Skip to main content

Advertisement

Log in

Effects of Histidine and N-Acetylcysteine on Doxorubicin-Induced Cardiomyopathy in Rats

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

The amino acids histidine and n-acetylcysteine have many biological activities such as antioxidant effect. The present study investigated the effects of histidine and n-acetylcysteine on the heart lesions induced by doxorubicin (DOX) in rats. Forty-eight male Wistar rats were divided into two major groups treated intraperitoneally (i.p.) with normal saline and 4 mg/kg of DOX, respectively. Each group was further divided into four subgroups that were treated with separate and combined i.p. injections of histidine and n-acetylcysteine (NAC) at a same dose of 40 mg/kg. Electrocardiography (ECG) was recorded using lead II. The heart lesions were evaluated by light microscopy. Serum levels of creatine phosphokinase and lactate dehydrogenase and heart tissue malondialdehyde levels were measured. Histidine and especially NAC at a same dose of 40 mg/kg recovered ECG changes, improved heart lesions and prevented biochemical changes induced by DOX. Co-administration of histidine and NAC showed better responses when compared with them used alone. The results of the present study showed protective effects for histidine and NAC on the heart. Reduction in free radical-induced toxic effects may be involved in cardioprotective properties of histidine and NAC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Minotti, G., Menna, P., Salvatorelli, E., Cairo, G., & Gianni, L. (2004). Anthracyclines: Molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacological Review, 56, 185–229.

    Article  CAS  Google Scholar 

  2. Singal, P. K., & Iliskovic, N. (1998). Doxorubicin-induced cardiomyopathy. New England Journal of Medicine, 339, 900–905.

    Article  CAS  PubMed  Google Scholar 

  3. Simunek, T., Sterba, M., Popelova, O., Adancova, M., Hrdina, R., & Gersl, V. (2009). Anthracycline-induced cardiotoxicity: Overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacological Reports, 91, 154–171.

    Article  Google Scholar 

  4. Octavia, Y., Tocchetti, C. G., Gabrielson, K. L., Janssens, S., Crijins, H. J., & Moens, A. L. (2012). Doxorubicin-induced cardiomyopathy: From molecular mechanisms to therapeutic strategies. Journal of Molecular and Cellular Cardiology, 52, 1213–1225.

    Article  CAS  PubMed  Google Scholar 

  5. Volkova, M., & Russell, R, 3rd. (2011). Anthracycline cardiotoxicity: Prevalence, pathogenesis and treatment. Current Cardiology Reviews, 7, 214–220.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Ito, T., Muraoka, S., Takahashi, K., Fujio, Y., Schaffer, W., & Azuma, J. (2009). Beneficial effects of taurine treatment against doxorubicin-induced cardiotoxicity in mice. Advances in Experimental Medicine and Biology, 643, 65–74.

    Article  CAS  PubMed  Google Scholar 

  7. Todorova, V. K., Kaufmann, Y., Hennings, L., & Kimberg, V. S. (2010). Oral glutamine protects against acute doxorubicin-induced cardiotoxicity in tumor-bearing rats. Journal of Nutrition, 140, 44–48.

    Article  CAS  PubMed  Google Scholar 

  8. Farshid, A. A., Tamaddonfard, E., Belasius, M. S., & Hamzeh-Gooshchi, N. (2009). Histopathological comparison of the effects of histidine and ketotifen in a rat model of colitis. Bulletin of the Veterinary Institute in Pulawy, 53, 795–800.

    Google Scholar 

  9. Farshid, A. A., Tamaddonfard, E., & Morvaridi, A. (2011). Effects of histidine and dexamethasone on the local inflammation induced by histamine in rats. Veterinary Research Forum, 2, 31–36.

    Google Scholar 

  10. Farshid, A. A., Tamaddonfard, E., & Ranjbar, S. (2013). Oral administration of vitamin C and histidine attenuate cyclophosphamide-induced hemorrhagic cystitis in rats. Indian Journal of Pharmacology, 45, 126–129.

    Article  PubMed Central  PubMed  Google Scholar 

  11. Farshid, A. A., Tamaddonfard, E., & Yahyaee, F. (2010). Effects of histidine and N-acetylcysteine on diclofenac-induced anti-inflammatory response in acute inflammation in rats. Indian Journal of Experimental Biology, 48, 1136–1142.

    CAS  PubMed  Google Scholar 

  12. Tamaddonfard, E., & Rahimi, S. (2004). Central effect of histamine and peripheral effect of histidine on the formalin-induced pain responses in mice. Clinical and Experimental Pharmacology and Physiology, 31, 518–522.

    Article  CAS  PubMed  Google Scholar 

  13. Wade, A. M., & Tucker, H. N. (1998). Antioxidant characteristics of L-histidine. The Journal of Nutritional Biochemistry, 9, 308–315.

    Article  CAS  Google Scholar 

  14. Obata, T., Aomine, M., & Yamanaka, Y. (1999). Protective effect of histidine on iron (II)-induced hydroxyl radical generation in rat hearts. Journal of Physiology (Paris), 93, 216–218.

    Article  Google Scholar 

  15. Kelly, G. S. (1998). Clinical application of N-acetylcysteine. Alternative Medicine Review, 3, 114–127.

    CAS  PubMed  Google Scholar 

  16. Doroshow, J. H., Locker, G. Y., Ifrim, I., & Myers, C. E. (1981). Prevention of doxorubicin cardiac toxicity in the mouse by N-acetylcysteine. The Journal of Clinical Investigation, 68, 1053–1064.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Arica, V., Demir, I. H., Tutanc, M., Barsarslan, F., Arica, S., Karcoiglu, M., et al. (2013). N-acetylcysteine prevents doxorubicin-induced cardiotoxicity in rats. Human and Experimental Toxicology, 32, 655–661.

    Article  CAS  PubMed  Google Scholar 

  18. Singh, D. K., & Lippman, S. M. (1998). Cancer chemoprevention part 1: Retinoids and carotenoids and other classic antioxidants. Oncology, 12, 1643–1660.

    CAS  PubMed  Google Scholar 

  19. Bayne, K. (1996). Revised, guide for the care and use of laboratory animals. American physiological society. Physiologist, 39, 208–211.

    Google Scholar 

  20. Clark, J. D., Gebhart, G. F., Conder, J. C., Keeling, M. E., & Kohn, D. F. (1997). Special report: The 1996 guide for the care and use of laboratory animals. Institute of Laboratory Animals Research Journal, 38, 41–48.

    Article  Google Scholar 

  21. Xin, Y. F., Zhou, G. L., Deng, Z. Y., Chen, Y. X., Wu, Y. G., Xu, P. S., et al. (2007). Protective effect of Lycium barbarum on doxorubicin-induced cardiotoxicity. Phytotherapy Research, 21, 1020–1024.

    Article  CAS  PubMed  Google Scholar 

  22. Kolarovic, J., Popovic, M., Zlinska, J., Trivic, S., & Vojnovic, M. (2010). Antioxidant activity of celery and parseley in rats treated with doxorubicin. Molecules, 15, 6193–6204.

    Article  CAS  PubMed  Google Scholar 

  23. Tariq, M., Morais, C., Soki, S., Al Sulaiman, M., & Al Khader, A. (1999). N-acetylcysteine attenuates cyclosporine-induced nephrotoxicity in rats. Nephrology, Dialysis, Transplantation, 14, 923–929.

    Article  CAS  PubMed  Google Scholar 

  24. Kakulavarapu, V., Rao, R., Reddy, P. V. B., Tong, X., & Norenberg, M. D. (2010). Brain edema in acute liver failure: Inhibition by L-histidine. American Journal of Pathology, 176, 1400–1408.

    Article  Google Scholar 

  25. Farraj, A. K., Hazari, M. S., & Cascio, W. E. (2011). The utility of the small rodent electrocardiogram in toxicity. Toxicological Sciences, 121, 11–30.

    Article  CAS  PubMed  Google Scholar 

  26. Ammar, E.-S. M., Said, S. A., El-Damarawy, S. L., & Suddek, G. M. (2013). Cardioprotective effect of grape-seed proanthocyanidins on doxorubicin-induced cardiac toxicity in rats. Pharmaceutical Biology, 51, 339–344.

    Article  CAS  Google Scholar 

  27. Ohkawa, H., Ohishi, N., & Yagi, K. (1979). Assay of lipid peroxidase in normal tissue by thiobarbituric acid reaction. Analytical Biochemistry, 95, 351–358.

    Article  CAS  PubMed  Google Scholar 

  28. Jensen, R. A., Acton, E. M., & Peters, J. H. (1984). Electrocardiographic and transmembrane potential effects of 5-iminodaunorubicin in the rat. Cancer Research, 44, 4030–4039.

    CAS  PubMed  Google Scholar 

  29. Shan, S., Mohan, M. M., Kasture, S., Sanna, C., & Maxia, A. (2009). Protective effect of Ephedra nebrodensis on doxorubicin-induced cardiotoxicity in rats. Iranian Journal of Pharmacology and Therapeutics, 8, 61–66.

    Google Scholar 

  30. van Acker, S. A., Kramer, K., Voest, E. E., Grimbergen, J. A., Zhang, J., van der Vijgh, W. J., et al. (1996). Doxorubicin-induced cardiotoxicity monitored by ECG in freely moving mice. A new model to test potential protectors. Cancer Chemotherapy and Pharmacology, 38, 95–101.

    Article  PubMed  Google Scholar 

  31. Dudka, J., Gieroba, R., Korga, A., Burdan, F., Matysiak, W., Jodlowska-Jedrich, B., et al. (2012). Different effects of resveratrol on dose-related doxorubicin-induced heart and liver toxicity. Evidence Based Complementary and Alternative Medicine, 2012, 606183. doi:10.1155/2012/606183.

    Article  PubMed Central  PubMed  Google Scholar 

  32. Abd Elbaky, A. N., Ali, A. A., & Ahmed, R. A. (2010). Cardioprotective effect of simvastatin on doxorubicin-induced oxidative cardiotoxicity in rats. Journal of Basic and Applied Sciences, 6, 29–38.

    CAS  Google Scholar 

  33. Yagamura, M., Fadillioglu, E., & Erdogan, H. (2003). Erdosteine prevents doxorubicin-induced cardiotoxicity in rats. Pharmacological Research, 48, 377–382.

    Article  Google Scholar 

  34. Xu, M. F., Tang, P. L., Qian, Z. M., & Ashraf, M. (2001). Effects by doxorubicin on the myocardium are mediated by oxygen free radicals. Life Sciences, 68, 889–901.

    Article  CAS  PubMed  Google Scholar 

  35. Koti, B. C., Vishwanathswamy, A. H. M., Wagawade, J., & Thippeswamy, A. H. M. (2009). Cardioprotective effect of lipistat against doxorubicin induced myocardial toxicity in albino rats. Indian Journal of Experimental Biology, 47, 41–46.

    CAS  PubMed  Google Scholar 

  36. Mokni, M., Hamlaoui-Guesmi, S., Amir, M., Marzuki, L., Limam, F., & Aouan, E. (2012). Grape seed and skin extract protects against acute chemotherapy toxicity induced by doxorubicin in rat heart. Cardiovascular Toxicology, 12, 158–165.

    Article  PubMed  Google Scholar 

  37. Lebrecht, D., Geist, A., Ketelsen, U. P., Haberstroh, J., Setzer, B., & Walker, U. A. (2007). Dexrazoxane prevents doxorubicin-induced long-term cardiotoxicity and protect myocardial mitochondria from genetic and functional lesions in rats. British Journal of Pharmacology, 151, 771–778.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Moore, K., & Roberts, L. J. (1998). Measurement of lipid peroxidation. Free Radical Research, 28, 659–671.

    Article  CAS  PubMed  Google Scholar 

  39. Chatterjee, A., Zhang, J., Honbo, N., & Karliner, J. S. (2010). Doxorubicin cardiotoxicity. Cardiology, 115, 155–162.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Lee, Y. T., Hsu, C. C., Lin, M. H., Liu, K. S., & Yin, M. C. (2005). Histidine and carnosine delay diabetic deterioration in mice and protect human low density lipoprotein against oxidation and glycation. European Journal of Pharmacology, 513, 145–150.

    Article  CAS  PubMed  Google Scholar 

  41. Li, S. Q., Zhao, G., Li, J., & Qian, W. (1998). Effect of histidine on myocardial mitochondria and platelet aggregation during thrombic cerebral ischemia in rats. Zhongguo Yao Li Xu Bao, 19, 493–496.

    CAS  Google Scholar 

  42. Cai, Q., Takemura, G., & Ashraf, M. (1995). Antioxidative properties of histidine and its effect on myocardial injury during ischemia/reperfusion in isolated rat heart. Journal of Cardiovascular Pharmacology, 25, 147–155.

    Article  CAS  PubMed  Google Scholar 

  43. Villani, F., Galimberti, M., Monti, E., Piccinini, F., Lanza, E., Rozza, A., et al. (1990). Effect of glutathione and N-acetylcysteine on in vitro and in vivo cardiac toxicity of doxorubicin. Free Radical Research Communications, 11, 145–151.

    Article  CAS  PubMed  Google Scholar 

  44. Powell, S. R., & McCay, P. B. (1988). Inhibition of doxorubicin-initiated membrane damage by N-acetylcysteine: possible mediation by a thiol-dependent, cytosolic inhibitor of lipid peroxidation. Toxicology and Applied Pharmacology, 96, 175–184.

    Article  CAS  PubMed  Google Scholar 

  45. Park, E. S., Kim, S. D., Lee, M. H., Lee, H. S., Lee, I. S., Sung, J. K., et al. (2003). Protective effect of N-acetylcysteine and selenium against doxorubicin toxicity in rats. Journal of Veterinary Science, 4, 129–136.

    PubMed  Google Scholar 

  46. Kockar, M. C., Naziroglu, M., Celik, O., Tola, H. T., Bayram, D., & Koyu, A. (2010). N-acetylcysteine modulates doxorubicin-induced oxidative stress and antioxidant vitamin concentrations in liver of rats. Cell Biochemistry and Function, 28, 673–677.

    Article  CAS  PubMed  Google Scholar 

  47. Dobrzynska, I., Skrzydlewska, E., Kasacka, I., & Figaszewiski, Z. (2000). Protective effect of N-acetylcysteine on rat liver cell membrane during methanol intoxication. Journal of Pharmacy and Pharmacology, 52, 547–552.

    Article  CAS  PubMed  Google Scholar 

  48. Peterson, J. W., Boldogh, I., Popov, P. L., Saini, S. S., & Chopra, A. K. (1998). Anti-inflammatory and antisecretory potential of histidine in salmonella challenged mouse small intestine. Laboratory Investigation, 78, 523–534.

    CAS  PubMed  Google Scholar 

  49. Lamson, D. W., & Brignall, M. S. (1999). Antioxidants in cancer therapy: Their actions and interactions with oncologic therapies. Alternative Medicine Review, 4, 304–329.

    CAS  PubMed  Google Scholar 

  50. Kalaiselvi, P., Pragasam, V., Chinnikishnan, S., Veera, C. K., Sundarapandiyan, R., & Varalakshmi, P. (2005). Counteracting adriamycin-induced oxidative stress by administration of N-acetylcysteine and vitamin E. Clinical Chemistry and Laboratory Medicine, 43, 834–840.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Amir Abbas Farshid.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Farshid, A.A., Tamaddonfard, E., Simaee, N. et al. Effects of Histidine and N-Acetylcysteine on Doxorubicin-Induced Cardiomyopathy in Rats. Cardiovasc Toxicol 14, 153–161 (2014). https://doi.org/10.1007/s12012-013-9239-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-013-9239-6

Keywords

Navigation