Oxidative stress induced cardiomyocytes injury by Tamoxifen and abrogates by zinc supplement in adult female rabbits

  • Mohammed Ali, S. M.
  • Ahmed E. Abood


Tamoxifen (TAM) is used in breast cancer chemotherapy since its approval by the Food and  Drug Administration in 1977. However, TAM therapy is accompanied with cardiomyocytes apoptosis. Oxidative stress and inflammation are the major implicated mechanisms contributing to TAM apoptosis. In this study, we explored whether zinc (Zn) supplementation could prevent TAM-induced cardiomyocytes injury in adult female rabbits. Rabbits were received zinc orally (0.3 mg/ kg body weight / day for 42 days) in zinc group, Tamoxifen group were received orally (0.25 mg/ kg body weight for 42 days), and combination (Zn+Tam) group were received equal dose from zinc and tamoxifen. To study the effect of the tamoxifen (selective estrogen receptor modulator) on the cardiac muscle. Results showed of histopathological study of heart taken from zinc treated group not showed any important abnormalities in histological appearance, tamoxifen group in heart tissue showed a massive necrotic tissue  and a huge inflammatory cell infiltration to damaged area and combination group lesion showed active inflammatory process which included blood vessels congestion, edema formation,  inflammatory cell aggregation especially macrophage and Myocyte vacuolization. As a consequence, the finding of the research Tam induction over production of reactive oxygen species (ROS) within cardiac cell and the imbalance between the ROS generating system and the antioxidant system can lead to a potentially harmful to tissues and cells.


1. Abdo, A. I., Tran, H. B., Hodge, S., Beltrame, J. F., & Zalewski, P. D. (2021). Zinc homeostasis alters zinc transporter protein expression in vascular endothelial and smooth muscle cells. Biological Trace Element Research, 199(6), 2158-2171.‏
2. Abdul-Katum, A. H. (2008). Comparative study between the prophylactics Effects of aqueous extract of Black Currant (Vitis vinferia. L) and vitamin E on some biological parameters related with heart diseases in oxidative Stressed rats: Abdul-Katum, AH and Khudair, KK. The Iraqi Journal of Veterinary Medicine, 32(2), 227-252.‏
3. Ahmed, N. S., Samec, M., Liskova, A., Kubatka, P., & Saso, L. (2021). Tamoxifen and oxidative stress: an overlooked connection. Discover Oncology, 12(1), 1-15.‏
4. Al-Bajari, S., Al-Akash, M., & Ismail, H. K. (2019). Experimental detection of antioxidant and atherogenic effects of grapes seeds extracts in rabbits. Iraqi Journal of Veterinary Sciences, 33(2), 243-249.‏
5. Ali, Z. S., & Khudair, K. K. (2019). Synthesis, Characterization of Silver Nanoparticles Using Nigella sativa Seeds and Study Their Effects on the Serum Lipid Profile and DNA Damage on the Rats’ Blood Treated with Hydrogen Peroxide: Zainab Sattar Ali and Khalisa Khadim Khudair. The Iraqi Journal of Veterinary Medicine, 43(2), 23-37.‏
6. Amara S, Abdelmelek H, Garrel C, Guiraud P, Douki T, Ravanat JL, Favier A, Sakly M, Ben Rhouma K. (2008). Preventive effect of zinc against cadmium-induced oxidative stress in the rat testis. J Reprod Dev 54(2): 129-34.
7. Betrie, A. H., Brock, J. A., Harraz, O. F., Bush, A. I., He, G. W., Nelson, M. T., ... & Ayton, S. (2021). Zinc drives vasorelaxation by acting in sensory nerves, endothelium and smooth muscle. Nature communications, 12(1), 1-14.‏
8. Bruno S, Maisonneuve P, Castellana P, Rotmensz N, Rossi S, Maggioni M, et al. Incidence and risk factors for non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian tamoxifen chemoprevention trial. Bmj. 2005; 330(7497):932.
9. Cuzick J, Powles T, Veronesi U et al. Overview of the main outcomes in breastcancer prevention trials. Lancet 2003; 361: 296–300.

10. Deshpande, J. D., Joshi, M. M., & Giri, P. A. (2013). Zinc: The trace element of major importance in human nutrition and health. Int J Med Sci Public Health, 2(1), 1-6.‏
11. Fisher, B., Dignam, J., Bryant, J., & Wolmark, N. (2001). Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. Journal of the National Cancer Institute, 93(9), 684-690.‏
12. Ghosh, M., Manna, P., & Sil, P. C. (2011). Protective role of a coumarin-derived schiff base scaffold against tertiary butyl hydroperoxide (TBHP)-induced oxidative impairment and cell death via MAPKs, NF-κB and mitochondria-dependent pathways. Free radical research, 45(5), 620-637.‏
13. Hueb, C. K., Aldrighi, J. M., Kallás, E., & Ramires, J. A. F. (2005). Repercussions of raloxifen, tamoxifen and estrogen on aortic atherosclerotic lesions of female rabbits submitted to ovariectomy and hypercholesterol diet. Maturitas, 50(1), 30-38.‏
14. Inst 2001; 93: 684–690.
15. Kanaan, G. N., & Harper, M. E. (2017). Cellular redox dysfunction in the development of cardiovascular diseases. Biochimica et Biophysica Acta (BBA)-General Subjects, 1861(11), 2822-2829.‏
16. Kusleikaite, M., Stonkus, S., & Kusleika, S. (2003). The effect of zinc on endothelium-dependent relaxation of blood-vessels and on the ultrastructure of endothelial cells under immobilization stress. Journal of trace elements in medicine and biology, 17(3), 193-198.‏
17. Lipscombe, L. L., Fischer, H. D., Yun, L., Gruneir, A., Austin, P., Paszat, L., ... & Rochon, P. A. (2012). Association between tamoxifen treatment and diabetes: A population‐based study. Cancer, 118(10), 2615-2622.‏
18. Maremanda KP, Khan S, Jena G. (2014). Zinc protects cyclophosphamide-induced testicular damage in rat: Involvement of metallothionein, tesmin and Nrf2. Biochem Biophys Res Commun 445: 591–596
19. Morshedi R, Ahmadizadeh M, Angali KA. (2014). Protective Effects of zinc supplementation on renal toxicity in rats exposed to cadmium. Jundishapur J Health Sci 6(3): e21717
20. Nelson ER, Wardell SE, McDonnell DP. The molecular mechanisms underlying the pharmacological actions of estrogens, SERMs and oxysterols: implications for the treatment and prevention of osteoporosis. Bone 2013;53:42-50.
21. Nordenskjöld, B., Rosell, J., Rutqvist, L. E., Malmström, P. O., Bergh, J., Bengtsson, N. O., ... & Carstensen, J. (2005). Coronary heart disease mortality after 5 years of adjuvant tamoxifen therapy: results from a randomized trial. Journal of the National Cancer Institute, 97(21), 1609-1610.‏
22. Perez, E. A. (2007). Safety profiles of tamoxifen and the aromatase inhibitors in adjuvant therapy of hormone-responsive early breast cancer. Annals of Oncology, 18, viii26-viii35.‏
23. Ribeiro, M. P., Santos, A. E., & Custódio, J. B. (2014). Mitochondria: the gateway for tamoxifen-induced liver injury. Toxicology, 323, 10-18.‏
24. Rosell, J., Nordenskjöld, B., Bengtsson, N. O., Fornander, T., Hatschek, T., Lindman, H., ... & Carstensen, J. (2013). Effects of adjuvant tamoxifen therapy on cardiac disease: results from a randomized trial with long-term follow-up. Breast cancer research and treatment, 138(2), 467-473.‏
25. Soussi A, Gargouri M, El Feki A. (2018). Effects of co-exposure to lead and zinc on redox status, kidney variables, and histopathology in adult albino rats. Toxicol Ind Health 34(7): 469-480.
26. Tabassum, H., Parvez, S., Rehman, H., Dev Banerjee, B., Siemen, D., & Raisuddin, S. (2007). Nephrotoxicity and its prevention by taurine in tamoxifen induced oxidative stress in mice. Human & experimental toxicology, 26(6), 509-518.‏
27. Taras TL, Wurz GT, Linares GR, et al. Clinical pharmacokinetics of toremifene. Clin Pharmacokinet 2000 Nov; 39 (5): 327-34
28. Vignozzi, L., Filippi, S., Comeglio, P., Cellai, I., Sarchielli, E., Morelli, A., ... & Maggi, M. (2014). Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit. Molecular and cellular endocrinology, 384(1-2), 143-154.‏
29. Zhu, D., Su, Y., Zheng, Y., Fu, B., Tang, L., & Qin, Y. X. (2018). Zinc regulates vascular endothelial cell activity through zinc-sensing receptor ZnR/GPR39. American Journal of Physiology-Cell Physiology, 314(4), C404-C414.‏