Doksorubisin Uygulamasının Karaciğer, Böbrek ve Kalp Dokularındaki Ghrelin Ekspresyonuna Etkisi

Amaç: Doksorubusin(Dx), kliniklerde oldukça yaygın olarak kullanılan ve oksidatif stresi artırıcı etki ile hücre hasarına yol açtığı bilinen antrasiklin grubu antibiyotiklerdendir. Ghrelin’in, glutatyon peroksidaz (GSH-Px) enzim aktivitesini artırarak serbest oksijen radikallerinin oluşumunu azalttığı bilinmektedir. Bu çalışmada, Dx uygulamasına bağlı oluşan olası doku hasarına karşı sıçan karaciğer, kalp ve böbrek dokularındaki endojen ghrelin ekspresyonunun immünohistokimyasal metodlarla tesbit edilmesi amaçlandı. Gereç ve Yöntem: Çalışmada 14 adet erişkin, Wistar Albino cinsi erkek sıçan kullanıldı. Sıçanlar her grupta 7 denek olmak üzere iki gruba ayrıldı. Grup I’deki sıçanlar kontrol olarak kullanıldı. Grup II’yi oluşturan deneklere çalışmanın 1. günü tek doz 10 mg/kg intraperitoneal (ip) Dx uygulandı ve deney süresi olan 14 gün boyunca herhangi bir işlem yapılmadı. Deneyin sonunda sıçanlar dekapite edilerek karaciğer, kalp ve böbrek dokuları çıkartıldı. Rutin histolojik takipler sonucunda dokular parafin bloklara gömüldü. Parafin kesitlere Avidin-biyotin kompleks metodu uygulanarak ghrelin immünreaktivitesine bakıldı. Dokulardaki immunreaktivitenin belirlenmesi için immunboyama yapıldı ve gruplar arası sitoplazmik boyamanın derecesi semi-kantitatif olarak değerlendirildi. Bulgular: Kontrol grubuna ait karaciğer dokularındaki ghrelin immunreaktivitesi orta derece (+2) iken, kalp ve böbrek doku kesitlerinde hafif (+1) olarak değerlendirildi. Dx grubu sıçan dokularındaki immünreaksiyon; karaciğerde (+1) hafif, kalp ve böbrek dokularında şiddetli (+3 ) olarak ayırt edildi. Sonuç: Dx kullanımı sonucu oluşan karaciğer, kalp ve böbrek dokularındaki hasar karşısında, endojen bir antioksidan olan ghrelin, dokudan dokuya değişiklik gösteren bir salınım sergilemektedir.

The Effects of Doxorubicin on The Expression of Ghrelin in The Liver, Kidneys and Cardiac Tissues

The Effects of Doxorubicin on The Expression of Ghrelin in The Liver, Kidneys and Cardiac Tissues Objective: Doxorubicin is an anthracycline group antibiotic that has effects on cell damage by increasing oxidative stress. It is known that ghrelin is a strong endogen growth hormone releaser and reduces free radical production via increasing Glutathione peroxidase activity. In this study, we purposed to evaluate the effects doxorubicin application on ghrelin immunoreactivity in liver, heart and kidney tissues of rats using immunohistochemical methods. Material and Method: In this study, 14 adult Wistar Albino male rats were used. Rats were divided into two groups equally (n=7). The rats in the first group were used as control. The second group of rats were injected single dose doxorubicin 10 mg/kg intraperitonealy (i.p.) on 1st day of experimental study and there is no any application during 14 days. At the end of the study, rats were decapitated and liver, heart and kidney tissues removed. Following routine procedures, the tissues were set into the paraffin block and examined using immunohistochemical stain method. Immunohistochemical evaluation was based on the assessment of the prevalence of staining. Results: Ghrelin immunoreactivity was observed as +2 in control group and 1+ in doxorubicine groups in liver tissue. In control group, 1+ ghrelin immunoreactivity was observed in heart and kidney tissues. There is a significant increase in heart and kidney tissues in Dx group and +3 ghrelin immunoreactivity was observed. Conclusion: According to results of this study performed immunohistochemically, ghrelin different shows immunreactivty across damage caused by doxorubicin in the liver, kidney and heart tissue.

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  • 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. Kayaalp SO, Türker A. Kanser kemoterapisinin esasları ve antineoplastik ilaçlar. In: kayaalp SO (Editors). Rasyonel Tedavi yönünden Tibbi Farmakoloji. 12. Baskı, İstanbul: Güneş Basımevi, 2009: 331. O'Brien BA, Harmon BV, Cameron DP, Allan DJ. Nicotinamide prevents the development of diabetes in the cyclophosphamide- induced NOD mouse model by reducing beta-cell apoptosis. J Pathol 2000; 191: 86-92. Yagmurca M, Bas O, Mollaoglu H, et al. Protective effects of erdosteine on doxorubicin-induced hepatotoxicity in rats. Arch Med Res 2007; 38: 380-5. Weijl NI, Cleton FJ, Osanto S. Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treat Rev 1997; 23: 209-40. Evans LM, Davies JS, Anderson RA, et al. The effect of GH replacement therapy on endothelial function and oxidative stress in adult growth hormone deficiency. Eur J Endocrinol 2000; 142: 254-62. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402: 656-60. Korbonits M, Bustin SA, Kojima M, et al. The expression of the growth hormone secretagogue receptor ligand ghrelin in normal and abnormal human pituitary and other neuroendocrine tumors. J Clin Endocrinol Metab 2001; 86: 881-7. Fukushima N, Hanada R, Teranishi H, et al. Ghrelin directly regulates bone formation. J Bone Miner Res 2005; 20: 790-8. Li Z, Li Y, Zhang W. Ghrelin receptor in energy homeostasis and obesity pathogenesis. Prog Mol Biol Transl Sci 2013; 114: 45-87. Gnanapavan S, Kola B, Bustin SA, et al. The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans. J Clin Endocrinol Metab 2002; 87: 2988. Iseri SO, Sener G, Yuksel M, et al. Ghrelin against alendronate- induced gastric damage in rats. J Endocrinol 2005; 187: 399- 406. Kawczynska-Drozdz A, Olszanecki R, Jawien J, et al. Ghrelin inhibits vascular superoxide production in spontaneously hypertensive rats. Am J Hypertens 2006; 19: 764-7. Zwirska-Korczala K, Adamczyk-Sowa M, Sowa P, et al. Role of leptin, ghrelin, angiotensin II and orexins in 3T3 L1 preadipocyte cells proliferation and oxidative metabolism. J Physiol Pharmacol 2007; 58: 53-64. Kalender Y, Yel M, Kalender S. Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats. The effects of vitamin E and catechin. Toxicology 2005; 209: 39-45. Chen Y, Jungsuwadee P, Vore M, Butterfield DA, St Clair DK. Collateral damage in cancer chemotherapy: oxidative stress in nontargeted tissues. Mol Interv 2007; 7: 147-56. Karım S, Bhandarı U, Kumar H, Salam A, Sıddıquı MAA, Pıllai KK. Doxorubicin induced cardiotoxicity and its modulation by drug. Ind J Pharmacol 2001; 33: 203-7. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50: 707-9. Bodart V, Febbraio M, Demers A, et al. CD36 mediates the cardiovascular action of growth hormone-releasing peptides in the heart. Circ Res 2002; 90: 844-9. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34. 35. 36. Küçüksu M. Metabolik sendrom olusturulmus sıçanlarda enalapril maleate’ın ghrelin ve obestatin üzerine Etkisi. Uzmanlık Tezi. 2009; 61-74. Chang L, Ren Y, Liu X, et al. Protective effects of ghrelin on ischemia/reperfusion injury in the isolated rat heart. J Cardiovasc Pharmacol 2004; 43: 165-70. Baquiran DC, Gallagher J (Editors). Lippincott’s cancer chemotherapy handbook, Philadelphia: PA: W. B. Saunders Company, 2001. Iseri SO, Sener G, Saglam B, Ercan F, Gedik N, Yegen BC. Ghrelin alleviates biliary obstruction-induced chronic hepatic injury in rats. Regul Pept 2008; 146: 73-9. Xu Z, Lin S, Wu W, et al. Ghrelin prevents doxorubicin- induced cardiotoxicity through TNF-alpha/NF-kappaB pathways and mitochondrial protective mechanisms. Toxicology 2008; 247: 133-8. Beaumont NJ, Skinner VO, Tan TM, et al. Ghrelin can bind to a species of high density lipoprotein associated with paraoxonase. J Biol Chem 2003; 278: 8877-80. Wojtacki J, Lewicka-Nowak E, Lesniewski-Kmak K. Anthracycline-induced cardiotoxicity: clinical course, risk factors, pathogenesis, detection and prevention--review of the literature. Med Sci Monit 2000; 6: 411-20. Morishima I, Matsui H, Mukawa H, et al. Melatonin, a pineal hormone with antioxidant property, protects against adriamycin cardiomyopathy in rats. Life Sci 1998; 63: 511-21. Nagaya N, Kangawa K. Ghrelin, a novel growth hormone- releasing peptide, in the treatment of chronic heart failure. Regul Pept 2003; 114: 71-7. Palus S, von Haehling S, Doehner W, et al. Effect of application route of the ghrelin analog BIM-28131 (RM-131) on body weight and body composition in a rat heart failure model. Int J Cardiol 2013; 168: 2369-74. Rizzo M, Rizvi AA, Sudar E, et al. A review of the cardiovascular and anti-atherogenic effects of ghrelin. Curr Pharm Des 2013; 19: 4953-63. Cao Y, Tang J, Yang T, et al. Cardioprotective effect of ghrelin in cardiopulmonary bypass involves a reduction in inflammatory response. PLoS One 2013; 81: e55021. Aoki H, Nakata M, Dezaki K, et al. Ghrelin counteracts salt- induced hypertension via promoting diuresis and renal nitric oxide production in Dahl fats. Endocr J 2013; 60: 571-81. Baquiran DC, Gallagher J (Editors). Lippincott’s Cancer Chemotherapy Handbook, Philadelphia: PA: W. B. Saunders Company, 2001. Injac R, Strukelj B. Recent advances in protection against doxorubicin-induced toxicity. Technol Cancer Res Treat 2008; 7: 497-516. Menna P, Salvatorelli E, Minotti G. Cardiotoxicity of antitumor drugs. Chem Res Toxicol 2008; 21: 978-89. Dagli AF, Aydin S, Karaoglu A, Akpolat N, Ozercan IH, Ozercan MR. Ghrelin expression in normal kidney tissue and renal carcinomas. Pathol Res Pract 2009; 205: 165-73. Lin Y, Matsumura K, Fukuhara M, Kagiyama S, Fujii K, Iida M. Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in sıçans. Hypertension 2004; 43: 977-82.
Fırat Tıp Dergisi-Cover
  • ISSN: 1300-9818
  • Başlangıç: 2015
  • Yayıncı: Fırat Üniversitesi Tıp Fakültesi
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