Hasarına Karşı Krisinin Etkileri. Kocatepe Vet. Derg. 2020; 13(2):161-171.
31. Lamberti M, Porto S, Marra M, Zappavigna S, Grimaldi A, Feola D, Pesce D, Naviglio S, Spina A, Sannolo N. 5-Fluorouracil induces apoptosis in rat cardiocytes through intracellular oxidative stress. J. Exp. Cancer Res. 2012; 31(1):60.
32. Lee M-H, Yoon S, Moon J-O. The flavonoid naringenin inhibits dimethylnitrosamine-induced liver damage in rats. Biol. Pharm. Bull. 2004; 27(1):72–76.
33. Leitão RFC, Ribeiro RA, Bellaguarda EAL, Macedo FDB, Silva LR, Oriá RB, Vale ML, Cunha FQ, Brito GAC. Role of nitric oxide on pathogenesis of 5-fluorouracil induced experimental oral mucositis in hamster. Cancer Chemother. Pharmacol. 2007; 59(5):603–12.
34. Leopoldini M, Russo N, Toscano M. The molecular basis of working mechanism of natural polyphenolic antioxidants. Food Chem. 2011; 125(2):288–306.
35. Liu Y, Wu H, Nie Y, Chen J, Su W, Li P. Naringin attenuates acute lung injury in LPS-treated mice by inhibiting NF-κB pathway. Int. Immunopharmacol. 2011; 11(10):1606–1612.
36. Love WE, Bernhard JD, Bordeaux JS. Topical imiquimod or fluorouracil therapy for basal and squamous cell carcinoma: a systematic review. Arch. Dermatol. 2009; 145(12):1431–1438.
37. Matouk AI, Taye A, Heeba GH, El-Moselhy MA. Quercetin augments the protective effect of losartan against chronic doxorubicin cardiotoxicity in rats. Environ. Toxicol. Pharmacol. 2013; 36(2):443–450.
38. Montanari A, Widmer W, Nagy S. Health promoting phytochemicals in citrus fruit and juice products. Funct. Food Phytochem. Springer; 1997. p. 31–52.
39. Naidu MUR, Ramana GV, Rani PU, Suman A, Roy P. Chemotherapy-induced and/or radiation therapy-induced oral mucositis-complicating the treatment of cancer. Neoplasia. 2004; 6(5):423–431.
40. Nora El-hoseany M. Protective Effect of Captopril against 5- Fluorouracil-Induced Hepato and Nephrotoxicity in Male Albino Rats. J. Am. Sci. 2012; 8(2):680–685.
41. Oršolić N, Gajski G, Garaj-Vrhovac V, Đikić D, Prskalo ZŠ, Sirovina D. DNA-protective effects of quercetin or naringenin in alloxan-induced diabetic mice. Eur. J. Pharmacol. 2011; 656(1–3):110–118.
42. Özyurt H, Özyurt B, Söğüt S, Şahin Ş, Temel İ, Akyol Ö. Bleomisin ile Olusturulan Akciğer Fibrozisinde Pürin Katabolizması Enzim Aktiviteleri Üzerine CAPE nin Etkisi. Fırat Tıp Derg. 2007; 12(3):168–172
43. Ramadori G, Cameron S. Effects of systemic chemotherapy on the liver. Ann. Hepatol. 2010; 9(2):133–143.
44. Rashid S, Ali N, Nafees S, Hasan SK, Sultana S. Mitigation of 5-Fluorouracil induced renal toxicity by chrysin via targeting oxidative stress and apoptosis in wistar rats. Food Chem. Toxicol.. 2014; 66:185–193.
45. Rašković A, Stilinović N, Kolarović J, Vasović V, Vukmirović S, Mikov M. The protective effects of silymarin against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. Molecules. 2011; 16(10):8601–8613.
46. Renugadevi J, Prabu SM. Naringenin protects against cadmium-induced oxidative renal dysfunction in rats. Toxicolog. 2009; 256(1–2):128–134.
47. Santandreu FM, Valle A, Oliver J, Roca P. Resveratrol potentiates the cytotoxic oxidative stress induced by chemotherapy in human colon cancer cells. Cell. Physiol. Biochem. 2011; 28(2):219–228.
48. Şengül E, Gelen V, Gedikli S, Özkanlar S, Gür C, Çelebi F, Çınar A. The protective effect of quercetin on cyclophosphamide-Induced lung toxicity in rats. Biomed. Pharmacother. 2017; 92:303-307.
49. Serafini M, Villano D, Spera G, Pellegrini N. Redox molecules and cancer prevention: the importance of understanding the role of the antioxidant network. Nutr. Cancer. 2006; 56(2):232–240.
50. Sghaier M Ben, Skandrani I, Nasr N, Franca M-GD, Chekir-Ghedira L, Ghedira K. Flavonoids and sesquiterpenes from Tecurium ramosissimum promote antiproliferation of human cancer cells and enhance antioxidant activity: A structure–activity relationship study. Environ. Toxicol. Pharmacol. 2011; 32(3):336–48.
51. Singh D, Chander V, Chopra K. Protective effect of naringin, a bioflavonoid on ferric nitrilotriacetate-induced oxidative renal damage in rat kidney. Toxicology. 2004; 201(1–3):1–8.
52. So F V, Guthrie N, Chambers AF, Carroll KK. Inhibition of proliferation of estrogen receptor-positive MCF-7 human breast cancer cells by flavonoids in the presence and absence of excess estrogen. Cancer Lett. 1997; 112(2):127–133.
53. Sobrero AF, Aschele C, Bertino JR. Fluorouracil in colorectal cancer--a tale of two drugs: implications for biochemical modulation. J. Clin. Oncol. 1997; 15(1):368–381.
54. Stein A, Voigt W, Jordan K. Chemotherapy-induced diarrhea: pathophysiology, frequency and guideline-based management. Ther. Adv. Med. Oncol. 2010; 2(1):51–63.
55. Teixeira KC, Soares FS, Rocha LGC, Silveira PCL, Silva LA, Valença SS, Dal Pizzol F, Streck EL, Pinho RA. Attenuation of bleomycin-induced lung injury and oxidative stress by N-acetylcysteine plus deferoxamine. Pulm. Pharmacol. Ther. 2008; 21(2):309–316.
56. Turgut NH, Kara H, Elagoz S, Deveci K, Gungor H, Arslanbas E. The protective effect of naringin against bleomycin-induced pulmonary fibrosis in Wistar rats. Pulm. Med. 2016;2016.
57. Wong VKW, Shapourıfar-Tehranı S, Kıtada S, Choo PH, lee DA. Inhibition of rabbit ocular fibroblast proliferation by 5-fluorouracil and cytosine arabinoside. J. Ocul. Pharmacol. 1991; 7(1):27–39.
58. Yılmaz AB, Yur F. Ratlarda deneysel akciğer fibrozisinde nitrik oksit oksidasyon ürünleri ve kan gazları düzeylerinin araştırılması. Yüzüncü Yıl Üniversitesi Vet. Fakültesi Derg. 2010; 21(3):135–139.
59. Yin X-Y, Jiang J-M, Liu J-Y, Zhu J-R. Effects of endogenous nitric oxide induced by 5-fluorouracil and L-Arg on liver carcinoma in nude mice. World J. Gastroenterol. 2007; 13(46):6249.
60. Yoshino F, Yoshida A, Nakajima A, Wada-Takahashi S, Takahashi S, Lee MC. Alteration of the redox state with reactive oxygen species for 5-fluorouracil-induced oral mucositis in hamsters. PLoS One. 2013; 8(12):e82834.