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Amelioration of cisplatin-induced nephrotoxicity by grape seed extract and fish oil is mediated by lowering oxidative stress and DNA damage

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Abstract

Cisplatin (CP) is a chemotherapeutic drug used in treatment of malignancies. However, its clinical utility is limited by nephrotoxicity. The purpose of the present study was to investigate the protective role of grape seed proanthocyanidin extract (GSPE) (100 mg/kg/day) or fish oil (FO) (5 ml/kg/day) against cisplatin induced nephrotoxicity in terms of biochemical parameters, oxidative stress and DNA damage. CP nephrotoxiciy is manifested by increased levels of serum creatinine, urea and uric acid, accompanied by their decrease in urine. Na, K and Ca levels were altered in both serum and urine. In addition, cisplatin caused a decrease in renal GSH, SH-group, SOD, GST, and Na–K–ATPase levels. However the levels of MDA, H2O2 and NO were increased. Also, we assessed the renal genotoxic potential of cisplatin as manifested by an increase in the tail length of DNA, tail intensity (DNA %) and tail moment. On the other hand, administration of GSPE or FO pre-cisplatin treatment ameliorated the current changes in most of the above tested parameters, particularly oxidative stress, endogenous antioxidant defense system and DNA damage indicating their curative effect. Thus, it can be concluded that the consumption of GSPE or FO might be useful for preventing nephrotoxicity caused by cisplatin treatment.

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Abbreviations

CP:

Cisplatin

GSPE:

Grape seed proanthocyanidin extract

FO:

Fish oil

DNA:

Deoxyribonucleic acid

SH:

Sulfhydryl group

SOD:

Superoxide dismutase

GST:

Glutathione-S-transferase

ATPase:

Adenosine Triphosphatase

MDA:

Malondialdehyde

H2O2 :

Hydrogen peroxide

NO:

Nitric oxide

References

  • Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  Google Scholar 

  • Ajith TA, Nivitha V, Usha S (2007) Zingiber officinale Rosco alone and in combination with α- tocopherol protect the kidney against cisplatin-induced acute renal failure. Food Chem Toxic 45:921–927

    Article  CAS  Google Scholar 

  • Ali BH, Bashir AA (1994) Effect of fish oil treatment on gentamicin nephrotoxicity in rats. Anal Nutr Metab 38:336–339

    Article  CAS  Google Scholar 

  • Ali BH, Al Moundhri MS, Tag Eldin MT, Nemmar A, Tanira MO (2007) The ameliorative effect of cysteine prodrug L-2-oxothiazolidine-4-carboxylic acid on cisplatin-induced nephrotoxicity in rats. Fundam Clin Pharmacol 21:547–553

    Article  CAS  Google Scholar 

  • Arany I, Safirstein RL (2003) Cisplatin nephrotoxicity. Semin Nephrol 23:460–464

    Article  CAS  Google Scholar 

  • Ariga T (2004) The antioxidant function, preventive action on disease and utilization of proanthocyanidins. BioFactors 21:197–201

    Article  CAS  Google Scholar 

  • Atessahin A, Yilmaz S, Karahan I, Ceribasi AO, Karaoglu A (2005) Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats. Toxicol 212:116–123

    Article  CAS  Google Scholar 

  • Aydogan S, Yapislar H, Artis S, Aydogan B (2008) Impaired erythrocytes deformability in H2O2-induced oxidative stress: protective effect of L-carnosine. Clin Hemorheol Microcirc 39:93–98

    CAS  Google Scholar 

  • Badary OA, Abdel-Maksoud S, Ahmed WA, Owieda GH (2004) Naringenin attenuates cisplatin nephrotoxicity in rats. Life Science 76:2125–2135

    Article  CAS  Google Scholar 

  • Bagchi D, Bagchi M, Stohs SJ, Das DK, Ray SD, Kuszynski CA, Joshi SS, Pruess HG (2000) Free radicals and grape seed pranthocynidin extract: importance in human health and disease prevention. Toxicol 148:187–197

    Article  CAS  Google Scholar 

  • Bagchi D, Gargb A, Krohn RL, Bagchi M, Tran MX, Stohs SJ (1997) Oxygen free radical scavenging abilities of vitamins C and E, and a grape seed proanthocyanidin extract in vitro. Res Commun Mol Pathol Pharmacol 95:179–189

    CAS  Google Scholar 

  • Barabas K, Milner R, Lurie D, Adin C (2008) Cisplatin: a review of toxicities and therapeutic applications. Vet Comp Oncol 6:1–18

    Article  CAS  Google Scholar 

  • Basnakian AG, Apostolov EO, Yin X, Napirei M, Mannherz HG, Shah SV (2005) Cisplatin nephrotoxicity is mediated by deoxyribonuclease I. J Am Soc Nephrol 16:697–702

    Article  CAS  Google Scholar 

  • Berners-Price SJ, Kuchel PW (1990) Reaction of cis- and trans-[PtCl2(NH3)2] with reduced glutathione inside human red blood cells, studied by 1H and 15N-[1H] DEPT NMR. J Lab Clin Med 61(38):327–345

    Google Scholar 

  • Beutler E, Duron O, Kelly BM (1963) An improved method for the detection of blood glutathione. J Lab Clin Med 61:882–888

    CAS  Google Scholar 

  • Bonting SL, Simon KA, Hawkins NM (1961) Studies on sodium potassium—activated adenosine triphosphatase. Arch Biochem Biohpys 95:416–421

    Article  CAS  Google Scholar 

  • Celik I, Tuluce Y (2006) Effects of indoleacetic acid and kinetin on lipid peroxidation and antioxidant defense in various tissues of rats. Pestic Biochem Phys 84:49–54

    Article  CAS  Google Scholar 

  • Cetin A, Kaynar L, Kocyigit I, Hacioglu SK, Saraymen R, Ozturk A, Orhan O, Sagdic O (2008) The effect of grape seed extract on radiation induced oxidative stress in the rat liver. Turk J Gasrtoenterol 19:92–98

    Google Scholar 

  • Chandrasekar B, Fernandes G (1994) Decreased pro-inflammatory cytokines and increased antioxidant enzyme gene expression by ω-3 lipids in murine lupus nephritis. Biochem Biophys Res Commun 200:893–898

    Article  CAS  Google Scholar 

  • Cherry SM, Hunt PA, Hassold TJ (2004) Cisplatin disrupts mammalian spermatogenesis, but does not recombination or chromosome segregation. Mutat Res 564:115–128

    Article  CAS  Google Scholar 

  • Chirino YI, Sanchez-Gonzalez DJ, Martinez CM, Cruz C, Pedraza Chaverri J (2008) Protective effects of apocynin against cisplatin-induced oxidative stress and nephrotoxicity. Toxicol 245:18–23

    Article  CAS  Google Scholar 

  • Daugaard G, Abildgaard U (1989) Cisplatin nephrotoxicity: a review. Cancer Chemother Pharmacol 25:1–9

    Article  CAS  Google Scholar 

  • De Martinis BS, Bianchi M (2001) Effect of vitamin C supplementation against cisplatin–induced toxicity and oxidative DNA damage in rats. Pharmacol Res 44:317–320

    Article  CAS  Google Scholar 

  • El-Daly ES (1996) Effect of methimazole and fish oil treatment on gentamicin nephrotoxicity. J Islamic Acad Sci 9:37–48

    Google Scholar 

  • Ellman GL (1959) Tissue sulphydryl group. Arch Biochem Biophys 82:70–77

    Article  CAS  Google Scholar 

  • Erdogan H, Fadillioglu E, Ozgocmen S, Sogut S, Ozyurt B, Akyol O, Ardicoglu O (2004) Effect of fish oil supplementation on plasma oxidant/antioxidant status in rats. Prostaglandin Leukot Essent Fatty Acids 71:149–152

    Article  CAS  Google Scholar 

  • Fine AM (2000) Oligomeric proanthocyanidin complexes: history, structure, and phytopharmaceutical applications. Alter Med Rev 5:144–151

    CAS  Google Scholar 

  • Fouad AA, Morsy MA, Gomaa W (2008) Protective effect of carnosine against cisplatin-induced nephrotoxicity in mice. Environ Toxicol Pharmacol 24:292–297

    Article  CAS  Google Scholar 

  • Groeneveld PH, Kwappenberg KM, Langermans JA, Nibbering PH, Curtis L (1996) Nitric oxide production correlates with renal insufficiency and multiple organ dysfunction syndrome in severe sepsis. Int Care Med 22:1197–1202

    Article  CAS  Google Scholar 

  • Guendez R, Kallithraka S, Makris DP, Kefalas P (2005) Determination of low molecular weight polyphenolics constituents in grape (vitis vinifera) seed extracts: correlation with antiradial activity. Food Chem 89:1–9

    Article  CAS  Google Scholar 

  • Habig WH, Pabst MJ, Jakoby WB (1974) Glutathion-S-Transferase the first enzyme step in mercapturic acid formation. J Biol Chem 1:7139–7150

    Google Scholar 

  • Hassan HA, Abdel-Aziz AF (2010) Evaluation of free radical-scavenging and anti-oxidant properties of black berry against fluoride toxicity in rats. Food Chem Toxicol 48:1999–2004

    Article  CAS  Google Scholar 

  • Hassan HA, Al-Rawi MM (2013) Grape seeds proanthocyanidin extract as a hepatic-reno-protective agent against gibberellic acid induced oxidative stress and cellular alterations. Cytotechnology. doi:10.1007/s10616-012-9506-6

  • Hassan HA, Isa AM, El-Kholy WM, Nour SE (2013) Testicular disorders induced by plant growth regulators: cellular protection with proanthocyanidins grape seeds extract. Cytotechnology. doi:10.1007/s10616-012-9525-3

  • Ishige K, Schubert D, Sagara Y (2001) Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med 30:433–446

    Article  CAS  Google Scholar 

  • Jung M, Hotter G, Vinas JL, Sola A (2009) Cisplatin upregulates mitochondrial nitric oxide synthase and peroxynitrite formation to promote renal injury. Toxicol Appl Pharmacol 234:236–246

    Article  CAS  Google Scholar 

  • Karthikeyan K, Sarala Bai BR, Niranjali Devaraj S (2007a) Cardioprotective effect of grape seed proanthocyanidins on isoproterenol induced myocardial injury in rats. Int J Cardiol 115:326–333

    Article  CAS  Google Scholar 

  • Karthikeyan K, Sarala Bai BR, Niranjali Devaraj S (2007b) Cardioprotective effect of grape seed proanthocyanidins on isoproterenol-induced myocardial injury in rats. Int J Cardiol 115:326–333

    Article  CAS  Google Scholar 

  • Kim YH, Kim YW, Oh YJ, Back NI, Chung SA, Chung HG, Jeong TS, Choi MS, Lee KT (2006) Protective effect of the ethanol extract of the roots of Brassica rapa on cisplatin-induced nephrotoxicity in LLC-PK 1 cells and rats. Biol Pharm Bull 29:2436–2441

    Article  CAS  Google Scholar 

  • Lehotsky J, Kaplan P, Racay P, Matejovicova M, Drgova A, Mezesova V (1999) Membrane ion transport systems during oxidative stress in rodent brain: protective effect of stobadine and other antioxidants. Life Sci 65:1951–1958

    Article  CAS  Google Scholar 

  • Leung FW (1992) Fish oil protects against ethanol-induced gastric mucosal injury in rats. Dig Dis Sci 37:636–637

    Article  CAS  Google Scholar 

  • Liao Y, Lu X, Lu C, Li G, Jin Y, Tang H (2008) Selection of agents for prevention of cisplatin-induced hepatotoxicity. Pharmacol Res 57:125–131

    Article  CAS  Google Scholar 

  • Misra HP, Fridovich I (1972) The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biol Chem 247:3170–3175

    CAS  Google Scholar 

  • Montgomery C, Dymock F (1961) The determination of nitrite in water. Analyst 86:141–146

    Article  Google Scholar 

  • Noori S, Mahboob T (2010) Antioxidant effect of carnosine pretreatment on cisplatininduced renal oxidative stress in rats. Ind J Clin Biochem 25:86–91

    Article  CAS  Google Scholar 

  • Ohkawa H, Wakatsuki A, Kaneda C (1982) Assay for lipid peroxides in animals tissues by thiobarbituric acid reaction. Anal Biochem 95:351–358

    Article  Google Scholar 

  • Pabla N, Dong Z (2008) Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 73:994–1007

    Article  CAS  Google Scholar 

  • Partibha R, Sameer R, Rataboli PV, Bhiwgade DA, Dhume CY (2006) Enzymatic studies of cisplatin-induced oxidative stress in hepatic tissue of rats. Eur J Pharmacol 532:290–293

    Article  CAS  Google Scholar 

  • Priyamvada SM, Priyadarshini NA, Arivarasu N, Farooq S, Khan SA, Khan Md, Khan W, Yusufi ANK (2008) Studies on the protective effect of dietary fish oil on gentamicin- induced nephrotoxicity and oxidative damage in rat kidney. Prostaglandins Leukot Essent Fat Acids 78:369–381

    Article  CAS  Google Scholar 

  • Ray SD, Kumar MA, Bagchi D (1999) In vivo abrogation of acetaminophen induced hepatic genomic DNA fragmentation and apoptotic cell death by a novel grape seed proanthocyanidin extract. Arch Biochem Biophys 369:42–58

    Article  CAS  Google Scholar 

  • Razzaque MS (2007) Cisplatin nephropathy: is cytotoxicity avoidable? Nephrol Dial Transplant 22:2112–2116

    Article  CAS  Google Scholar 

  • Ricardo da Silva JM, Darmon N, Fenandez Y, Mitjavila S (1991) Oxygen free radical scavenger capacity in aqueous models of different procyanidins from grape seeds. J Agric Food Chem 39:1549–1552

    Article  Google Scholar 

  • Rice-Evans CA, Miller NJ, Paganda G (1996) Structure antioxidant activity relationships of flavonoids and phenolic acids. Free Rad Biol Med 20:933–956

    Article  CAS  Google Scholar 

  • Robbiano L, Baroni D, Carrozzino R, Mereto E, Brambilla G (2004) DNA damage and micronuclei induced in rat and human kidney cells by six chemicals carcinogenic to the rat kidney. Toxicol 204:187–195

    Article  CAS  Google Scholar 

  • Roychowdhury S, Wolf G, Keilhoff G, Bagchi D, Horn T (2001) Protection of primary glial cells by grape seed proanthocyanidin extract against nitrosative/oxidative stress. Nitric oxide: Biol Chem 5:137–149

    Article  CAS  Google Scholar 

  • Rybak LP, Mukherjea D, Jajoo S, Ramkumar V (2009) Cisplatin ototoxicity and protection: clinical and experimental studies. Tohoku J Exp Med 219:177–186

    Article  CAS  Google Scholar 

  • Saad SY, Najjar TA, Alashari M (2004) Role of nonselective adenosine receptor blockade and phosphodiesterase inhibition in cisplatin-induced nephrogonadal toxicity in rats. Clin Exp Pharmacol Physiol 31:862–867

    Article  CAS  Google Scholar 

  • Sadowitz PD, Hubbard BA, Dabrowiak JC, Goodisman J, Tacka KA, Aktas MK, Cunningham MJ, Dubowy RL, Souid A-K (2002) Kinetics of cisplatin binding to cellular DNA and modulations by thiol-blocking agents and thiol drugs. Drug Metab Dispos 30:183–190

    Article  CAS  Google Scholar 

  • Sasaki YF, Nishidate E, Izumiyama F, Matsusaka N, Tsuda S (1997) Simple detection of chemical mutagens by the alkaline single-cell gel electrophoresis (Comet) assay in multiple mouse organs. Mutat Res 391:215–231

    Article  CAS  Google Scholar 

  • Satoh M, Kashihara N, Fujimoto S, Horike H, Tokura T, Namikoshi T, Sasaki T, Makino H (2003) A novel free radical scavenger, edarabone, protects against cisplatin-induced acute renal damage in vitro and in vivo. J Pharmacol Exp Ther 305:1183–1190

    Article  CAS  Google Scholar 

  • Shan Y, Ye X, Xin H (2010) Effect of the grape seed proanthocynidin extract on the free radical and energy metabolism indicators during the movement. Sci Res Essay 5:148–153

    Google Scholar 

  • Simopoulos AP (1991) Omega-3 fatty acids in health and disease and in growth and development. Am J Clin Nutr 54:438–463

    CAS  Google Scholar 

  • Speck RF, Lauterburgh BH (1991) Fish oil protects mice against acetaminophen hepatotoxocity in vivo. Hepatol 13:557–561

    CAS  Google Scholar 

  • Spranger I, Sun B, Mateus AM, Freitas V, Ricardo-da-Silva JM (2008) Chemical characterization and antioxidant activity of oligomeric and polymeric procyanidin fractions from grape seeds. Food Chem 108:519–532

    Article  CAS  Google Scholar 

  • Stewart DJ, Benjamin RS, Luna M (1982) Human tissue distribution of platinum after cis-diaminedichloroplatinum. Cancer Chemother Pharmacol 10:51–54

    Article  CAS  Google Scholar 

  • Sun BS, Belchior GP, Ricardo-da-silva JM, Spranger MI (1999) Isolation and purification of dimeric and trimeric procyanidins from grape seeds. J A Chromatography 841:115–121

    Article  CAS  Google Scholar 

  • Taguchi T, Nazneen A, Abid MR, Razzaque MS (2005) Cisplatin-associated nephrotoxicity and pathological events. Contrib Nephrol 148:107–121

    Article  CAS  Google Scholar 

  • Thakkar RR, Wang OL, Zerouga M, Stillwell W, Haq A, Kissling R (2000) Docosahexaenoic acid reverses cyclosporin-A induced changes in membrane structure and function. Biochim Biophys Acta 1474:183–195

    Article  CAS  Google Scholar 

  • Valavanidisa A, Vlahogiannia T, Dassenakisb M, Scoullosb M (2006) Molecular biomarkers of oxidative stress in aquatic organisms in relation to toxic environmental pollutants. Ecotoxicol Environ Saf 64:178–189

    Article  CAS  Google Scholar 

  • Waller RA, Duncan DB (1969) Bayes rule for the symmetric multiple comparison problems. J Am Stat Assoc 64:1484–1503

    Google Scholar 

  • Weijl NI, Cleton FJ, Osanto S (1997) Free radicals and antioxidants in chemotherapy-induced toxicity. Cancer Treat Rev 23:209–240

    Google Scholar 

  • Wu YJ, Muldoon LL, Neuwelt EA (2005) The chemoprotective agent N-acetylcysteine blocks cisplatin-induced apoptosis through caspase signaling pathway. J Pharmacol Exp Ther 312:424–431

    Article  CAS  Google Scholar 

  • Yamakoshi J, Saito M, Kataoka S, Kikuchi M (2002) Safety evaluation of proanthocyanidin-rich extract from grape seeds. Food Chem Toxicol 40:599–607

    Article  CAS  Google Scholar 

  • Yilmaz HR, Iraz M, Sogut S, Ozyurt ZY, Akyol O, Gergerlioglu S (2004) The effects of erdostiene on the activity of some metabolic enzymes during cisplatin-induced nephrotoxicity in rats. Pharmacol Res 50:287–290

    Article  CAS  Google Scholar 

  • Yin X, Apostolov EO, Shah SV, Wang X, Bogdanov KV, Buzder T, Stewart AG, Basnakian AG (2007) Cisplatin-induced nephrotoxicity is mediated by DNase I and endonuclease G in mice. J Am Soc Nephrol 16:697–702

    Google Scholar 

  • Yousef MI, Saad AA, El- Shennawy LK (2009) Protective effect of grape seed proanthocynidins extract against oxidative stress induced by cisplatin in rats. Food Chem Toxicol 47:1176–1183

    Article  CAS  Google Scholar 

  • Yuce A, Atessahin A, Ceribası AO, Aksakal M (2007) Ellagic acid prevents cisplatin-induced oxidative stress in liver and heart tissue of rats. Basic Clin Pharmacol Toxicol 101:345–349

    Article  CAS  Google Scholar 

  • Zhang YY, Li WG, Wu YJ, Bai DC, Liu NF (2005) Proanthocyanidin from grape seeds enhances doxorubicin-induced antitumor effect and reverses drug resistance in doxorubicin-resistant K562/DOX cells. Can J Physiol Phamacol 83:309–318

    Article  CAS  Google Scholar 

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Hassan, H.A., Edrees, G.M., El-Gamel, E.M. et al. Amelioration of cisplatin-induced nephrotoxicity by grape seed extract and fish oil is mediated by lowering oxidative stress and DNA damage. Cytotechnology 66, 419–429 (2014). https://doi.org/10.1007/s10616-013-9589-8

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