Sıçanlarda Parasetamol Kaynaklı Testis Toksisitesinde Terapötik Bir Ajan Olarak Bor: Biyokimyasal Bir Bakış Açısı

Öz

Çalışmada, sıçan testis dokusunda parasetamol (PR) kaynaklı toksisiteye karşı borun koruyucu etkileri çeşitli biyokimyasal parametreler kullanılarak araştırıldı. Sıçanlar beş gruba ayrıldı ve altı gün boyunca oral yoldan 50 ve 100 mg/kg bor (sodyum pentaborat) verildi, ardından toksisiteyi oluşturmak için tek doz 1 g/kg parasetamol verildi. Testis dokuları ELISA kullanılarak değerlendirildi ve süperoksit dismutaz (SOD), katalaz (CAT), glutatyon peroksidaz (GPx), sistein-aspartik asit proteaz (Kaspaz-3), malondialdehit (MDA), indirgenmiş glutatyon (GSH), tümör nekroz faktörü-α (TNF-α) ve interlökin-1 beta (IL-1β) düzeyleri değerlendirildi. PR grubunda SOD, CAT, GPx aktiviteleri ve GSH düzeylerinde anlamlı azalma, MDA düzeylerinde ise artış gözlendi. Bor (B) tedavisinin parasetamol kaynaklı testis toksisitesinde antioksidan seviyelerini artırırken lipid peroksidasyonunu, inflamasyonu ve apoptozis belirteçlerini azalttığı bulundu (p<0,001). Çalışma, borun parasetamol kaynaklı testis hasarını hafifletmede etkili olabileceği sonucuna vardı.

Anahtar Kelimeler

• bor
• inflamasyon
• oksidatif stres
• parasetamol toksisitesi
• testiküler hasar

Boron as a protective agent in reducing paracetamol-induced testicular toxicity in rats: A biochemical perspective

Öz

In the study, the protective effects of boron against paracetamol (PR)-induced toxicity in rat testicular tissue were investigated using various biochemical parameters. Rats were categorized into five groups and administered 50 and 100 mg/kg of boron (sodium pentaborate) orally for six days, followed by a single dosage of 1 g/kg of paracetamol to induce toxicity. Testicular tissues were assessed using ELISA and levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), cysteine-aspartic acid protease (Caspase-3), malondialdehyde (MDA), reduced glutathione (GSH), tumor necrosis factor-α (TNF-α), and interleukin-1 beta (IL-1β) were assessed. A significant decrease in SOD, CAT, GPx activities and GSH levels and an increase in MDA levels were observed in the PR group. Boron (B) treatment was found to increase antioxidant levels while decreasing lipid peroxidation, inflammation and apoptosis markers in paracetamol-induced testicular toxicity (p<0.001). The study concluded that boron may be effective in alleviating paracetamol-induced testicular damage.

Anahtar Kelimeler

• boron
• inflammation
• oxidative stress
• paracetamol toxicity
• testicular damage

Kaynakça

1. [1] Freo, U., Ruocco, C., Valerio, A., Scagnol, I., & Nisoli, E. (2021). Paracetamol: A review of guideline recommendations. Journal of Clinical Medicine, 10(15), 3420. https://doi.org/10.3390/JCM10153420
2. [2] James, L. P., Mayeux, P. R., & Hinson, J. A. (2003). Acetaminophen-induced hepatotoxicity. Drug Metabolism and Disposition, 31(12), 1499-1506. https://doi.org/10.1124/dmd.31.12.1499
3. [3] Prescott, L. F. (2000). Paracetamol, alcohol and the liver. British Journal of Clinical Pharmacology, 49(4), 291-301. https://doi.org/10.1046/j.1365-2125.2000.00167.x
4. [4] Ahmed, M. B., & Khater, M. R. (2001). Evaluation of the protective potential of Ambrosia maritima extract on acetaminophen-induced liver damage. Journal of Ethnopharmacology, 75(2-3), 169-174. https://doi.org/10.1016/S0378-8741(00)00400-1
5. [5] El-Maddawy, Z. K., & El-Sayed, Y. S. (2018). Comparative analysis of the protective effects of curcumin and N-acetyl cysteine against paracetamol-induced hepatic, renal, and testicular toxicity in Wistar rats. Environmental Science and Pollution Research, 25, 3468-3479. https://doi.org/10.1007/s11356-017-0750-3
6. [6] Hiragi, S., Yamada, H., Tsukamoto, T., Yoshida, K., Kondo, N., Matsubara, T., ... & Kuroda, T. (2018). Acetaminophen administration and the risk of acute kidney injury: A self-controlled case series study. Clinical Epidemiology, 10, 265-276. https://doi.org/10.2147/CLEP.S158110 [7] Boekelheide, K. (2005). Mechanisms of toxic damage to spermatogenesis. JNCI Monographs, 2005(34), 6-8. https://doi.org/10.1093/JNCIMONOGRAPHS/LGI006
7. [8] Banihani, S. A. (2018). Effect of paracetamol on semen quality. Andrologia, 50(1). https://doi.org/10.1111/ AND.12874
8. [9] Bolaños, L., Lukaszewski, K., Bonilla, I., & Blevins, D. (2004). Why boron? Plant Physiology and Biochemistry, 42(11), 907-912. https://doi.org/10.1016/J. PLAPHY.2004.11.002

9. [10] Lovatt, C. J., & Dugger, W. M. (1984). Boron. In E. Frieden (Ed.), Biochemistry of the Essential Ultratrace Elements (Vol. 3, pp. 389-421). https://doi.org/10.1007/978-1-4684-4775-0_17
10. [11] Devirian, T. A., & Volpe, S. L. (2003). The physiological effects of dietary boron. Critical Reviews in Food Science and Nutrition, 43(2). https://doi.org/10.1080/10408690390826491
11. [12] Nielsen, F. H. (2017). Historical and recent aspects of boron in human and animal health. Journal of Boron, 2(3), 153-160. https://dergipark.org.tr/en/pub/boron/ issue/33625/373093
12. [13] Dessordi, R., Spirlandeli, A. L., Zamarioli, A., Volpon, J. B., & Navarro, A. M. (2017). Boron supplementation improves bone health of non-obese diabetic mice. Journal of Trace Elements in Medicine and Biology, 39, 169-175. https://doi.org/10.1016/j.jtemb.2016.09.011
13. [14] Meacham, S. L., Taper, L. J., & Volpe, S. L. (1994). Effects of boron supplementation on bone mineral density and dietary, blood, and urinary calcium, phosphorus, magnesium, and boron in female athletes. Environmental Health Perspectives, 102(suppl 7), 79- 82. https://doi.org/10.1289/EHP.94102S779
14. [15] Armstrong, T. A., Spears, J. W., & Lloyd, K. E. (2001). Inflammatory response, growth, and thyroid hormone concentrations are affected by long-term boron supplementation in gilts. Journal of Animal Science, 79(6), 1549-1556. https://doi.org/10.2527/2001.7961549x
15. [16] Uluisik, I., Karakaya, H. C., & Koc, A. (2018). The importance of boron in biological systems. Journal of Trace Elements in Medicine and Biology, 45, 156-162. https://doi.org/10.1016/J.JTEMB.2017.10.008
16. [17] Türkez, H., Geyikoǧlu, F., Tatar, A., Keleş, S., & Özkan, A. (2007). Effects of some boron compounds on peripheral human blood. Zeitschrift für Naturforschung C, 62(11- 12), 889-896. https://doi.org/10.1515/znc-2007-11-1218
17. [18] Ince, S., Kucukkurt, I., Cigerci, I. H., Fidan, A. F., & Eryavuz, A. (2010). The effects of dietary boric acid and borax supplementation on lipid peroxidation, antioxidant activity, and DNA damage in rats. Journal of Trace Elements in Medicine and Biology, 24(3), 161-164. https://doi.org/10.1016/j.jtemb.2010.01.003
18. [19] Kucukkurt, I., Ince, S., Demirel, H. H., Turkmen, R., Akbel, E., & Celik, Y. (2015). The effects of boron on arsenic-ınduced lipid peroxidation and antioxidant status in male and female rats. Journal of Biochemical and Molecular Toxicology, 29(12), 564-571. https://doi.org/10.1002/jbt.21729
19. [20] Smoum, R., Rubinstein, A., Dembitsky, V. M., & Srebnik, M. (2012). Boron containing compounds as protease inhibitors. Chemical Reviews, 112(7), 4156-4220. https://doi.org/10.1021/cr608202m
20. [21] Fry, R. S., Brown Jr, T. T., Lloyd, K. E., Hansen, S. L., Legleiter, L. R., Robarge, W. P., & Spears, J. W. (2011). Effect of dietary boron on physiological responses in growing steers inoculated with bovine herpesvirus type- 1. Research in Veterinary Science, 90(1), 78-83. https:// doi.org/10.1016/J.RVSC.2010.04.016
21. [22] Comba, B., Oto, G., Mis, L., Özdemir, H., & Comba, A. (2016). Effects of borax on inflammation, haematological parameters and total oxidant-antioxidant status in rats applied 3-methylcholanthrene. Kafkas Üniversitesi Veteriner Fakültesi Dergisi, 22(4). https://doi.org/10.9775/kvfd.2016.15001
22. [23] Acaroz, U., Ince, S., Arslan-Acaroz, D., Gurler, Z., Demirel, H. H., Kucukkurt, I., ... & Zhu, K. (2019). Bisphenol-A induced oxidative stress, inflammatory gene expression, and metabolic and histopathological changes in male Wistar albino rats: Protective role of boron. Toxicology Research, 8(2), 262-269. https://doi.org/10.1039/C8TX00312B
23. [24] Cengiz, M., Sahinturk, V., Cetik Yildiz, S., Kulcanay Şahin, İ., Bilici, N., Onur Yaman, S., … & Ayhanci, A. (2020). Cyclophosphamide induced oxidative stress, lipid peroxidation, apoptosis and histopathological changes in rats: Protective role of boron. Journal of Trace Elements in Medicine and Biology, 62, 126574. https://doi.org/10.1016/j.jtemb.2020.126574
24. [25] Aba, P. E., Ozioko, I. E., Udem, N. D., & Udem, S. C. (2014). Some biochemical and haematological changes in rats pretreated with aqueous stem bark extract of Lophira lanceolata and intoxicated with paracetamol (acetaminophen). Journal of Complementary and Integrative Medicine, 11(4), 273-277. https://doi.org/10.1515/jcim-2014-0007
25. [26] Ucar, F., Taslipinar, M. Y., Alp, B. F., Aydin, I., Aydin, F. N., Agilli, M., ... & Ozcan, A. (2013). The effects of N acetylcysteine and ozone therapy on oxidative stress and inflammation in acetaminophen-induced nephrotoxicity model. Renal Failure, 35(5), 640-647. https://doi.org/10.3109/0886022X.2013.780530
26. [27] Ince, S., Keles, H., Erdogan, M., Hazman, O., & Kucukkurt, I. (2012). Protective effect of boric acid against carbon tetrachloride–induced hepatotoxicity in mice. Drug and Chemical Toxicology, 35(3), 285-292. https://doi.org/10.3109/01480545.2011.607825
27. [28] Abdel-Zaher, A. O., Abdel-Rahman, M. M., Hafez, M. M., & Omran, F. M. (2007). Role of nitric oxide and reduced glutathione in the protective effects of aminoguanidine, gadolinium chloride and oleanolic acid against acetaminophen-induced hepatic and renal damage. Toxicology, 234(1-2), 124-134. https://doi.org/10.1016/j.tox.2007.02.014
28. [29] Başaran, N., Duydu, Y., Bacanlı, M., Anlar, H. G., Dilsiz, S. A., Üstündağ, A., ... & Bolt, H. M. (2020). Evaluation of oxidative stress and immune parameters of boron exposed males and females. Food and Chemical Toxicology, 142, 111488. https://doi.org/10.1016/j.fct.2020.111488
29. [30] Salem, G. A., Shaban, A., Diab, H. A., Elsaghayer, W. A., Mjedib, M. D., Hnesh, A. M., & Sahu, R. P. (2018). Phoenix dactylifera protects against oxidative stress and hepatic injury induced by paracetamol intoxication in rats. Biomedicine & Pharmacotherapy, 104, 366-374. https://doi.org/10.1016/j.biopha.2018.05.049
30. [31] Masson, M. J., Collins, L. A., Carpenter, L. D., Graf, M. L., Ryan, P. M., Bourdi, M., & Pohl, L. R. (2010). Pathologic role of stressed-induced glucocorticoids in drug-induced liver injury in mice. Biochemical and Biophysical Research Communications, 397(3), 453- 458. https://doi.org/10.1016/j.bbrc.2010.05.126
31. [32] Ozkaya, O., Genc, G., Bek, K., & Sullu, Y. (2010). A case of acetaminophen (paracetamol) causing renal failure without liver damage in a child and review of literature. Renal Failure, 32(9), 1125-1127. https://doi.org/10.3109/0886022X.2010.509830
32. [33] Sundari, K., Karthik, D., Ilavenil, S., Kaleeswaran, B., Srigopalram, S., & Ravikumar, S. (2013). Hepatoprotective and proteomic mechanism of Sphaeranthus indicus in paracetamol induced hepatotoxicity in Wistar rats. Food Bioscience, 1, 57-65. https://doi.org/10.1016/j.fbio.2013.03.004
33. [34] Mohammed, H. O., & Sabry, R. M. (2020). The possible role of curcumin against changes caused by paracetamol in testis of adult albino rat (histological, immunohistochemical and biochemical study). Egyptian Journal of Histology, 43(3), 819-834. https://doi.org/10.21608/EJH.2019.18599.1189
34. [35] Diab, K. A., Fahmy, M. A., Hassan, E. M., Hassan, Z. M., Omara, E. A., & Abdel-Samie, N. S. (2020). Inhibitory activity of black mulberry (Morus nigra) extract against testicular, liver and kidney toxicity induced by paracetamol in mice. Molecular Biology Reports, 47(3), 1733-1749. https://doi.org/10.1007/s11033-020-05265-1
35. [36] Khayyat, L. I. (2021). Extra virgin olive oil protects the testis and blood from the toxicity of paracetamol (overdose) in adult male rats. Biology, 10(10), 1042. https://doi.org/10.3390/BIOLOGY10101042
36. [37] Aksu, E. H., Ozkaraca, M., Kandemir, F. M., Ömür, A. D., Eldutar, E., Küçükler, S., & Çomaklı, S. (2016). Mitigation of paracetamol-induced reproductive damage by chrysin in male rats via reducing oxidative stress. Andrologia, 48(10), 1145-1154. https://doi.org/10.1111/AND.12553
37. [38] Kucukkurt, I., Akbel, E., Karabag, F., & Ince, S. (2015). The effects of dietary boron compounds in supplemented diet on hormonal activity and some biochemical parameters in rats. Toxicology and Industrial Health, 31(3), 255-260. https://doi.org/10.1177/0748233712469648
38. [39] Hakki, S. S., Malkoc, S., Dundar, N., Kayis, S. A., Hakki, E. E., Hamurcu, M., ... & Götz, W. (2015). Dietary boron does not affect tooth strength, micro-hardness, and density, but affects tooth mineral composition and alveolar bone mineral density in rabbits fed a high-energy diet. Journal of Trace Elements in Medicine and Biology, 29, 208-215. https://doi.org/10.1016/j.jtemb.2014.10.007
39. [40] Jin, E., Ren, M., Liu, W., Liang, S., Hu, Q., Gu, Y., & Li, S. (2017). Effect of boron on thymic cytokine expression, hormone secretion, antioxidant functions, cell proliferation, and apoptosis potential via the extracellular signal-regulated kinases 1 and 2 signaling pathway. Journal of Agricultural and Food Chemistry, 65(51), 11280-11291. https://doi.org/10.1021/acs.jafc.7b04069
40. [41] Pizzorno, L. (2015). Nothing boring about boron. Integrative Medicine: A Clinician's Journal, 14(4), 35. https://pmc.ncbi.nlm.nih.gov/articles/PMC4712861/
41. [42] Krishnan, B. B., Selvaraju, S., Gowda, N. K. S., Subramanya, K. B., Pal, D., Archana, S. S., & Bhatta, R. (2019). Dietary boron supplementation enhances sperm quality and immunity through influencing the associated biochemical parameters and modulating the genes expression at testicular tissue. Journal of Trace Elements in Medicine and Biology, 55, 6-14. https://doi.org/10.1016/J.JTEMB.2019.05.004
42. [43] Bustos-Obregón, E., & Olivares, C. (2012). Boron as testicular toxicant in mice (Mus domesticus). International Journal of Morphology, 30(3), 1106-1114. https://doi.org/10.4067/S0717-95022012000300057
43. [44] Aktas, S., Kum, C., & Aksoy, M. (2020). Effects of boric acid feeding on the oxidative stress parameters in testes, sperm parameters and DNA damage in mice. Journal of Trace Elements in Medicine and Biology, 58, 126447. https://doi.org/10.1016/J.JTEMB.2019.126447
44. [45] Su, Z., Yang, Z., Xu, Y., Chen, Y., & Yu, Q. (2015). Apoptosis, autophagy, necroptosis, and cancer metastasis. Molecular Cancer, 14(48), 1-14. https://doi.org/10.1186/s12943-015-0321-5
45. [46] Singh, P., & Lim, B. (2022). Targeting apoptosis in cancer. Current Oncology Reports, 24(3), 273-284. https://doi.org/10.1007/s11912-022-01199-y
46. [47] Mustafa, M., Ahmad, R., Tantry, I. Q., Ahmad, W., Siddiqui, S., Alam, M., ... & Islam, S. (2024). Apoptosis: A comprehensive overview of signaling pathways, morphological changes, and physiological significance and therapeutic implications. Cells, 13(22), 1838. https://doi.org/10.3390/CELLS1322183
47. [48] Asadi, M., Taghizadeh, S., Kaviani, E., Vakili, O., Taheri- Anganeh, M., Tahamtan, M., & Savardashtaki, A. (2022). Caspase-3: Structure, function, and biotechnological aspects. Biotechnology and Applied Biochemistry, 69(4), 1633-1645. https://doi.org/10.1002/BAB.2233
48. [49] Garlanda, C., Dinarello, C. A., & Mantovani, A. (2013). The interleukin-1 family: Back to the future. Immunity, 39(6), 1003-1018. https://doi.org/10.1016/j.immuni.2013.11.010
49. [50] Vilček, J., & Feldmann, M. (2004). Historical review: Cytokines as therapeutics and targets of therapeutics. Trends in Pharmacological Sciences, 25(4), 201-209. https://doi.org/10.1016/j.tips.2004.02.011
50. [51] Ekaluo, U. B., Ikpeme, E. V., & Udokpoh, A. E. (2009). Sperm head abnormality and mutagenic effects of aspirin, paracetamol and caffeine containing analgesics in rats. The Internet Journal of Toxicology, 7(1), 1-9. https://ispub.com/IJTO/7/1/10849
51. [52] Acaroz, U., Ince, S., Arslan-Acaroz, D., Gurler, Z., Kucukkurt, I., Demirel, H. H., ... & Zhu, K. (2018). The ameliorative effects of boron against acrylamide-induced oxidative stress, inflammatory response, and metabolic changes in rats. Food and Chemical Toxicology, 118, 745-752. https://doi.org/10.1016/j.fct.2018.06.029