Asetaminofenin indüklediği nefrotoksisiteye karşı montelukastın önleyici etkisi: Deneysel bir çalışma

Abstract

Amaç: Bir astım ilacı olan Montelukast, dokular üzerinde anti-inflamatuar etkiye sahiptir. Sıçan modellerinde montelukastın (MK) asetaminofen (APAP) ile indüklenen böbrek hasarı üzerindeki tedavi edici etkisini araştırmayı amaçladık. Gereç ve Yöntemler: Yirmi dört sıçan rastgele her biri altı hayvandan oluşan dört gruba ayrıldı. APAP intraperitoneal olarak 1000 mg/kg/gün tek doz olarak uygulandı. Tedavi grubundaki MK dozu 10 mg/kg olup APAP sonrası oral gavaj ile uygulandı. Diğer gruplar APAP + Salin grubu ve kontrol grubuydu. Nefrotoksisiteyi belirlemek için doku malondialdehit (MDA), indirgenmiş glutatyon (GSH) ve Nitrik oksit (NO) seviyelerini ölçtük. Bulgular: APAP grubundaki serum üre ve kreatinin seviyeleri kontrol ve APAP + MK gruplarındaki sıçanlara göre anlamlı derecede yüksek ölçüldü. APAP ile tedavi edilen sıçanlarda GSH seviyesi önemli ölçüde azaldı. Bununla birlikte, MK verilmesi tedavi grubunda GSH seviyesini önemli ölçüde arttırdı. Tek başına APAP ile tedavi edilen sıçanlardaki doku MDA seviyeleri kontrol grubu ve APAP + MK grubuna kıyasla önemli ölçüde yüksekti. NO seviyesi, APAP ile tedavi edilen grupta yükselmiş olarak ölçüldü. Bununla birlikte, MK tedavi grubundaki NO seviyeleri, APAP ile tedavi edilen gruptan önemli ölçüde düşüktü. Ayrıca, tek başına APAP grubuna kıyasla MK tedavi grubunda bazı morfolojik geri kazanımlar gözlendi. Sonuç: MK’nin APAP kaynaklı renal toksisite ve disfonksiyonu üzerinde faydalı etkileri vardır. Ancak uygun kullanımı ve etkileri göstermek için klinik çalışmalara ihtiyaç vardır.

Keywords

• Asetaminofen
• Böbrek
• Montelukast
• Nefrotoksisite
• Oksidatif stres

Preventive effects of montelukast against acetaminophen-induced nephrotoxicity: An experimental study

Abstract

Objective: Montelukast, an asthma drug, has an anti-inflammatory effect on tissues. We aimed to investigate therapeutic effect of montelukast (MK) on acetaminophen (APAP) - induced renal damage in rat models. Material and Methods: Twenty-four rats were randomly divided into four groups of six animals each. APAP was administered intraperitoneally as a single dose of 1000 mg/kg/day. In the treatment group, MK dose was 10 mg/kg and administered by oral gavage after APAP. The other groups were APAP + Saline group and the control group. We measured tissue malondialdehyde (MDA), reduced glutathione (GSH), and Nitric oxide (NO) levels to determine the nephrotoxicity. Results: Serum Blood Urea Nitrogen (BUN) and creatinine levels were measured significantly higher in APAP group than rats in the control and APAP + MK groups. The level of GSH was significantly diminished in APAP-treated rats. However, the administration of MK significantly increased the level of GSH in the MK treatment group. Tissue MDA levels in rats treated with APAP alone were significantly higher compared to the control group and APAP + MK group. The level of NO was measured as elevated in APAP treated group. However, NO levels in the MK treatment group were significantly lower than APAP treated group. Furthermore, some morphological recoveries were observed in the MK treatment group compared to APAP alone group. Conclusion: MK has beneficial effects on APAP-induced renal toxicity and dysfunction. However, clinical studies are needed to demonstrate appropriate use and effects.

Keywords

• Acetaminophen
• Kidney
• Montelukast
• Nephrotoxicity
• Oxidative stress

References

1. 1. Mahmood I, Waters DH. A comparative study of uranyl nitrate and cisplatin-induced renal failure in rat. Eur J Drug Metab Pharmacokinet. 1994;19(4):327–36.
2. 2. Yu YL, Yiang GT, Chou PL, Tseng HH, Wu TK, Hung YT, et al. Dual role of acetaminophen in promoting hepatoma cell apoptosis and kidney fibroblast proliferation. Mol Med Rep. 2014;9(6):2077–84.
3. 3. Ilbey YO, Ozbek E, Cekmen M, Somay A, Ozcan L, Otünctemur A, et al. Melatonin prevents acetaminophen-induced nephrotoxicity in rats. Int Urol Nephrol. 2009;41(3):695–702.
4. 4. Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB. Acetaminophen induced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther. 1973;187(1):211–7.
5. 5. Bessems JGM, Vermeulen NPE. Paracetamol (acetaminophen)-induced toxicity: Molecular and biochemical mechanisms, analogues and protective approaches. Vol. 31, Critical Reviews in Toxicology. 2001. p. 55–138.
6. 6. Aharony D. Pharmacology of leukotriene receptor antagonists. Vol. 157, American Journal of Respiratory and Critical Care Medicine. 1998. p. S214-8.
7. 7. Wallace JL, McKnight GW, Keenan CM, Byles NIA, MacNaughton WK. Effects of leukotrienes on susceptibility of the rat stomach to damage and investigation of the mechanism of action. Gastroenterology. 1990;98(5 Pt 1):1178–86.
8. 8. Huang HS, Ma MC, Chen CF, Chen J. Changes in nitric oxide production in the rat kidney due to CaOx nephrolithiasis. Neurourol Urodyn. 2006;25(3):252–8.

9. 9. Schubert SY, Neeman I, Resnick N. A novel mechanism for the inhibition of NF-kappaB activation in vascular endothelial cells by natural antioxidants. FASEB J. 2002;16(14):1931–3.
10. 10. Aviram M, Dornfeld L, Kaplan M, Coleman R, Gaitini D, Nitecki S, et al. Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: Studies in atherosclerotic mice and in humans. Drugs Exp Clin Res. 2002;28(2–3):49–62.
11. 11. Otunctemur A, Ozbek E, Cekmen M, Cakir SS, Dursun M, Polat EC, et al. Protective effect of montelukast which is cysteinyl-leukotriene receptor antagonist on gentamicin-induced nephrotoxicity and oxidative damage in rat kidney. Ren Fail. 2013;35(3):403–10.
12. 12. Şener G, Şehirli AÖ, Ayanoǧlu-Dülger G. Protective effects of melatonin, vitamin E and N-acetylcysteine against acetaminophen toxicity in mice: A comparative study. J Pineal Res. 2003;35(1):61–8.
13. 13. Sun VI, Oberley L, U’ V. A Simple Method for ClinicalAssay of SuperoxideDismutase. Clin Chem. 1988;34(3):497–500.
14. 14. Allen CT. Laboratory methods in histochemistry. 1st ed. Prophet E, Mills B, Arrington J, Sobin L, editors. Washington DC: American Registry of Pathology; 1992.
15. 15. Ayyildiz A, Nuhoglu B, Gülerkaya B, Çaydere M, Üstün H, Germiyanoglu C, et al. Effect of intraurethral Mitomycin-C on healing and fibrosis in rats with experimentally induced urethral stricture. Int J Urol. 2004;11(12):1122–6.
16. 16. Wasowicz W, Neve J, Peretz A. Optimized steps in fluorometric determination of thiobarbituric acid- reactive substances in serum: Importance of extraction pH and influence of sample preservation and storage. Clin Chem. 1993;39(12):2522–6.
17. 17. Moron MS, Depierre JW, Mannervik B. Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. BBA - Gen Subj. 1979;582(1):67–78.
18. 18. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951;193(1):265–75.
19. 19. Granger DL, Taintor RR, Boockvar KS, Hibbs JB. Measurement of nitrate and nitrite in biological samples using nitrate reductase and Griess reaction. Methods Enzymol. 1996;268:142–51.
20. 20. Prescott LF. Paracetamol Overdosage: Pharmacological Considerations and Clinical Management. Vol. 25, Drugs. 1983.
21. 21. Blakely P, McDonald BR. Acute renal failure due to acetaminophen ingestion: A case report and review of the literature. J Am Soc Nephrol. 1995;6(1).
22. 22. Trumper L, Monasterolo LA, Ochoa E, Elias MM. Tubular effects of acetaminophen in the isolated perfused rat kidney. Arch Toxicol. 1995;69(4).
23. 23. Lee SC, Tsai CC, Chen JC, Lin JG, Lin CC, Hu ML, et al. Effects of “Chinese yam” on hepato-nephrotoxicity of acetaminophen in rats. Acta Pharmacol Sin. 2002;23(6):503–8.
24. 24. Stollings JL, Wheeler AP, Rice TW. Incidence and characterization of acute kidney injury after acetaminophen overdose. J Crit Care. 2016;35.
25. 25. Jeffery WH, Lafferty WE. Acute renal failure after acetaminophen overdose: Report of two cases. Am J Hosp Pharm. 1981;38(9).
26. 26. Cekmen M, Ilbey YO, Ozbek E, Simsek A, Somay A, Ersoz C. Curcumin prevents oxidative renal damage induced by acetaminophen in rats. Food Chem Toxicol. 2009;47(7).
27. 27. Karthivashan G, Kura AU, Arulselvan P, Isa NM, Fakurazi S. The modulatory effect of Moringa oleifera leaf extract on endogenous antioxidant systems and inflammatory markers in an acetaminophen-induced nephrotoxic mice model. PeerJ. 2016;2016(7).
28. 28. Reiter R, Acuña-Castroviejo D, Tan D, Burkhardt S. Free Radical-Mediated Molecular Damage. Ann N Y Acad Sci. 2001;939(1):200–15.
29. 29. Coskun AK, Yigiter M, Oral A, Odabasoglu F, Halici Z, Mentes O, et al. The effects of montelukast on antioxidant enzymes and proinflammatory cytokines on the heart, liver, lungs, and kidneys in a rat model of cecal ligation and puncture-induced sepsis. ScientificWorldJournal. 2011;11:1341–56.
30. 30. Cuciureanu M, Cǎruntu ID, Pǎduraru O, Stoica B, Jerca L, Crauciuc E, et al. The protective effect of montelukast sodium on carbon tetrachloride induced hepatopathy in rat. Prostaglandins Other Lipid Mediat. 2009;88(3–4):82–8.
31. 31. Ross D. Glutathione, free radicals and chemotherapeutic agents. Pharmacol Ther. 1988;37(2):231–49.
32. 32. Li C, Liu J, Saavedra JE, Keefer LK, Waalkes MP. The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced nephrotoxicity in mice. Toxicology. 2003;189(3):173–80.
33. 33. Şener G, Sakarcan A, Şehirli Ö, Ekşioǧlu-Demiralp E, Şener E, Ercan F, et al. Chronic renal failure-induced multiple-organ injury in rats is alleviated by the selective CysLT1 receptor antagonist montelukast. Prostaglandins Other Lipid Mediat. 2007;83(4):257–67.
34. 34. Beytur A, Ciftci O, Oguz F, Oguzturk H, Yılmaz F. Montelukast attenuates side effects of cisplatin including testicular, spermatological, and hormonal damage in male rats. Cancer Chemother Pharmacol. 2012;69(1):207–13.
35. 35. Moses MA, Addison PD, Neligan PC, Ashrafpour H, Huang N, McAllister SE, et al. Inducing late phase of infarct protection in skeletal muscle by remote preconditioning: Efficacy and mechanism. Am J Physiol - Regul Integr Comp Physiol. 2005;289(6 58-6).
36. 36. Wu S, Zhu X, Jin Z, Tong X, Zhu L, Hong X, et al. The protective role of montelukast against intestinal ischemia-reperfusion injury in rats. Sci Rep. 2015;5.
37. 37. Goldstein R, Schnellmann R. Toxic Responses of the Kidney. In: Klaassenn C, Amdur M, Doll J, editors. Casarett & Doull’s toxicology: The basic science of poisons. 5th ed. New York: Mc Graw- Hill Co; 1996. p. 117–42.
38. 38. Manautou JE, Silva VM, Hennig GE, Whiteley HE. Repeated dosing with the peroxisome proliferator clofibrate decreases the toxicity of model hepatotoxic agents in male mice. Toxicology. 1998;127(1–3):1–10.
39. 39. El-Sokkary GH, Abdel-Rahman GH, Kamel ES. Melatonin protects against lead-induced hepatic and renal toxicity in male rats. Toxicology. 2005;213(1–2):25–33.