PROTECTIVE EFFECT OF ZILEUTON AND MK-866 AGAINST HEPATIC DAMAGE INDUCED BY DOXORUBICIN
Objective: The present study was designed to investigate the protective effect of Zileuton and MK-886 against hepatic damage induced by doxorubicin.
Methods: A total of 30 healthy adult male albino rats were randomized and rats were divided into five groups, six animals in each: Control negative group, Vehicle group: Rats were given ethanol i.p., Dx group: Doxorubicin (15 mg/kg), Mk group: Mk-886-treated rats given 0.6 mg/kg of Mk-886 i.p, and Z group: Zileuton-treated rats given zileuton 10 mg/kg i.p. Biochemical tests of the serum for ASAT and ALAT level were estimated. Serum glutathione (GSH) concentrations (μg/ml) were determined using GSH ELISA Kit, while serum malondialdehyde (MDA) concentrations (ng/ml) were determined using MDA ELISA Kit. Livers were removed from each rat and fixed in 10% neutral-buffered formalin and embedded in paraffin for histopathological studies.
Results: MK- and zileuton-treated groups showed higher GSH levels and lower MDA levels as compared with Dx-treated group. MK-886 associated with significant p<0.05 decreased the liver enzymes in comparison with doxorubicin-treated rats. Zileuton showed insignificant (p>0.05) changes. The liver tissues that treated with Dx only showed several histopathological changes such as moderate sinusoidal dilation, vacuolation, mild-to-moderate hepatocyte necrosis/degeneration and inflammatory cell infiltration, and severe congestion. Liver tissues that treated by zileuton with Dx showed sinusoidal dilation, vacuolation, mild congestion, and inflammatory cell infiltration, while those treated with Mk-886 plus Dx showed nearly normal liver pathophysiology.
Conclusion: It has been concluded that Zileuton and MK-886 have protective effects against hepatic damage induced by doxorubicin.
2. Swift LP, Cutts SM, Rephaeli A, Nudelman A, Phillips DR. Activation of adriamycin by the pH-dependent formaldehyde-releasing prodrug hexamethylenetetramine. Mol Cancer Ther 2003;2:189-98.
3. Sbitti EY, Ichou M, Errihani H. The role of chemotherapy in the treatment of Kaposi’s sarcoma. J Cancer Sci Ther 2011;3:145-8.
4. Kaur A, Kumar MK. Doxorubicin: A critical review on toxicity. J Pharm Res 2012;5:2890-4.
5. Injac R, Strukelj B. Recent advances in protection against doxorubicin-induced toxicity. Technol Cancer Res Treat 2008;7:497-516.
6. Bulucu F, Ocal R, Karadurmus N, Sahin M, Kenar L, Aydin A, et al. Effects of N-acetylcysteine, deferoxamine and selenium on doxorubicin-induced hepatotoxicity. Biol Trace Elem Res 2009;132:184-96.
7. Raškovi? A, Stilinovi? N, Kolarovi? J, Vasovi? V, Vukmirovi? S, Mikov M, et al. The protective effects of silymarin against doxorubicin-induced cardiotoxicity and hepatotoxicity in rats. Molecules 2011;16:8601-13.
8. Indu R, Azhar TS, Nair A, Nair CK. Amelioration of doxorubicin induced cardio-and hepato-toxicity by carotenoids. J Cancer Res Ther 2014;10:62-7.
9. Heide RS, L’Ecuyer TJ. Molecular basis of anthracycline-induced cardiotoxicity. Heart Metab 2007;35:1-4.
10. El-Sayyad HI, Ismail MF, Shalaby FM, Abou-El-Magd RF, Gaur RL, Fernando A, et al. Histopathological effects of cisplatin, doxorubicin and 5-flurouracil (5-FU) on the liver of male albino rats. Int J Biol Sci 2009;5:466-73.
11. Gunda S, Kour SM. Evaluation of hepatoprotective effect of morin against doxorubicin-induced hepatotoxicity in Wistar rats. Eur J Biomed Pharm Sci 2018;5:663-8.
12. Mezher MN, Dakhil AS, Abdul-Jawad DH. Role of epstein-barr virus (EBV) in human females with breast cancer. J Pharm Sci Res 2017;9:1173-7.
13. Peters-Golden M, Henderson WR Jr. Leukotrienes. N Engl J Med 2007;357:1841-54.
14. Hadi NR, Mohammad BI, Ajeena IM, Sultan AM, Majeed S, Hussain T, et al. Leukotriene synthesis inhibitors modulate atherosclerosis progression in hypercholesterolemic rabbits. Res J Pharm Biol Chem Sci 2015;6:362-70.
15. Hadi NR, Mohammad BI, Almudhafer A, Yousif N, Sultan AM. Montelukast and zileuton retard the progression of atherosclerosis via down-regulation of the inflammatory and oxidative pathways. J Clin Exp Cardiolog 2013;4:250.
16. Dakhil AS. Association of serum concentrations of proinflammatory cytokines and hematological parameters in rheumatoid arthritis patients. J Pharm Sci Res 2017;9:1966-74.
17. Mansour MA, El-Kashef HA, Al-Shabanah OA. Effect of captopril on doxorubicin-induced nephrotoxicity in normal rats. Pharmacol Res 1999;39:233-7.
18. Rossi A, Pergola C, Koeberle A, Hoffmann M, Dehm F, Bramanti P, et al. The 5-lipoxygenase inhibitor, zileuton, suppresses prostaglandin biosynthesis by inhibition of arachidonic acid release in macrophages. Br J Pharmacol 2010;161:555-70.
19. Dakhil AS. Biosynthesis of silver nanoparticle (AgNPs) using Lactobacillus and their effects on oxidative stress biomarkers in rats. J King Saud Univ Sci 2017;29:462-7.
20. Lee IC, Kim SH, Baek HS, Moon C, Bae CS, Kim SH, et al. Melatonin improves adriamycin-induced hepatic oxidativedamage in rats. Mol Cell Toxicol 2013;9:257-65.
21. Jamieson D, Boddy AV. Pharmacogenetics of genes across the doxorubicin pathway. Expert Opin Drug Metab Toxicol 2011;7:1201-10.
22. Llesuy SF, Arnaiz SL. Hepatotoxicity of mitoxantrone and doxorubicin. Toxicology 1990;63:187-98.
23. Dakhil AS, Al-Hajjiah NN, Shlash RF. Identification of factor viii gene mutations in patients with haemophilia A. Int J Res Pharm Sci 2018;9:274-28.
24. Pedrycz A, Wieczorski M, Czerny K. The influence of a single dose of Adriamycin on the pregnant rat female liver-histological and histochemical evaluation. Ann Univ Mariae Curie Sklodowska Med 2004;59:319-23.
25. Miranda CJ, Makui H, Soares RJ, Bilodeau M, Mui J, Vali H, et al. Hfe deficiency increases susceptibility to cardiotoxicity and exacerbates changes in iron metabolism induced by doxorubicin. Blood 2003;102:2574-80.
26. Mohamad RH, El-Bastawesy AM, Zekry ZK, Al-Mehdar HA, Al- Said MG, Aly SS, et al. The role of curcuma longa against doxorubicin (Adriamycin)-induced toxicity in rats. J Med Food 2009;12:394-402.
27. Al-Hajjiah NN, Almkhadree MA. The effect of maternal anemia on the anthropometric measurements in full-term neonates. Asian J Pharm Clin Res 2018;11:3680-1.
28. Al-Hajjiah NN, Al-Shamsi MM, Al-Shami MM. The rate of parental refusal lumbar puncture in the maternity and children teaching hospital in Diwaniyah, Iraq. J Pharm Sci Res 2018;10:2680-1.
29. Tu XK, Yang WZ, Wang CH, Shi SS, Zhang YL, Chen CM, et al. Zileuton reduces inflammatory reaction and brain damage following permanent cerebral ischemia in rats. Inflammation 2010;33:344-52.
30. Ma K, Chen Y, Liang X, Miao J, Zhao Q. Inhibition of 5-lipoxygenase inhibitor zileuton in high-fat diet-induced nonalcoholic fatty liver disease progression model. Iran J Basic Med Sci 2017;20:1207-12.
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