Protective effects of tamoxifen and raloxifene on apoptosis and oxidative stress in the kidney and liver of ovariectomized rats

Abstract

In the postmenopausal period, women undergo physical and morphological changes that may result in insufficiency and deterioration in physiological functions. It is accepted that oxidative stress is involved in the etiology of postmenopausal changes. It is known that the decrease in ovarian hormones, especially 17β-estradiol (17-β) after menopause induces apoptosis and oxidative stress in many tissues. It is well known that 17-β has an antioxidant role in non-menopausal women. Recently, we observed that the treatments of 17-β, raloxifene (RAL), and tamoxifen (TAM) diminished apoptotic factors, oxidative stress, and mitochondrial membrane depolarization in the brain and dorsal root ganglia of ovariectomized rats. There is no enough information about the effects of triple therapy [17-β, and selective estrogen receptor modulators (TAM and RAL)] effects on liver and kidney tissues. We aimed to investigate the effects of 17-β, TAM, and RAL on apoptosis, cell viability (MTT), and oxidative stress in the kidney and OV+TAM, and OV+RAL. 17-β, TAM, and RAL were subcutaneously given to three groups (OV+17-β, OV+TAM, and OV+RAL) for 14 days after ovariectomy. While kidney and liver cells lipid peroxidation levels were high in the OV group, they were low in the OV+17-β, OV+TAM, and OV+RAL groups. The treatments of 17-β, TAM, and RAL in the groups of OV+17-β, OV+TAM, and OV+RAL increased the glutathione peroxidase (GSH Px) activity and glutathione (GSH) levels in the cells of kidney and liver. In addition, the MTT level of kidney and liver cells was low in the OV group and higher in the OV+17-β, OV+TAM, and OV+RAL groups. The treatments of OV+17-β, OV+TAM, and OV+RAL decreased the apoptosis and ROS levels in kidney and liver cells. In conclusion, we observed that 17-β, TAM, and RAL administrations were beneficial on cell viability (MTT), apoptosis, and ROS levels in the kidney and liver cells of OV rats by modulating antioxidant systems. liver of bilateral ovariectomized (OV) rats. Forty female rats used in the experiment, and they were divided into five groups as control, OV, OV+17-β,

Keywords

• 17β-estradiol
• Raloxifene
• Tamoxifen
• Apoptosis
• Oxidative stress

References

1. Arteaga E, Villaseca P, Bianchi M, Rojas A, Marshall G. 2003. Raloxifene is a better antioxidant of low-density lipoprotein than estradiol or tamoxifen in postmenopausal women in vitro. Menopause. 10(2):142-6. doi: 10.1097/00042192-200310020-00005.
2. Azarkish F, Nematbakhsh M, Fazilati M. 2013. N-acetylcysteine prevents kidney and lung disturbances in renal ischemia/reperfusion injury in rat. Int J Prev Med 4:1139–1146.
3. Brady CW. 2015. Liver disease in menopause. World J Gastroenterol. 7;21(25):7613-20. doi: 10.3748/wjg.v21.i25.7613.
4. Dilek M, Nazıroğlu M, Oral BH, Övey İS, Küçükyaz M, Mungan MT, Kara HY, Sütçü R. 2010. Melatonin modulates hippocampus NMDA receptors, blood and brain oxidative stress levels in ovariectomized rats. J Membr Biol. 233:135-142.
5. Doshi SB, Agarwal A. 2013. The role of oxidative stress in menopause. J Mid-Life Health 4:140-146.
6. El-Gendy, A. A., Elsaed, W. M., & Abdallah, H. I. 2019. Potential role of estradiol in ovariectomy-induced derangement of renal endocrine functions. Renal failure, 41(1), 507–520. https://doi.org/10.1080/0886022X.2019.1625787.
7. Espino J, Bejarano I, Redondo PC, Rosado JA, Barriga C, Reiter RJ, Pariente JA, Rodríguez AB. 2010. Melatonin reduces apoptosis induced by calcium signaling in human leukocytes: Evidence for the involvement of mitochondria and Bax activation. J Membr Biol. 233:105-118.
8. Fidarov AF, Vihma V, Bogautdinov RP, Morozkina SN, Shavva AG, Tikkanen MJ. 2015. Novel structural features increase the antioxidant effect of estrogen analogues on low density lipoprotein. J Steroid Biochem Mol Biol. 154:142-9. doi: 10.1016/j.jsbmb.2015.08.001.

9. Gong X, Cao P, Liu L, Lin Y, Yang Q, Zhou L, Wu T, Luo M. (2018). Tamoxifen Prevents D-galactosamine/Lipopolysaccharide-Induced Murine Acute Hepatic Failure through Inhibition of Oxidative Stress and Mmd-2 Upregulation. Immunol Invest. 2018 Aug;47(6):547-557. doi: 10.1080/08820139.2018.1464024.
10. Halliwell B. 2006. Oxidative stress and neurodegeneration: where are we now? J Neurochem 97:1634-1658.
11. Huang Y, B. Laı,B P. Zheng,B Y. C. Zhua And T. Yaoa,B. 2007. Raloxifene acutely reduces glutamate-induced intracellular calcium increase in cultured rat cortical neurons via inhibition of high-voltage-actıvated calcium current. Neuroscience 147:334-341.
12. Jordan VC. 2003. Tamoxifen: A most unlikely pioneering medicine. Nat Rev Drug Discov 2:205-213.
13. Konyalioglu S, Durmaz G, Yalcin A. 2007. The potential antioxidant effect of raloxifene treatment: a study on heart, liver and brain cortex of ovariectomized female rats. Cell Biochem Funct. 25(3):259-66. doi: 10.1002/cbf.1328. PMID: 16927419.
14. Kramer PR, Bellinger LL. 2013. Modulation of temporomandibular joint nociception and inflammation in male rats after administering a physiological concentration of 17beta-oestradiol. Eur J Pain 17:174-184
15. Kumar P, Kale RK, Baquer NZ. 2011. Estradiol modulates membrane-linked ATPases, antioxidant enzymes, membrane fluidity, lipid peroxidation, and lipofuscin in aged rat liver. J Aging Res. 580245.
16. Lamas AZ, Caliman IF, Dalpiaz PL, de Melo AF, Jr. Abreu GR, Lemos EM, Bissoli NS. 2015. Comparative effects of estrogen raloxifene and tamoxifen on endothelial dysfunction inflammatory markers and oxidative stress in ovariectomized rats. Life Sci 124 101-109.
17. Lawrence RA, Burk RF. 1976. Glutathione peroxidase activity in selenium-deficient rat liver. Biochem Biophys Res Com 71:952-958.
18. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. 1951. Protein measurement with the Folin- Phenol reagent. J Biol Chem 193:265-275.
19. Ltaif M, Gargouri M, Magné C, El Feki A, Soussi A. 2020. Protective effects of Avena sativa against oxidative stress-induced kidney damage resulting from an estrogen deficiency in ovariectomized Swiss mice model. J Food Biochem. 44(6):e13205. doi: 10.1111/jfbc.13205.
20. Mann V, Huber C, Kogianni G, Collins F, Noble B. 2007. The antioxidant effect of estrogen and Selective Estrogen Receptor Modulators in the inhibition of osteocyte apoptosis in vitro. Bone. 40(3):674-84. doi: 10.1016/j.bone.2006.10.014.
21. Moreira PI, Custodio J, Nunes E, Moreno A, Oliveira CR, Santos MS. 2007. Estradiol affects liver mitochondrial function in ovariectomized and tamoxifen-treated ovariectomized female rats. Toxicol Appl Pharmacol 221:102-110.
22. Moreira PI, Custódio JB, Nunes E, Oliveira PJ, Moreno A, Seiça R, Oliveira CR, Santos MS. 2011. Mitochondria from distinct tissues are differently affected by 17β-estradiol and tamoxifen. J Steroid Biochem Mol Biol. 123:8-16.
23. Moreira PJ, Custodio JB, Oliveira CR, Santos MS. 2005. Brain mitochondrial injury induced by oxidative stress-related events is prevented by tamoxifen. Neuropharmacology, 48 (3) pp. 435-447.
24. Nazıroğlu M, Şimşek M, Şimşek H, Aydilek N, Özcan Z, Atılgan R. 2004. Effects of hormone replacement therapy, vitamin C and E supplementation on antioxidants levels, lipid profiles and glucose homeostasis in postmenopausal women with Type 2 diabetes. Clin. Chim Acta 344: 63-71.
25. Nazıroglu M. 2009. Role of selenium on calcium signaling and oxidative stress-induced molecular pathways in epilepsy. Neurochem Res. 34: 2181-2191.
26. Nazarewicz RR, Zenebe WJ, Parihar A, Larson SK, Alidema E, Choi J, Ghafourifar P. (2007). Tamoxifen induces oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthase. Cancer Res. 1;67(3):1282-90. doi: 10.1158/0008-5472.CAN-06-3099
27. Nishi Y, Satoh M, Nagasu H, Kadoya H, Ihoriya C, Kidokoro K, Sasaki T, Kashihara N. 2013. Selective estrogen receptor modulation attenuates proteinuria-induced renal tubular damage by modulating mitochondrial oxidative status. Kidney Int. 83(4):662-73. doi: 10.1038/ki.2012.475.
28. Parvez S, Tabassum H, Rehman H, Banerjee BD, Athar M, Raisuddin S. (2006). Catechin prevents tamoxifen-induced oxidative stress and biochemical perturbations in mice. Toxicology. 15;225(2-3):109-18. doi: 10.1016/j.tox.2006.05.009.
29. Placer ZA, Cushman L, Johnson BC. 1966. Estimation of products of lipid peroxidation (malonyl dialdehyde) in biological fluids. Analytical Biochem 16:359-364.
30. Schubert C, Raparelli V, Westphal C, Dworatzek E, Petrov G, Kararigas G, Regitz-Zagrosek V. 2016. Reduction of apoptosis and preservation of mitochondrial integrity under ischemia/reperfusion injury is mediated by estrogen receptor β. Biol Sex Differ 23;7:53. doi: 10.1186/s13293-016-0104-8.
31. Schweizer U, Bräuer AU, Köhrle J, Nitsch R, Savaskan NE. 2004. Selenium and brain function: a poorly recognized liaison. Brain Res Brain Res Rev 45:164-178.
32. Shukla J, Sharma U, Kar R, Varma IK, Juyal S, Jagannathan NR, Bandopadhyaya GP. 2009. Tamoxifen-2-hydroxylpropyl-beta-cyclodextrin-aggregated nanoassembly for nonbreast estrogen-receptor-positive cancer therapy. Nanomedicine (Lond). 4(8):895-902.
33. Thompson KA, Bardone-Cone AM. 2019. Evaluating attitudes about aging and body comparison as moderators of the relationship between menopausal status and disordered eating and body image concerns among middle-aged women. Maturitas. 124:25-31. doi: 10.1016/j.maturitas.2019.03.014.
34. Xu Z, Mu S, Liao X, Fan R, Gao W, Sun Y, Wu W, Jia Q. 2020. Estrogen protects against liver damage in sepsis through inhibiting oxidative stress mediated activation of pyroptosis signaling pathway. PLoS One. 1;15(10):e0239659. doi: 10.1371/journal.pone.0239659.
35. Yaffe K, Kruger K, Sarkar S, Grady D, Barrett- Connor E, Cox DA. 2001. Cognitive function in postmenopausal women treated with raloxifene. N Engl J Med 3441:1207-1213.
36. Yang SH, Liu R, Perez EJ, Wen Y, Stevens SM, Valencia T, Brun-Zinkernagel AM, Prokai L, Will Y, Dykens J, Koulen P, Simpkins J. 2004. Mitochondrial localization of estrogen receptor beta, Proc. Natl. Acad. Sci. U.S.A. 101:4130-4135.
37. Yazğan B, Yazğan Y, Övey İS, Nazıroğlu M. 2016. Raloxifene and Tamoxifen Reduce PARP Activity, Cytokine and Oxidative Stress Levels in the Brain and Blood of Ovariectomized Rats. J Mol Neurosci. 60(2):214-22. doi: 10.1007/s12031-016-0785-9.
38. Yazğan Y, Nazıroğlu M. 2017. Ovariectomy-Induced Mitochondrial Oxidative Stress, Apoptosis, and Calcium Ion Influx Through TRPA1, TRPM2, and TRPV1 Are Prevented by 17β-Estradiol, Tamoxifen, and Raloxifene in the Hippocampus and Dorsal Root Ganglion of Rats. Mol Neurobiol. 54(10):7620-7638. doi: 10.1007/s12035-016-0232-5.
39. Zhang Y, Milatovic D, Aschner M, Feustel PJ, Kimelberg HK. 2007. Neuroprotection by tamoxifen in focal cerebral ischemia is not mediated by an agonist action at estrogen receptors but is associated with antioxidant activity. Exp. Neurol., 204 (2) pp. 819-827.