عه اثرات محافظتی رزوراترول (Resveratrol) بر سمیّت کبدی داروی شیمی‌درمانی سیسپلاتین در موش صحرایی
محورهای موضوعی :
آسیب شناسی درمانگاهی دامپزشکی
رامین کفاشی‌الهی
1
(دانشگاه آزاد اسلامی، واحد تبریز، دانشکده دامپزشکی، استادیار گروه آموزشی علوم درمانگاهی، تبریز، ایران.)
تاریخ دریافت : 1392/09/12
تاریخ پذیرش : 1393/04/03
تاریخ انتشار : 1392/12/01
کلید واژه:
موش صحرایی,
رزوراترول,
سیسپلاتین,
سمیت کبدی,
چکیده مقاله :
دارو درمانی سرطان که با استفاده از مواد طبیعی، صناعی یا بیولوژیک انجام می شود، با عوارضی همراه است. سیسپلاتین به عنوان یک داروی ضدسرطان، در دوزهای بالا برای کبد سمّی است. معلوم شده که استرس اکسیداتیو در سمّیت سیسپلاتین دخیل است. با توجه به اثرات آنتی اکسیدانی رزوراترول، این مطالعه، برای ارزیابی اثرات محافظتی آن در برابر سمیّت کبدی سیسپلاتین در موش صحرایی انجام شد. 40 سر موش صحرایی نر ویستار به طور تصادفی در چهار گروه مساوی تقسیم گردید. گروه 1 به عنوان شاهد انتخاب شد. برای ایجاد آسیب کبدی، سیسپلاتین (mg/kg 3) هر 5 روز یکبار به‌صورت داخل صفاقی به گروه‌های 2 تا 4 تزریق شد. گروه 3 سیلیمارین (mg/kg 100) و گروه 4 رزوراترول (mg/kg 20) را با تزریق داخل صفاقی روزانه به‌مدت 4 هفته دریافت کردند. در پایان، سطوح سرمی آنزیم‌های آسپارتات و آلانین آمینوترانسفراز و لاکتات دهیدروژناز و بیلی‌روبین تام، آلبومین و پروتئین تام اندازه گیری شد. میزان مالون دی آلدئید، گلوتاتیون احیاء و فعالیت آنزیم های سوپراکسید دیسموتاز، کاتالاز، گلوتاتیون پراکسیداز و گلوتاتیون ردوکتاز نیز در هموژنات بافت کبد اندازه گیری شد. در نهایت، یافته های بیوشیمیایی با نتایج هیستوپاتولوژی مطابقت داده شد. در گروه 4، رزوراترول به‌طور معنی‌داری (001/0p<) میزان افزایش یافته آنزیم‌های شاخص آسیب کبد و بیلی‌روبین تام را کاهش و سطوح کاهش یافته آلبومین و پروتئین تام سرم را به‌طور معنی‌داری (001/0p<) افزایش داد. رزوراترول در این گروه، به طور معنی‌داری (001/0p<) میزان پراکسیداسیون لیپیدی را کاهش و سطوح آنتی اکسیدان های کبد را افزایش داد. از لحاظ آسیب شناسی بافتی نیز تغییرات با یافته های بیوشیمیایی همراستا بودند. نتایج بررسی حاضر نشان داد که رزوراترول با خواص آنتی‌اکسیدانی خود، کبد موش های صحرایی را در برابر سمّیت سیسپلاتین محافظت می کند.
چکیده انگلیسی:
Drug therapy of cancer which is carried out by natural, synthetic or biological substances is associated with complications. Cisplatin as an anticancer drug, is hepatotoxic at high doses. Oxidative stress has been proven to be involved in cisplatin-induced toxicity. Because of antioxidant potential of resveratrol, this study was conducted to assess the protective effects of resveratrol, on cisplatin-induced hepatotoxicity in the rat. Forty male Wistar rats were randomly divided into four equal groups. Group 1 was used as control. For induction of hepatic injury in groups 2-4, cisplatin (3 mg/kg) was injected once every five days intraperitoneally. Groups 3 and 4 received silymarin (100 mg/kg) and resveratrol (20 mg/kg) respectively, daily for 4 weeks via intraperitoneal route. At the end of experiment, serum levels of aspartate and alanine transaminases, lactate dehydogenase and total bilirubin, albumin and total proteins were assessed. Malondialdehyde, reduced glutathione and activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase were assayed in liver homogenates. Finally, the biochemical findings were matched with histopathological verification. In group 4, resveratrol significantly (p<0.001) decreased the elevated levels of serum biomarkers of hepatic injury and total bilirubin, and significantly (p<0.001) increased the reduced levels of serum albumin and total proteins. In this group, resveratrol significantly (p<0.001) decreased the lipid peroxidation and elevated the decreased values of hepatic antioxidants. Histopathologically, the changes were in agreement with biochemical findings. The results obtained showed resveratrol, because of its anti-oxidant potential, exerts a protective effect against cisplatin induced hepatotoxicity in rats.
منابع و مأخذ:
Aamdal, S., Fodstad, O. and Pihl A. (1987). Some procedures to reduce cis-platinum toxicity reduce antitumour activity. Cancer Treatment Reviews, 14(3-4): 389-395.
Baluchnejadmojarad, T., Roghani, M., Homayounfar, H. and Khaste Khodaie, Z. (2009). Protective effects of chronic administration of silymarin on blood glucose and lipids and oxidative stress in diabetic rats. Journal of Semnan University of Medical Sciences, 10(2): 143-150.
Borch, R.F. and Markman, M. (1989). Biochemical modulation of cisplatin toxicity. Pharmacology & Therapeutics, 41: 371-380.
Chance, B., Greenstein, D.S. and Roughton, R.J.W. (1952). The mechanism of catalase action. 1. Steady-state analysis. Archives of Biochemistry and Biophysics, 37(2):301-321.
Chirino, Y.I. and Pedraza-Chaverri, J. (2009) Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Experimental and Toxicologic Pathology, 61(3):223-242.
Claiborne, A. (1985). Catalase activity. In: Boca Raton FL, editor. CRC Handbook of methods for oxygen radical research. Florida: CRC Press, Boca Raton, pp: 283-284.
Collodel, G., Federicoa, M., Gerniniania, S., Martini, B. and Bonechi, E. (2011). Effect of trans-resveratrol on induced oxidative stress in human sperm and in rat germinal cells. Reproductive Toxicology, 31: 239-246.
Cooper, J.S., Pajak, T.F., Forastiere, A.A., Jacobs, J., Campbell, B.H., Saxman, S.B., et al. (2004). Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. New England Journal of Medicine, 350(19): 1937-1944.
Curtis, S.J., Mortiz, M. and Sondgrass, P.J. (1972). Serum enzymes derived from liver cell fractions. I. The response to carbon tetrachloride intoxication in rats. Gastroentrology, 62(1):84-92.
Fraga, C.G., Leibouitz, B.E. and Toppel A.L. (1988). Lipid peroxidation measured as TBARS in tissue slices: characterization and comparison with homogenates and microsomes. Free Radical Biology and Medicine, 4: 155-161.
Franciscoa, M., Morenob, D.A., Carteaa, M.E., Ferreresb, F., Viguerab, C.G. and Velascoa, P. (2009). Simultaneous identification of glucosinolates and phenolic compounds in a representative collection of vegetable Brassica rapa. Journal of Chromatography A, 1216(38): 6611-6619.
Frei, A., Zimmermann, A. and Weigand, K. (1984). The N-terminal propeptide of collagen type III in serum reflects activity and degree of fibrosis in patients with chronic liver disease. Hepatology, 4(5): 830-834.
Hanigan M.H. and Devarajan, P. (2003). Cisplatin nephrotoxicity: molecular mechanisms. Cancer Therapeutics, 1:47-61.
Iraz, M., Ozerol, E., Gulec, M., Tasdemir, S., Idiz, N., Fadillioglu, E., et al. (2006). Protective effect of caffeic acid phenethyl ester (CAPE) administration on cisplatin-induced oxidative damage to liver in rat. Cell Biochemistry and Function, 24(4): 357-361.
Iseri, S., Ercan, F., Gedik, N., Yuksel, M. and Alican, I. (2007). Simvastatin attenuates cisplatin-induced kidney and liver damage in rats. Toxicology, 230(2-3): 256-264.
Jeandet, P., Bessis R. and Gautheron, B. (1991). The production of resveratrol (3, 5, 4'-trihydroxystilbene) by grape berries in different developmental stages. American Journal of Enology and Viticulture, 42: 41-46.
Kabir, F. and Pazdezh, P. (2002). Handbook of Normal Values in Domestic Animals. Tehran: Norbakhsh, pp: 16-262.
Kawai, Y., Nakao, T., Kunimura, N., Kohda, Y. and Gemba, M. (2006). Relationship of intracellular calcium and oxygen radicals to Cisplatin-related renal cell injury. Journal of Pharmacological Sciences, 100: 65-72.
Kim, S.H., Hong, K.O., Chung, W.Y., Hwang, J.K. and Park, K.K. (2004). Abrogation of cisplatin-induced hepatotoxicity in mice by xanthorrhizol is related to its effect on the regulation of gene transcription. Toxicology and Applied Pharmacology, 196: 346-355.
Koc, A., Duru, M., Ciralik, H., Akcan, R. and Sogut, S. (2005). Protective agent, erdosteine, against cisplatin-induced hepatic oxidant injury in rats. Molecular and Cellular Biochemistry, 278(1-2): 79-84.
Lee, K.J., Choi, J.H., Khanal, T., Hwang, Y.P., Chung, Y.C. and Jeong, H.G. (2008). Protective effect of caffeic acid phenethyl ester against carbon tetrachloride-induced hepatotoxicity in mice. Toxicology, 248: 18-24.
Lehman, T.A., Modali, R., Boukamp, P., Stanek, J., Bennett, W.P., Welsh, J.A., et al. (1993). p53 mutations in human immortalized epithelial cell lines. Carcinogenesis, 14(5): 833-839.
Liao, Y, Lu, X., Lu, C., Li, G., Jin, Y. and Tang, H. (2008). Selection of agents for prevention of cisplatin-induced hepatotoxicity. Pharmacological Research, 57(2): 125-131.
Mansour, H.H., Hafez, H.F. and Fahmy, N.M. (2006). Silymarin modulates cisplatin-induced oxidative stress and hepatotoxicity in rats. Journal of Biochemistry and Molecular Biology, 39: 656-661.
Martins, N.M., Santos, N.A., Curti, C., Bianchi, M.L. and Santos, A.C. (2008). Cisplatin induces mitochondrial oxidative stress with resultant energetic metabolism impairment, membrane rigidification and apoptosis in rat liver. Journal of Applied Toxicology, 28: 337-344.
Mohandas, J., Marshall, J.J., Duggin, G.G., Horvath, J.S.L. and Tille, D.G. (1984). Low activities of glutathione-related enzymes as factors in the genesis of urinary bladder cancer. Cancer, 44: 5086-5091.
Naik, S.R. and Panda, V.S. (2008). Hepatoprotective effect of Ginkgoselect Phytosome in rifampicin induced liver injurym in rats: Evidence of antioxidant activity. Fitoterapia, 79(6): 439-445.
Nishikimi, M., Rao, N.A. and Yagi, K. (1972). The occurrence of superoxide anion in the reaction of reduced phenazine methosulphate and molecular oxygen. Biochemical and Biophysical Research Communications, 46: 849-854.
Oktem, G., Uysal, A., Oral, O., Sezer, E.D. and Olukman M. (2010). Resveratrol attenuates doxorubicin-induced cellular damage by modulating nitric oxide and apoptosis. Experimental and Toxicologic Pathology, 64: 471-479.
Pradeep, K., Mohan, C.V.R., Gobianand, K. and Karthikeyan, S. (2007). Silymarin modulates the oxidant–antioxidant imbalance during diethylnitrosamine induced oxidative stress in rats. European Journal of Pharmacology, 560: 110-116.
Pratibha, R., Sameer, R., Rataboli, P.V., Bhiwgade, D.A. and Dhume, C.Y. (2006). Enzymatic studies of cisplatin induced oxidative stress in hepatic tissue of rats. European Journal of Pharmacology, 532(3): 290-293.
Rabik, C.A. and Dolan, M.E. (2007). Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treatment Reviews, 33: 9-23.
Ramakrishnan, G., Raghavendran, H.R., Vinodhkumar, R. and Devaki, T. (2006). Suppression of N-nitrosodiethylamine induced hepatocarcinogenesis by silymarin in rats. Chemico-Biological Interactions, 161: 104-114.
Rebecca, T. (2003). Hepatoprotection via the Il-6/Stat3 pathway. Journal of Clinical Investigation, 112: 978-980.
Rotruck, I.T., Pope, A.L., Ganther, H.E., Swanson, A.B., Hafeman, D.G. and Hoekstra, W.G. (1973). Selenium: Biochemical role as a component of glutathione peroxidase. Science, 179: 588-590.
Sadzuka, Y., Shoji, T. and Takino, Y. (1992). Effect of cisplatin on the activities of enzymes which protect against lipid peroxidation. Biochemical Pharmacology, 43: 1872-1875.
Sanchez-Moreno, C., Larrauri, J.A. and Saura-Calixto, F. (1999). Free radical scavenging capacity and inhibition of lipid oxidation of wines, grape juices and related polyphenolic constituents. Food Research International, 32: 407-412.
Shingai, Y., Fujimoto, A., Nakamura, M. and Masuda, T. (2011). Structure and function of the oxidation products of polyphenols and identification of potent lipoxygenase inhibitors from fe-catalyzed oxidation of resveratrol. Journal of Agricultural and Food Chemistry, 59: 8180-8186.
Stockham, S.L. and Scott, M.A. (2002). Fundamentals of Veterinary Clinical Pathology. Ames: Iowa State University Press, pp: 434-459.
Su, H.C., Hung, L.M. and Chen, J.K. (2006). Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats. American Journal of Physiology- Endocrinology and Metabolism, 290: E1339-E1346.
Teitz, N.W. (1987). Fundamentals of Clinical Chemistry. Philadelphia: NB Saunders Company, pp: 638.
Thabrew, M.I., Joice, P.D. and Rajatissa, W. (1987). A comparative study of the efficacy of Pavetta indica and Osbeckia octanda in the treatment of liver dysfunction. Planta Medica, 53(3): 239-241.
Uguralp, S., Usta, U. and Mizrak, B. (2005). Resveratrol may reduce apoptosis of rat testicular germ cells after experimental testicular torsion. European Journal of Pediatric Surgery, 15: 333-336.
Yousef, M.I., Saad, A.A. and El-Shennawy, L.K. (2009). Protective effect of grape seed proanthocyanidin extract against oxidative stress induced by cisplatin in rats. Food and Chemical Toxicology, 47(6): 1176-1183.
Yulug, E., Tured, S., Alver, A., Kutlu, O., Karaguzel, E. and Kahraman C. (2013). Effects of Resveratrol on Testis Damage in Streptozotocin Induced Diabetic Rats. Journal of Animal and Veterinary Advances, 12(6): 747-753.
Zhang, J.G. and Lindup, W.E. (1993). Role of mitochondria in cisplatin-induced oxidative damage exhibited by rat renal cortical slices. Biochemical Pharmacology, 45: 2215-2222.
