Kemoterapi Kaynaklı Hepatotoksisiteye Karşı Ellajik Asitin Koruyucu Etkileri

Year 2020, , 124 - 130, 30.08.2020

Alper Yalçın , Hikmet Keleş , Tahir Kahraman , Mehmet Fatih Bozkurt , Hasan Aydın

https://doi.org/10.18678/dtfd.748816

Cited By: 2

Abstract

Amaç: Siklofosfamid (CP), hepatotoksisite dahil olmak üzere, toksik yan etkilerine rağmen yaygın olarak kullanılan kemoterapötik bir ajandır. Ellajik asit (EA) antioksidan bir ajandır ve serbest radikal süpürücü aktiviteler sergilemektedir. Bu deneysel çalışmada, EA'nın, CP'ye bağlı karaciğer hasarı üzerindeki etkileri araştırılmıştır.

Gereç ve Yöntemler: Yirmi dört adet Sprague-Dawley türü sıçan (180-220 gr) dört eşit gruba ayrıldı. Hepatotoksisite oluşturmak için intraperitonal olarak tek doz 150 mg/kg CP verildi. CP uygulamasından 20 dakika önce ve 4 ila 8 saat sonra oral yolla farklı dozlarda (50 ve 75 mg/kg) EA uygulandı. Serumun biyokimyasal analizlerinin yanı sıra böbrek dokularının histopatolojik değerlendirmesi ve kaspaz-3 için immünohistokimyasal değerlendirme yapıldı.

Bulgular: CP uygulanan grup, kontrol grubuna kıyasla, serum hepatik enzimleri olan aspartat aminotransferaz (AST) ve alanin aminotransferaz (ALT)’da önemli bir artış gösterdi. Benzer şekilde, total trigliserit (TG) ve çok düşük yoğunluklu lipoprotein kolesterol (VLDL-C) seviyeleri önemli ölçüde arttı. Ayrıca, yüksek yoğunluklu lipoprotein kolesterol (HDL-C) seviyeleri, kontrol grubuna kıyasla anlamsız olarak azaldı. Her iki EA dozunda da VLDL-C, AST, ALT seviyeleri önemli ölçüde azalırken, HDL-C seviyesi önemli bir artış gösterdi. 75 mg/kg EA tedavisi, total kolesterol (TC) konsantrasyonunda önemsiz bir artışa neden oldu. CP uygulanan grubun karaciğerlerinde mikroskobik olarak önemli derecede konjesyon, ödem, dejenerasyon ve nekroz gözlendi. Bununla beraber EA-75 grubundaki hayvanlarda ödem, dejenerasyon ve nekroz önemli ölçüde azaldı. Ayrıca kaspaz-3 ekspresyonu EA-75 grubunda anlamlı şekilde azaldı.

Sonuç: Bu sonuçlar sıçanlarda CP'nin neden olduğu hepatotoksisitede EA'nın koruyucu etkisi olduğunu göstermiştir.

Keywords

kaspaz-3, siklofosfamid, ellajik asit, hepatotoksisite, lipidler

Protective Effects of Ellagic Acid Against Chemotherapy-Induced Hepatotoxicity

Abstract

Aim: Cyclophosphamide (CP) is a commonly used chemotherapeutic agent despite its toxic adverse effects, including hepatotoxicity. Ellagic acid (EA) is an antioxidant agent and exhibits free radical scavenging activities. In this experimental study, the effects of EA on CP-induced liver injury were investigated.

Material and Methods: Twenty-four Sprague-Dawley rats (180-220 gr) were separated into four equal groups. A single dose of 150 mg/kg CP was given intraperitoneally to generate hepatotoxicity. Different doses (50 and 75 mg/kg) of EA were administered orally 20 minutes before, 4 and 8 hours after CP administration. The histopathological evaluation of kidney tissues and immunohistochemical evaluation for caspase-3 were conducted as well as the serum biochemical analyses.

Results: CP treated group exhibited a significant increase in serum hepatic enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), compared to the control group. Similarly, the total triglycerides (TG) and very-low-density lipoprotein cholesterol (VLDL-C) levels increased significantly. Additionally, the high-density lipoprotein cholesterol (HDL-C) levels decreased, which was not significant, compared to the control group. At both EA doses, VLDL-C, AST, ALT levels decreased significantly while HDL-C level revealed a significant increase. 75 mg/kg EA treatment caused a non-significant elevation in total cholesterol (TC) concentration. Microscopic analysis showed a significant congestion, edema, degeneration and necrosis in the livers of CP administered group. However, edema, degeneration, and necrosis were significantly reduced in animals treated with EA-75. In addition, caspase-3 expression significantly decreased in EA-75 group.

Conclusion: These results indicate the protective effects of EA in CP-induced hepatotoxicity in rats.

Keywords

caspase-3, cyclophosphamide, ellagic acid, hepatotoxicity, lipids

References

• Tripathi DN, Jena GB. Intervention of astaxanthin against cyclophosphamide-induced oxidative stress and DNA damage: a study in mice. Chem Biol Interact. 2009;180(3):398-406.
• Papaldo P, Lopez M, Marolla P, Cortesi E, Antimi M, Terzoli E, et al. Impact of five prophylactic filgrastim schedules on hematologic toxicity in early breast cancer patients treated with epirubicin and cyclophosphamide. J Clin Oncol. 2005;23(28):6908-18.
• El-Naggar SA, Abdel-Farid IB, Germoush MO, Elgebaly HA, Alm-Eldeen AA. Efficacy of Rosmarinus officinalis leaves extract against cyclophosphamide-induced hepatotoxicity. Pharm Biol. 2016;54(10):2007-16.
• Said E, Elkashef WF, Abdelaziz RR. Tranilast ameliorates cyclophosphamide-induced lung injury and nephrotoxicity. Can J Physiol Pharmacol. 2016;94(4):347-58.
• Ghobadi E, Moloudizargari M, Asghari MH, Abdollahi M. The mechanisms of cyclophosphamide-induced testicular toxicity and the protective agents. Expert Opin Drug Metab Toxicol. 2016;13(5):525-36.
• Asiri YA. Probucol attenuates cyclophosphamide-induced oxidative apoptosis, p53 and Bax signal expression in rat cardiac tissues. Oxid Med Cell Longev. 2010;3(5):308-16.
• Sharma PK, Misra AK, Singh V, Gupta A, Saroha S, Singh S. Cyclophosphamide and epirubicin-induced diabetes mellitus in breast cancer: A rare occurrence. J Pharmacol Pharmacother. 2016;7(3):146-8.
• Alenzi FQ, El-Bolkiny YE-S, Salem ML. Protective effects of Nigella sativa oil and thymoquinone against toxicity induced by the anticancer drug cyclophosphamide. Br J Biomed Sci. 2010;67(1):20-8.
• Li QZ, Sun J, Shen HT, Jia SF, Bai DS, Ma D. CdS nanoparticles of different lengths induce differential responses in some of the liver functions of mice. Bratisl Lek Listy. 2018;119(2):75-80.
• Yuksel S, Tasdemir S, Korkmaz S. Protective effect of thymoquinone against cyclophosphamide-induced genotoxic damage in human lymphocytes. Bratisl Lek Listy. 2017;118(4):208-11.
• Mahmoud AM, Germoush MO, Alotaibi MF, Hussein OE. Possible involvement of Nrf2 and PPARγ up-regulation in the protective effect of umbelliferone against cyclophosphamide-induced hepatotoxicity. Biomed Pharmacother. 2017;86:297-306.
• Postaci I, Coskun O, Senol N, Aslankoc R, Comlekci S. The physiopathological effects of quercetin on oxidative stress in radiation of 4.5 g mobile phone exposed liver tissue of rat. Bratisl Lek Listy. 2018;119(8):481-9.
• Honjo I, Suou T, Hirayama C. Hepatotoxicity of cyclophosphamide in man: pharmacokinetic analysis. Res Commun Chem Pathol Pharmacol. 1988;61(2):149-65.
• Mythili Y, Sudharsan PT, Selvakumar E, Varalakshmi P. Protective effect of DL-alpha-lipoic acid on cyclophosphamide induced oxidative cardiac injury. Chem Biol Interact. 2004;151(1):13-9.
• Shokrzadeh M, Ahmadi A, Naghshvar F, Chabra A, Jafarinejhad M. Prophylactic efficacy of melatonin on cyclophosphamide-induced liver toxicity in mice. Biomed Res Int. 2014;2014:470425.
• Weijl NI, Cleton FJ, Osanto S. Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treat Rev. 1997;23(4):209-40.
• Arora B, Choudhary M, Arya P, Kumur S, Choudhary N, Singh S. Hepatoprotective potential of Saraca ashoka (Roxb) De Wilde bark by carbon tetrachloride induced liver damage in rats. Bull Fac Pharm Cairo Univer. 2015;53(1):23-8.
• Koponen JM, Happonen AM, Mattila PH, Törrönen AR. Contents of anthocyanins and ellagitannins in selected foods consumed in Finland. J Agric Food Chem. 2007;55(4):1612-9.
• Liang WZ, Chou CT, Cheng JS, Wang JL, Chang HT, Chen I-S, et al. The effect of the phenol compound ellagic acid on Ca(2+) homeostasis and cytotoxicity in liver cells. Eur J Pharmacol. 2016;780:243-51.
• Hussein RH, Khalifa FK. The protective role of ellagitannins flavonoids pretreatment against N-nitrosodiethylamine induced-hepatocellular carcinoma. Saudi J Biol Sci. 2014;21(6):589-96.
• Seeram NP, Adams LS, Henning SM, Niu Y, Zhang Y, Nair MG, et al. In vitro antiproliferative, apoptotic and antioxidant activities of punicalagin, ellagic acid and a total pomegranate tannin extract are enhanced in combination with other polyphenols as found in pomegranate juice. J Nutr Biochem. 2005;16(6):360-7.
• Karimi J, Goodarzi MT, Tavilani H, Khodadadi I, Amiri I. Relationship between advanced glycation end products and increased lipid peroxidation in semen of diabetic men. Diabetes Res Clin Pract. 2011;91(1):61-6.
• Sarker U, Oba S. Antioxidant constituents of three selected red and green color Amaranthus leafy vegetable. Sci Rep. 2019;9(1):18233.
• Aladaileh SH, Abukhalil MH, Saghir SAM, Hanieh H, Alfwuaires MA, Almaiman AA, et al. Galangin activates Nrf2 signaling and attenuates oxidative damage, inflammation, and apoptosis in a rat model of cyclophosphamide-induced hepatotoxicity. Biomolecules. 2019;9(8):346.
• Devipriya N, Sudheer AR, Vishwanathan P, Menon VP. Modulatory potential of ellagic acid, a natural plant polyphenol on altered lipid profile and lipid peroxidation status during alcohol-induced toxicity: a pathohistological study. J Biochem Mol Toxicol. 2008;22(2):101-12.
• Lawson M, Vasilaras A, De Vries A, Mactaggart P, Nicol D. Urological implications of cyclophosphamide and ifosfamide. Scand J Urol Nephrol. 2008;42(4):309-17.
• Campbell I. Liver: metabolic functions. Anaesth Intensive Care Med. 2006;7(2):51-4.
• Tripathi DN, Jena GB. Astaxanthin intervention ameliorates cyclophosphamide-induced oxidative strese, DNA damage and early hepatocarcigonesis in rats: role of Nrf2, p53, p38 and phase-II enzymes. Mutat Res. 2010;696(1):69-80.
• Ray S, Chowdhury P, Pandit B, Ray SD, Das S. Exploring the antiperoxidative potential of morin on cyclophosphamide and flutamide-induced lipid peroxidation and changes in cholesterol profile in rabbit model. Acta Pol Pharm. 2010;67(1):35-44.
• Mythili Y, Sudharsan PT, Sudhahar V, Varalakshmi P. Protective effect of DL-alpha-lipoic acid on cyclophosphamide induced hyperlipidemic cardiomyopathy. Eur J Pharmacol. 2006;543(1-3):92-6.
• Ray S, Pandit B, Das S, Chakraborty S. Cyclophosphamide-induced lipid peroxidation and changes in cholesterol content: protective role of reduced glutathione. Iran J Pharm Sci. 2011;7(4):255-67.
• Amiot MJ, Riva C, Vinet A. Effects of dietary polyphenols on metabolic syndrome features in humans: a systematic review. Obes Rev. 2016;17(7):573-86.
• Kang I, Buckner T, Shay NF, Gu L, Chung S. Improvements in metabolic health with consumption of ellagic acid and subsequent conversion into urolithins: evidence and mechanisms. Adv Nutr. 2016;7(5):961-72.
• Ghosh D, Das UB, Ghosh S, Mallick M, Debnath J. Testicular gametogenic and steroidogenic activities in cyclophosphamide treated rat: a correlative study with testicular oxidative stress. Drug Chem Toxicol. 2002;25(3):281-92.
• Yoshimura Y, Nishii S, Zaima N, Moriyama T, Kawamura Y. Ellagic acid improves hepatic steatosis and serum lipid composition through reduction of serum resistin levels and transcriptional activation of hepatic ppara in obese, diabetic KK-A(y) mice. Biochem Biophys Res Commun. 2013;434(3):486-91.
• Mehrzadi S, Fatemi I, Malayeri AR, Khodadadi A, Mohammadi F, Mansouri E, et al. Ellagic acid mitigates sodium arsenite-induced renal and hepatic toxicity in male Wistar rats. Pharmacol Rep. 2018;70(4):712-9.
• Aslan A, Gok O, Erman O, Kuloglu T. Ellagic acid impedes carbontetrachloride-induced liver damage in rats through suppression of NF-kB, Bcl-2 and regulating Nrf-2 and caspase pathway. Biomed Pharmacother. 2018;105:662-9.
• Caglayan C, Temel Y, Kandemir FM, Yildirim S, Kucukler S. Naringin protects against cyclophosphamide-induced hepatotoxicity and nephrotoxicity through modulation of oxidative stress, inflammation, apoptosis, autophagy, and DNA damage. Environ Sci Pollut Res Int. 2018;25(21):20968-84.
• Li X, Li B, Jia Y. The hepatoprotective effect of haoqin qingdan decoction against liver injury induced by a chemotherapeutic drug cyclophosphamide. Evid Based Complement Altern Med. 2015;2015:978219.
• Fouad AA, Qutub HO, Al-Melhim WN. Punicalagin alleviates hepatotoxicity in rats challenged with cyclophosphamide. Environ Toxicol Pharmacol. 2016;45:158-62.
• Rizk HA, Masoud MA, Maher OW. Prophylactic effects of ellagic acid and rosmarinic acid on doxorubicin-induced neurotoxicity in rats. J Biochem Mol Toxicol. 2017;31(12):e21977.
• Ding Y, Wang L, Song J, Zhou S. Protective effects of ellagic acid against tetrachloride-induced cirrhosis in mice through the inhibition of reactive oxygen species formation and angiogenesis. Exp Ther Med. 2017;14(4):3375-80.
• Mali VR, Bodhankar SL, Mohan V, Thakurdesai PA. Subacute toxicity of ellagic acid in cholesterol fed hyperlipidemic rats. Toxicol Int. 2008;15(2):91-5.
• Kang I, Espín JC, Carr TP, Tomás-Barberán FA, Chung S. Raspberry seed flour attenuates high-sucrose diet-mediated hepatic stress and adipose tissue inflammation. J Nutr Biochem. 2016;32:64-72.
• Ahad A, Ganai AA, Mujeeb M, Siddiqui WA. Ellagic acid, an NF-κB inhibitor, ameliorates renal function in experimental diabetic nephropathy. Chem Biol Interact. 2014;219:64-75.
• Kannan MM, Quine SD. Ellagic acid inhibits cardiac arrhythmias, hypertrophy and hyperlipidaemia during myocardial infarction in rats. Metabolism. 2013;62(1):52-61.
• Huang L-H, Elvington A, Randolph GJ. The role of the lymphatic system in cholesterol transport. Front Pharmacol. 2015;6:182.
• Yokoyama S. Assembly of high-density lipoprotein by the ABCA1/apolipoprotein pathway. Curr Opin Lipidol. 2005;16(3):269-79.
• Lei F, Zhang XN, Wang W, Xing DM, Xie WD, Su H, et al. Evidence of anti-obesity effects of the pomegranate leaf extract in high-fat diet induced obese mice. Int J Obes (Lond). 2007;31(6):1023-9.