Effects of N-Acetylcysteine, Deferoxamine and Selenium on Doxorubicin-Induced Hepatotoxicity

  • Fatih Bulucu
  • Ramazan Ocal
  • Nuri Karadurmus
  • Mustafa Sahin
  • Levent Kenar
  • Ahmet Aydin
  • Cagatay Oktenli
  • Bayram Koc
  • Volkan Inal
  • Levent Yamanel
  • Halil Yaman
Article

Abstract

The aims of our study were to evaluate the antioxidant defence mechanisms of liver tissue challenged by doxorubucin (DOX) and to compare the possible protective effects of N-acetylcysteine (NAC) (n = 10), deferoxamine (DOF) (n = 10), DOF+NAC (n = 10) and selenium (n = 9) on doxorubicin-induced hepatotoxicity. Fifty-six male rats (Mean weight = 250 ± 50 g) randomly divided into five groups. Animals in study groups were pretreated with a single dose of Dox, which was administered intravenously. Control group (n = 7) was treated with intravenous saline injection. Selenium was given intraperitoneally. Blood and urine samples were collected before sacrifice. Liver tissue samples were collected and tissue superoxide dismutase (SOD), glutathione peroxidase (GSH-px), CAT activity, MDA, Zn, iron and copper were determined. DFO decreased lipid peroxidation significantly. DFO and NAC decreased CAT activity significantly. Antioxidant regimes increase SOD activities significantly. DOF and NAC increase GSH-px activities and copper levels significantly. Beneficial effect of selenium seems to result from its stimulation of SOD but not to GSH-px. It has been found that DOF, NAC and selenium have protective effects on Dox-induced hepatocellular damage. DOF+NAC did not result additional benefit.

Keywords

Doxorubicin hepatotoxicity Deferoxamine N-acetylcysteine Selenium Rat 

References

  1. 1.
    Tomoki K, Fujita I, Itoh N, Muto N, Nakanishi T, Takahashi K, Azuma J, Tanaka K: Metallothionein acts as a cytoprotectant against doxorubicin toxicity. JPET 2000; 292:299–302.Google Scholar
  2. 2.
    Steinherz LJ, Steinherz PG, Tan CT, Heller G, Murphy ML: Cardiac toxicity 4 to 20 years after completing anthracycline therapy. JAMA 1991; 266:1672–7.CrossRefPubMedGoogle Scholar
  3. 3.
    Singal PK, Iliskovic N: Doxorubicin induced cardiomyopaty. N Engl J Med 1998; 339:900–905CrossRefPubMedGoogle Scholar
  4. 4.
    Kalender Y, Yel M, Kalender S: Doxorubicin hepatotoxicity and hepatic free radical metabolism in rats. The effects of vitamin E and catechin. Toxicology 2005; 209:39–45.CrossRefPubMedGoogle Scholar
  5. 5.
    Ganey PE,Kauffmann FC,Thurman RG: Oxygen-dependent hepatotoxicity due to doxorubicin: role of reducing equivalent supply in perfused rat liver. Mol Pharmacol 1988; 34: 695–701.PubMedGoogle Scholar
  6. 6.
    Bagchi D, Bagchi M, Hassoun E, Kelly J, Stohs SJ: Adriamycin-induced hepatic and myocardial lipid-peroxidation and DNA damage, and enhanced excretion of urinary lipid metabolites in rats. Toxicology 1995; 95: 1–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Durak I, Öztürk HS, Kavutcu M, Birey M, Yel M, Guven T, Olcay E, Kacmaz M, Canbolat O: Protective role of antioxidant vitamins on adriamycin-induced free radical production and cardiotoxicity in guinea pigs. Cancer Res Ther Cont 1998; 5: 133–141.Google Scholar
  8. 8.
    Marchand DJ, Renton KW: Depression of cytochrome P-450-dependent drug biotrnsfomation by adriamycin. Toxicol Appl Phamacol 1981; 58: 83–88.CrossRefGoogle Scholar
  9. 9.
    Babson JR, Abell NS, Reed DJ: Protective role of glutathione redox cycle against adriamycin-mediated toxicity in isolated hepatocytes. Biochem Pharmacol 1981; 30: 2299–2304.CrossRefPubMedGoogle Scholar
  10. 10.
    Afaq F, Abidi P, Rahman Q: N-acetyl L-cysteine attenuates oxidant-mediated toxicity induced by chrysotile fibers. Toxicol Letter 2000; 117: 53–60.CrossRefGoogle Scholar
  11. 11.
    De Beer EL, Bottone AE, Voest EE: Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: a review. Eur J Pharmacol 2001; 415: 1–11.PubMedGoogle Scholar
  12. 12.
    Gianni L, Zweier JL, Levy A, Myers CE: Characterization of the cycle of iron-mediated electron transfer from adriamycin to molecular oxygen. J Biol Chem 1985; 260:6820–6826.PubMedGoogle Scholar
  13. 13.
    Sinha BK, Polliti PM: Antracyclines. Cancer Chemother Biol Resp Modifier Ann 1990; 11:45–57.Google Scholar
  14. 14.
    Voest EE, Vreugdenhil G, Marx JJM: Iron-chelating agents in non-iron overload conditions. Ann Inter Med 1994; 120: 490–499.Google Scholar
  15. 15.
    Stadtman TC: Selenium-dependent enzymes. Annu Rev Biochem 1980; 49: 93–110.CrossRefPubMedGoogle Scholar
  16. 16.
    Stajn A, Zikic RV, Ognjanovic B, Saicic ZS, Pavlovic SZ, Kostic MM, Petrovic VM: Effect of cadmium and selenium on the antioxidant defence system in rat kidneys. Comp biochem Physiol 1997; 117C:167–172.Google Scholar
  17. 17.
    Bulucu F, Oktenli C, Kenar L, Koc B, Ocal R, Karadurmus N, Inal V, Yamanel L, Sanisoğlu YS, Aydin A: Detrimental effects of N-acetylcysteine plus desferoxamine combination in an experimental nephrotic syndrome model. Int J Toxicol. 2007; 26:525–532.CrossRefPubMedGoogle Scholar
  18. 18.
    Bulucu F, Oktenli C, Kenar L, Koc B, Ocal R, Inal V, Yamanel L, Yaman H, Sanisoğlu YS, Aydin A: Efficacy of deferoxamine, N-acetylcysteine and selenium treatments in rats with adriamycin-induced nephrotic syndrome. J Nephrol 2008; 21: 576–583.PubMedGoogle Scholar
  19. 19.
    Aydin A, Orhan H, Sayal A, Ozata M, Sahin G, Isimer A: Oxidative stress and nitric oxide related parameters in type II diabetes mellitus: effects of glycemic control. Clin. Biochem. 2001; 134: 65–70.CrossRefGoogle Scholar
  20. 20.
    Aebi H. Catalase in vitro. Methods. Enzymol 1984; 105: 121–6.CrossRefPubMedGoogle Scholar
  21. 21.
    Atkuri KR, Mantovani JJ, Herzenberg LA, Herzenberg LA. N-Acetylcysteine-a safe antidote for cysteine/glutathione deficiency. Curr Opin Pharmacol. 2007; 7:355–359.CrossRefPubMedGoogle Scholar
  22. 22.
    Gokcimen A, Cim A, Tola HT, Bayram D, Kocak A, Ozguner F, Ayata A:Protective effect of N-acetylcysteine, caffeic acid and vitamin E on doxorubicin hepatotoxicity. Hum Exp Toxicol 2007; 26: 519–525.CrossRefPubMedGoogle Scholar
  23. 23.
    Haliwell B: Protection against tissue damage in vivo by desferrioxamine: what is its mechanism of action? Free Radic biol Med 1989; 7:645–651.CrossRefGoogle Scholar
  24. 24.
    Schwarz K, Foltz CM: Selenium as an integral part of Factor 3 against dietary necrotic liver degeneration. J Am Chem Soc 1957; 79: 3292–3293.CrossRefGoogle Scholar
  25. 25.
    Rotruck JT, Pope AL, Ganther HE, Swanson AB, Hafeman DG, Hoekstra WG: Selenium: Biochemical role as a component of glutathione peroxidase. Science 1973; 179: 588–590.CrossRefPubMedGoogle Scholar
  26. 26.
    Low SC, Berry MJ: Knowing when not to stop:selenocysteine incorporation in eukaryotes. Trends in Biochem Sci 1996; 21: 203–208.Google Scholar
  27. 27.
    Stadtman TC: Selenium biochemistry. Ann Rev Biochem 1990; 59: 111–127.CrossRefPubMedGoogle Scholar
  28. 28.
    Valko M, Morris H, Cronin MT: Metals, toxicity and oxidative stress. Curr Med Chem 2005; 12: 1161–1208.CrossRefPubMedGoogle Scholar
  29. 29.
    El-Sharaky AS, Newairy AA, Badreldeen MM, Eweda SM, Sheweita SA: Protective role of selenium against renal toxicity induced by cadmium in rats. Toxicol 2007; 235: 185–193.CrossRefGoogle Scholar
  30. 30.
    de Freitas AS, Funck VR, Rotta MS, Bohrer D, Mörschbächer V, Puntel RL, Nogueira CW, Farina M, Aschner M, Rocha JB: Diphenyl diselenide, a simple organoselenium compound, decreases methylmercury-induced cerebral, hepatic and renal oxidative stress and mercury deposition in adult mice. Brain Res Bull 2009; 79: 77–87.Google Scholar
  31. 31.
    Fraga CG, Arias RF, Llesuy SF, Koch OR; Boveris A: Effect of vitamin E- and selenium-deficiency on rat liver chemiluminescence. Biochem. J. 1987; 242: 383–386.PubMedGoogle Scholar
  32. 32.
    Teixeira KC, Soares FS, Rocha LG, Silveira PC, Silva LA, Valença SS, Dal Pizzol F, Streck EL, Pinho RA: Attenuation of bleomycin-induced lung injury and oxidative stress by N-acetylcysteine plus deferoxamine. Pulm Pharmacol Ther 2008; 21: 309–316.CrossRefPubMedGoogle Scholar
  33. 33.
    Pinho RA, Silveira PC, Silva LA, Luiz Streck E, Dal-Pizzol F, Moreira JCF: N-acetylcysteine and deferoxamine reduce pulmonary oxidative stress and inflamation in rats after coal dust exposure. Environ Res 2005; 99:355–360.CrossRefPubMedGoogle Scholar
  34. 34.
    Ritter C, da Cunha AA, Echer IC, Andrades M, Reinke A, Lucchiari N, Rocha J, Streck EL, Menna-Barreto S, Moreira JC, Dal-Pizzol F: Effects of N-acetylcysteine plus deferoxamine in lipopolysaccharide-induced acute lung injury in the rat. Crit Care Med 2006; 34:471–477.CrossRefPubMedGoogle Scholar
  35. 35.
    Aguiar AS Jr, Tuon T, Soares FS, da Rocha LG, Silveira PC, Pinho RA: The effect of N-acetylcysteine and deferoxamine on exercise-induced oxidative damage in striatum and hippocampus of mice. Neurochem Res. 2008; 33:729–736. Epub 2007 Oct 17.CrossRefPubMedGoogle Scholar
  36. 36.
    Di-Pietro PB, Dias ML, Scaini G, Burigo M, Constantino L, Machado RA, Dal-Pizzol F, Streck EL: Inhibition of brain creatine kinase activity after renal ischemia is attenuated by N-acetylcysteine and deferoxamine administration. Neurosci Lett. 2008; 434: 139–43.CrossRefPubMedGoogle Scholar
  37. 37.
    Valvassori SS, Petronilho FC, Réus GZ, Steckert AV, Oliveira VB, Boeck CR, Kapczinski F, Dal-Pizzol F, Quevedo J: Effect of N-acetylcysteine and/or deferoxamine on oxidative stress and hyperactivity in an animal model of mania. Prog Neuropsychopharmacol Biol Psychiatry 2008; 32:1064–1068.CrossRefPubMedGoogle Scholar
  38. 38.
    Schnellmann JG, Pumford NR, Kusewitt DF, Bucci TJ, Hinson JA: Deferoxamine delays the development of the hepatotoxicity of acetaminophen in mice. Toxicol Lett. 1999; 106:79–88.CrossRefPubMedGoogle Scholar
  39. 39.
    Ritter C, Reinke A, Andrades M, Martins MR, Rocha J, Menna-Barreto S, Quevedo J, Moreira JC, Dal-Pizzol F: Protective effect of N-acetylcysteine and deferoxamine on carbon tetrachloride-induced acute hepatic failure in rats. Crit Care Med. 2004; 32(10):2079–83.CrossRefPubMedGoogle Scholar
  40. 40.
    Sweetman SC: Martindale. The Complete Drug Reference, 33 rd edition, 2002, The Pharmaceutical Press, London, pp: 1082.Google Scholar
  41. 41.
    Yağmurca M, Bas O, Mollaoglu H, Sahin O, Nacar A, Karaman O, Songur A: Protective effects of erdosteine on doxorubiicn-induced hepatotoxicity in rats. Arch Med Res 2007; 38:380–385.CrossRefPubMedGoogle Scholar
  42. 42.
    Doroshow JH, Locker GY, Myers CE: Enzymatic defenses of mouse hearth against reactive oxygen metabolites. J Clin Invest 1980; 65: 128–135.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  • Fatih Bulucu
    • 1
  • Ramazan Ocal
    • 1
  • Nuri Karadurmus
    • 1
  • Mustafa Sahin
    • 2
  • Levent Kenar
    • 3
  • Ahmet Aydin
    • 4
  • Cagatay Oktenli
    • 1
  • Bayram Koc
    • 1
  • Volkan Inal
    • 5
  • Levent Yamanel
    • 6
  • Halil Yaman
    • 3
  1. 1.Department of Internal MedicineGulhane Military Medical AcademyAnkaraTurkey
  2. 2.Department of EndocrinologyGulhane Military Medical AcademyAnkaraTurkey
  3. 3.Department of Biochemistry and Clinical BiochemistryGulhane Military Medical AcademyAnkaraTurkey
  4. 4.Department of Pharmaceutical SciencesGulhane Military Medical AcademyAnkaraTurkey
  5. 5.Department of Internal MedicineMilitary HospitalEskisehirTurkey
  6. 6.Department of the Intensive Care MedicineGulhane Military Medical AcademyAnkaraTurkey

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