Protective Effects of N-acetylcysteine and Selenium against Doxorubicin Toxicity in Rats

Park, Eun-Sung;Kim, Sun-Don;Lee, Min-Hye;Lee, Heung-Shik S.;Lee, In-Se;Sung, Je-Kyung;Yoon, Yeo-Sung

  • Published : 20030000

Abstract

To investigate the neutralizing effect of N-acetylcysteine (NAC) and selenium (Se) aganist doxorubicin (DOX) toxicity in rats, NAC (140 mg/kg, p.o.) and Se(0.5 mg/kg, p.o.) were administered for 2 days before DOX injection and then 3 times a week. Cell viability and the level of lipid peroxidation were examined in cultured-rat astrocytes, Severe morphologic changes in the kidney of DOX group; thickening of Bowmans capsule, presence of multifocal tubular casts were observed, but not in the other treated groups. Vacuoles in some hepatic cells and focal aggregation of stellate macrophages were also detected in DOX group, but not in the other treated groups. However, the severe inhibition of spermatogenesis was found in all treated groups. The cell viability of DOX (10 mg/ml) treated group and NAC (5 mM) or Se (0.001 mg/ml) combined-treated group was 52.5${\pm}$2.0 %, 85.3${\pm}$4.5 % and 75.5${\pm}$1.6 % respectively. In MDA (malondialdehyde) assay, the level of lipid peroxidation on DOX (10 mg/ml), NAC (5 mM) and Se (0.001 mg/ml) was 0.77${\pm}$0.06, 0.35${\pm}$0.06 and 0.54${\pm}$

Keywords

References

  1. Agapito, M.T., Antolin, Y., del Brio, M. T., Lopez-Burillo, S., Pablos, M. I. and Recio, J. M. Protective effect of melatonin against adriamycin toxicity in the rat. J. Pineal Res. 2001, 31(1), 23-30.
  2. Aschner, M., Lorscheider, F. L., Cowan, K. S., Conklin, D. R., Vimy, M. J. and Lash L. H. Metallothionein induction in fetal rat brain and neonatal primary astrocyte cultures by in utero exposure to elemental mercury vapor (HgO). Brain Res. 1997, 778(1), 222-232.
  3. Baba, H., Stephens, L. C., Strebel, F. R., Siddik, Z. H., Newman, R. A., Ohno, S. and Bull, J. M. C. Protective effect of ICRF-187 against normal tissue injury induced by adriamycin in combination with whole body hyperthermia, Cancer Res. 1991, 51, 3568-3577.
  4. Bagchi, D., Bagehi, M., Hassoun, E. A., Kelly, H. J. and Stohs, S. J. Adriamycin-induced hepatic and myocardial lipid peroxidation and DNA damage, and enhanced excretion of urinary lipid metabolites in rats. Toxicol. 1995, 95: 1-9.
  5. Benjelloun, A. S., Merville, P., Cambar, J. and Aparicio, M. Effects of a low-protein diet on urinary glycosaminoglycan excretion in adriamycin-treated rats. Nephron 1993, 64, 242-248.
  6. Bertani, T., Cutillo, F., Zoja, C., Broggini, M. and Remuzzi, G. Tubulo-interstitial lesions mediate renal damage in adriamycin glomerulopathy. Kidney Int. 1986, 30, 488-496.
  7. Bertani, T., Poggi, A., Pozzoni, R., Delaini, F., Sacchi, G., Thoua, Y., Mecca, G., Remuzzi, G. and Donati, M. B. Adriamycin-induced nephrotic syndrome in rats (sequence of pathologic events). Lab. Invest. 1982, 46, 16-23.
  8. Bertazzoli, C., Chieli, T., Ferni, G., Ricevuti, G. and Solcia, E. Chronic toxicity of adriamycin: a new antineoplastic antibiotic. Toxicol. Appl. Pharmacol. 1972, 21, 287-301.
  9. Blum, R. H. and Carter, S. K. Adriamycin, a new anticancer drug with significant clinical activity. Ann. Inter. Med. 1974, 80, 249-259
  10. Dimitrov, N. V., Hay, M. B., Siew, S., Hudler, D. A., Charamella, L, J. and Ullrey, D. E. Abrogation of adriamycin-induced cardiotoxicity by selenium in rabbits. Am. J. Pathol. 1987, 126, 367-383
  11. Domae, N., Sawada, H., Matsuyama, E., Konishi, T. and Uchino, H. Cardiomyopathy and other chronic toxic effects induced in rabbits by doxorubicin and possilbe prevention by coenzyme $Q_{10}$. Cancer Treat. Rep. 1981, 65, 79-91
  12. Fajardo, L. F., Eltringham., J. R., Stewart, J. R. and KIauber, M. R. Adriamycin nephrotoxicity. Lab. Invest. 1980, 43, 242-253.
  13. Folkers, K., Choe, J. Y. and Combs, A. B. Rescue by coenzyme $Q_{10}$ from electrocardiographic abnormalities caused by the toxicity of adriamycin in the rat. Proc. Natl. Acad. Sci. USA, 1978, 75(10), 5178-7180.
  14. Fujita, K., Shinpo, K., Yamada, K., Sato, T., Niimi, H., Shamoto, M., Nagatsu, T., Takeuehi, T. and Umezawa, H. Reduction of adriamycin toxicity by ascobat in mice and guinea pigs. Cancer Res. 1982, 42, 309-316.
  15. Giroux, L., Smeesters, C., Boury, F., Faure, M. P. and Jean, G. Adriamycin and adriamycin-DNA nephrotoxicity in rats. Lab. Invest. 1984, 50, 190-196.
  16. Goodman, J. and Hochstein, P. Generation of free radicals and lipid peroxidation by redox cycling of adriamycin and daunomycin. Biochem. Biophys. Res. Comm. 1977, 77, 797-803.
  17. Hall, R. L., Wilke, W. L. and Fettman, M. J. The progression of adriamycin-induced nephrotic syndrome in rats and the effect of captopril. Toxicol. Appl, Pharmacol. 1986, 82, 164-174.
  18. Herman, E. H., el-Hage, A. and Ferrans, V. J. Protective effect of ICRF-187 on doxorubicin-induced cardiac and renal toxicity in spontaneously hypertensive (SHR) and normotensive (WKY) rats. Toxicol. Appl. Pharmacol. 1988, 92, 42-53.
  19. Hu, S. T., Bradle, E. and Zbinden, G. Inhibition of cardiotoxic, nephrotoxic and neurotoxic effects of doxorubicin by ICRF-159. Pharmcology 1983, 26, 210-220.
  20. Kheir-Eldin, A. A., Motawi, T. K., Gad, M. Z. and Abd-ElGawad, H. M. Protective effect of vitamin E., beta-carotene and N-acetylcysteine from the brain oxidative stress induced in rats by lipopolysaccharide. Int. J. Biochem. Cell BioI. 2001, 33, 475-482.
  21. Mettler, F. P., Young, D. M. and Ward, J. M. Adriamycin-induced cardiotoxicity (cardiomyopathy and congestive heart failure) in rats. Cancer Res. 1977, 37, 2705-2713.
  22. Mimnaugh, E. G., Trush, M. A., Bhatnagar, M. and Gram, T. E. Enhancement of reative oxygen-dependent mitochondrial membrane lipid peroxidation by the anticancer drug adriamycin. Biochem. Pharmacol. 1985, 34, 847-856.
  23. Myers, C. E., McGuire, W. P., Liss, R. H., Ifrim, I., Grotzinger, K. G. and Young, R. C. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science 1977, 197, 165-167.
  24. Nam, S. Y. and Lee, J. S. Histopathological study on the effect of selenium and verapamil on cardiac lesions induced by adriamycin in rats, Seoul Univ. J. Vet. Sci. 1993, 18, 1-29.
  25. Okasora, T., Takikawa, T., Utsunomiya, Y., Senoh, I., Hayashibara, H., Shiraki, K., Kasagi, T. and Shimizu, F. Suppressive effect of superoxide dismutase on adriamycin nephropathy. Nephron 1992, 60, 199-203.
  26. Olson, H. M. and Capen, C. C. Chronic cardiotoxicity of doxorubicin(adriamycin) in the rat: morphologic and biochemical investigations. Toxicol. Appl. Pharmacol. 1978, 44, 605-616.
  27. Osweiler, G. D., Carson, T. L., Buck, W. B. and Van Gelder, G. A. Selenium, in : clinical and diagnostic veterinary toxicology. 3rd. ed. pp. 132-142. Kendall/Hunt Publishing Company Dubuque, Iowa, 1985.
  28. Park, E. S. and Lee, J. S. The effect of selenium on renal lesions induced by adriamycin in rats. Korean J. Vet. Res. 1997, 37(1), 41-57.
  29. Philips, F. S., Gilladoga, A., Marquardt, H., Sternberg, S. S. and Vial, P. M. Some observations on the toxicity of adriamycin (NSC-123127). Cancer Chemother. Rep. 1975, 6, 177-181.
  30. Powell, S. R. and McCay, P. B. Inhibition of doxorubicin-initiated membrane damage by N-acetylcysteine : possible mediation by a thiol-dependent, cytosolic inhibitor of lipid peroxidation. Toxicol. Appl. Pharmacol. 1988, 96, 175-184.
  31. Rehan, A., Johnson, K. J., Wiggins, R. C., Kunkel, R. C. and Ward, P. A. Evidence for the role of oxygen radicals in acute nephrotoxic nephritis. Lab. Invest. 1984, 51(4), 396-403.
  32. Rotruck, J. K., Pope, A. L., Ganther, H. E., Swanson, A. B., Hafeman, D. G. and Hoekstra, W. G. Selenium : biochemical role as a component of glutathione peroxidase. Science 1973, 179, 588-590.
  33. Sanai, T., Okuda, S., Onoyama, K., Motomura, K., Osato, S., Hori, K., Iseki, K. and Fujishima, M. Effect of different doses of aluminium hydroxide on renal deterioration and nutritional state in experimental chronic renal failure. Min. Electr. Met. 1991, 17, 160-165.
  34. Shinozawa, S., Fukuda, T., Araki, Y. and Oda, T. Effect of dextran sulfate on the survival time and mitochondrial function of adriamycin (doxorubicin)treated mice. Toxicol. Appl. Pharmacol. 1985, 79, 353-357.
  35. Solaini, G., Landi, L., Pasquali, P. and Rossi, C. A. Protective effect of endogenous coenzyme $Q_{10}$ on both lipid peroxidation and respiratory chain inactivation induced by an adriamycin-iron complex. Biochem Biophys. Res. Comm. 1987, 147, 572-580.
  36. Suzuki, Y., Ohnuma, T. and GoIsmith, M. A. Nephrotoxic effects of adriamycin in rabbits. Fed. Proc. 1978, 37, 320.
  37. Tan, C., Etcubanas, E., Wollner, N., Rosen, G., Gilladoga, A., Showel, J., Murphy, M. L. and Krakoff, I. H. Adriamycin-an antitumor antibiotic in the treatment of neoplasmic diseases. Cancer 1973, 32, 9-17.
  38. Victor, V. M. and De la Fuente, M. N-Acetylcysteine improves in vitro the function of macrophages from mice with endotoxin-induced oxidative stress. Free. Rad. Res. 2002, 36, 33-45.
  39. Wang, J. J., Cortes, E., Sinks, L. F. and Holland, J. F. Therapeutic effect and toxicity of adriamycin in patients with neoplastic disease. Cancer 1971, 28, 837-843.
  40. Washio, M., Nanishi, F., Okuda, S., Onoyama, K. and Fujishima, M. Alpha tocopherol improves focal glomerulosclerosis in rats with adriamycin-induced progressive renal failure. Nephron 1994, 68, 347-352.
  41. Zamora, R., Hidalgo, F. J. and Tappel, A. L. Comparative antioxidant effectiveness of dietary ${\beta}$-carotene, vitamin E, selenium and coenzyme Q10 in rat erythrocytes and plasma. J. Nutr. 1991, 121, 50-56.