Nebivolol effect on oxidative biomarkers in Tamoxifen-Induced Hepatotoxicity in Female White Albino Rats: In Vivo Study

Noor Ahmed Hammadi; Yassir Mustafa Kamal almullahummadi; Huda Jaber Waheed

doi:10.32947/ajps.v25i2.1157

Authors

Noor Ahmed Hammadi Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
Yassir Mustafa Kamal almullahummadi Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq
Huda Jaber Waheed Department of Pharmacology and Toxicology, College of Pharmacy, Mustansiriyah University, Baghdad, Iraq

DOI:

https://doi.org/10.32947/ajps.v25i2.1157

Keywords:

Hepatotoxicity, Tamoxifen, Nebivolol, GPX, MDA

Abstract

Liver injury can arise post-exposure to drugs or their metabolites, as well as herbal and dietary supplements^. Tamoxifen is a frequently used drug in breast cancer treatment. Unfortunately, Epidemiological studies have identified that Long-term tamoxifen treatment has been associated with the development of hepatotoxicity so it was used in this study to induce liver damage. Oxidative stress was the major implicated mechanism contributing to tamoxifen hepatotoxicity. Nebivolol is a third-generation selective beta1-adrenergic receptor blocker with vasodilator characteristics with significant antioxidant activity.

The presented study was conducted to investigate the possible protective role of nebivolol against rat hepatotoxicity induced by tamoxifen. Rats utilized in this study were randomized into five groups (6 in each group); Group 1- (Control) rats received distilled water (5mL/kg body weight orally) for 14 consecutive days. Group 2- Rats received distilled water for 12 consecutive days and tamoxifen (75mg/kg b.w., orally) on days 13 and 14 only. Group 3- Rats received Nebivolol (5 mg/kg b.w., orally for 14 consecutive days) and tamoxifen (75mg/kg b.w., orally) only on days 13 and 14. Group 4- Rats received Nebivolol (8 mg/kg b.w., orally for 14 consecutive days) and tamoxifen (75mg/kg b.w., orally) only on days 13 and 14. Group 5- Rats received Nebivolol (10 mg/kg b.w., orally for 14 consecutive days) and tamoxifen (75mg/kg b.w., orally) on days 13 and 14 only. The current study concluded that pre-administration of nebivolol with tamoxifen showed significant upregulation (P<0.05) in glutathione peroxidase (GPx) and significant downregulation (p<0.05) in malondialdehyde (MDA) each compared to corresponding levels in the tamoxifen-only treated group. In conclusion, this study demonstrated that pre-administration of nebivolol with tamoxifen attenuated its hepatotoxicity considering that nebivolol is a good choice, particularly for patients with hypertension requiring beta blockers and at risk for liver damage.

References

1- Fontana RJ, Liou I, et al. AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury. Hepatology. 2023;77(3):1036-65.

2- Buhrow SA, Koubek EJ, et al. Development and validation of a liquid chromatography-mass spectrometry assay for quantification of Z- and E- isomers of endoxifen and its metabolites in plasma from women with estrogen receptor-positive breast cancer. J Chromatogr B Analyt Technol Biomed Life Sci. 2023 Apr 15; 1221:123654.

3- VALLET, Amandine, et al. The AF-2 cofactor binding region is key for the selective SUMOylation of estrogen receptor alpha by antiestrogens. Journal of Biological Chemistry, 2023, 299.1.‏

4- Blackburn AM, Amiel SA, et al. Tamoxifen and liver damage. Br Med J (Clin Res Ed). 1984; 289:288.

5- E Owumi, Solomon, et al. "Chlorogenic acid abates oxido-inflammatory and apoptotic responses in the liver and kidney of Tamoxifen-treated rats." Toxicology research 10.2 (2021): 345-353

6- Ahmed, Nermin S., et al. "Tamoxifen and oxidative stress: an overlooked connection." Discover Oncology 12.1 (2021): 17.

7- Silvagno F, Vernone A, et al. The role of glutathione in protecting against the severe inflammatory response triggered by COVID-19. Antioxidants. 2020;9(7):624.

8- Aurellia N, Susilaningsih N, et al. Effect of Curcumin on Interleukin-6 Expression and Malondialdehyde Levels in Liver Fibrosis. Open Access Macedonian Journal of Medical Sciences. 2022;10(B):2319-26.

9- Schulz M, Klopp-Schulze L, et al. Adherence to tamoxifen in breast cancer patients: What role does the pharmacist play in German primary care? Can Pharm J (Ott). 2018 Dec 20;152(1):28-34.

10- Cominacini L, Fratta Pasini A, et al. Nebivolol and its 4-keto derivative increase nitric oxide in endothelial cells by reducing its oxidative inactivation. J Am Coll Cardiol. 2003; 42:1838–1844.

11- Oelze M, Daiber A, et al. Nebivolol inhibits superoxide formation by NADPH oxidase and endothelial dysfunction in angiotensin II-treated rats. Hypertension. 2006; 48:677–684.

12- Weiss R. Nebivolol: a novel beta-blocker with nitric oxide-induced vasodilatation. Vascular health and Risk management. 2006;2(3):303-8.

13- Iwakiri Y, Kim MY. Nitric oxide in liver diseases. Trends in Pharmacological Sciences. 2015;36(8):524-36.

14- Cerna P, Kotyzova D, et al. The effect of the oral iron chelator deferiprone on the liver damage induced by tamoxifen in female rats. Hemoglobin. 2011;35(3):255-61.

15- Mizar SM, Omar HA, et al. Nebivolol and chrysin protect the liver against ischemia/reperfusion-induced injury in rats. Beni-Suef University Journal of Basic and Applied Sciences. 2015;4(1):86-92.

16- Teixeira C, Franco E, , et al. Effects of nebivolol on liver fibrosis induced by bile duct ligation in Wistar rats. in vivo. 2013;27(5):635-40.

17- Refaie MMM, El-Hussieny M, et al. Protective role of nebivolol in cadmium-induced hepatotoxicity via downregulation of oxidative stress, apoptosis and inflammatory pathways. Environ Toxicol Pharmacol. 2018; 58:212-9.

18- SAS.2010.SAS/STAT Users Guide for Personal Computer. Release 9.13.SAS Institute, Inc., Cary, N.C., USA.

19- Hamdan, Sarah Saad, Yassir Mustafa Kamal, and Huda Jaber Waheed. "Astaxanthin effect on apoptotic biomarkers in methotrexate-induced liver injury." Al Mustansiriyah Journal of Pharmaceutical Sciences 22.3 (2022): 43-50.

20- Inam Sameh Arif, Yassir Mustafa Kamal, & Israa Burhan Raoof. (2022). Nrf2 as a modulator of oxidative stress. Al Mustansiriyah Journal of Pharmaceutical Sciences, 21(4), 17–23.

21- Bradbury M, Hutton B, et al. Time to update evidence-based guideline recommendations about concurrent tamoxifen and antidepressant use? A systematic review. Clinical Breast Cancer. 2022;22(3): e362-e73.

22- Saeed, I. J. R., Jassim, O. A., et al. Fatty liver formation in patients with breast cancer on tamoxifen therapy in Iraqi female. International Journal of Health Sciences, (2022): 6(S1), 3539≤ 3547.

23- Di Pasqua L.G, Cagna, M, et al. Detailed Molecular Mechanisms Involved in Drug-Induced Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: An Update. Biomedicines 2022, 10, 194.

24- Adikwu E, Ebinyo NC, et al. Protective effect of lycopene against tamoxifen-induced hepatotoxicity in albino rats. Biomedical and biotechnology research journal (BBRJ). 2020;4(1):69.

25- Mourad HH, Abd-El Razik AN, et al. Effect of sage oil on tamoxifen-induced hepatotoxicity and nephrotoxicity in female rats. Egyptian Pharmaceutical Journal. 2020;19(4):350.

26- Buca BR, Mititelu-Tartau L, et al. The Influence of Nitric Oxid Donors Nebivolol and S-Nitrosoglutathion of the Oxidatives Stress and Liver Function in Rats. Revista de Chimie. 2019;70(4):1360-3.