4-hidroksifenilboronik asitin HEPG2 hücre hattında asetaminofen ile indüklenen karaciğer hücre hasarı üzerine etkisinin araştırılması

Year 2022, Volume: 7 Issue: 3, 507 - 513, 30.09.2022

Muhammet Çelik , Pelin Aydın

https://doi.org/10.30728/boron.1079589

Abstract

Karaciğer; detoksifikasyon, metabolizma, sindirime yardımcı olan safra salgısını üretmek başta olmak üzere yüzlerce farklı iş yapan özel bir organdır. Karaciğer hastalıkları ve sonrasında gelişebilecek karaciğer yetersizliği insanlar için çok kritik bir klinik sorundur. Son yıllarda karaciğer hasarının kemoterapotiklerin, antiviral ilaçların ve bitkisel destekleyici ürün kullanımının artışı ile beraber insidansının arttığı görülmektedir. Bu nedenle günümüzde karaciğer hasarının tedavi edilebilmesi artık daha öncelikli olarak düşünülmektedir. Asetaminofen (APAP), dünyada en yaygın kullanılan, reçetesiz satılan analjezik ve antipiretik ilaçlarından biridir. Bununla beraber, aşırı dozda APAP alınmasına bağlı olarak karaciğer hasarı gelişebilir. APAP’ın N-asetil-benzokinonimin(NAPQI) metaboliti toksik etkinin ortaya çıkmasından sorumludur. NAPQI'nın hücre içi proteinlere, özellikle mitokondriyal proteinlere kovalent bağlanması, mitokondriyal oksidatif stresi ve nihayetinde hepatosit nekrozunu tetiklediği bilinmektedir. Bor içeren bileşiklerin antibakteriyel, antiviral, antioksidatif ve antiinflamatuvar özelliklerine sahip olduğu daha önceki çalışmalarda gösterilmiştir. Bor ve türevlerinin HIV, obezite, diabet ve kanser gibi hastalıkların tedavisinde faydaları bilinmektedir. Bu özellikleriyle antioksidan mekanizma üzerinden hepatosit nekrozu için umut vaat etmekte ve araştırılması gerekmektedir. Bu çalışmada, boronik asit türevi olan 4-hidroksifenilboronik asidin (4-OHFBA) APAP ile indüklenmiş karaciğer hasarındaki etkinliğinin araştırılması amaçlanmıştır. Elde edilen sonuçlara göre 4-OHFBA tedavisi ile yüksek AST ve ALT seviyelerinin düştüğü gözlemlenmiştir. Bu sonuçlar 4-OHFBA’nın karaciğer hasarının tedavisinde etkili olabileceğini göstermiştir.

Keywords

4-hidroksifenilboronik asit, asetaminofen, HEPG2, karaciğer hasarı, 4-hidroksifenilboronik asit, asetaminofen, HEPG2, karaciğer hasarı

Supporting Institution

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Project Number

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Thanks

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Investigation of the effect of 4-hydroxyphenylboronic acid on acetaminophen-induced liver cell injury in HEPG2 cell line.

Abstract

The liver is a special organ that does hundreds of different jobs, especially in detoxification, metabolism, producing bile secretion that helps digestion. Liver diseases and subsequent liver failure is a very critical clinical problem for humans. Recently, it has been detected that the incidence of liver damage has increased with the increase in the use of chemotherapeutics, antiviral drugs and herbal supplements. Therefore, it is important to treat liver damage. Acetaminophen (APAP) is one of the most widely prescribed analgesic and antipyretic drug in the world. However, liver damage may develop due to an overdose of acetaminophen. The N-acetyl-benzoquinonimine (NAPQI) metabolite of APAP is responsible for the occurrence of the toxic effect. Covalent binding of NAPQI to intracellular proteins, especially mitochondrial proteins, is known to trigger mitochondrial oxidative stress and ultimately hepatocyte necrosis. It has been shown in previous studies that boron-containing compounds have antibacterial, antiviral, antioxidative and anti-inflammatory properties. The benefits of boron and its derivatives in the treatment of diseases such as HIV, obesity, diabetes and cancer are known. With these properties, it shows promise for hepatocyte necrosis through the antioxidant mechanism. In this study, it was aimed to investigate the efficacy of 4-hydroxyphenylboronic acid (4-OHFBA), a derivative of boronic acid, in APAP-induced liver injury. According to the results obtained, it was found that high AST and ALT levels decreased with 4-OHFBA treatment. These results showed that 4-OHFBA may be effective in the treatment of liver damage.

Keywords

4-hydroxyphenylboronic acid, acetaminophen, HEPG2, liver damage, 4-hydroxyphenylboronic acid, acetaminophen, HEPG2, liver damage

Project Number

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References

• [1] Graham, G. G., Scott, K. F., & Day, R. O. (2005). Tolerability of paracetamol. Drug Safety, 28(3), 227-240.
• [2] Ramachandran, A., & Jaeschke, H. (2018). Acetaminophen toxicity: Novel insights into mechanisms and future perspectives. Gene Expression, 18(1), 19-30.
• [3] McGill, M. R., & Jaeschke, H. (2013). Metabolism and Disposition of Acetaminophen: Recent Advances in Relation to Hepatotoxicity and Diagnosis. Pharmaceutical Research, 30(9), 2174-2187.
• [4] Du, K., Ramachandran, A., & Jaeschke, H. (2016). Oxidative stress during acetaminophen hepatotoxicity: Sources, pathophysiological role and therapeutic potential. Redox Biology, 10, 148-156.
• [5] Larson, A. M., Polson, J., Fontana, R. J., Davern, T. J., Lalani, E., Hynan, L. S., Reisch, J. S., Schiødt, F. V., Ostapowicz, G., & Shakil, A. O. (2005). Acetaminophen‐induced acute liver failure: results of a United States multicenter, prospective study. Hepatology, 42(6), 1364-1372.
• [6] Bunchorntavakul, C., & Reddy, K. R. (2013). Acetaminophen-related hepatotoxicity. Clinics in liver disease, 17(4), 587-607.
• [7] Murray, K. F., Hadzic, N., Wirth, S., Bassett, M., & Kelly, D. (2008). Drug-related hepatotoxicity and acute liver failure. Journal of Pediatric Gastroenterology and Nutrition, 47(4), 395-405.
• [8] Jaeschke, H. (2015). Acetaminophen: Dose-Dependent Drug Hepatotoxicity and Acute Liver Failure in Patients. Digestive Diseases, 33(4), 464-471.
• [9] Chun, L. J., Tong, M. J., Busuttil, R. W., & Hiatt, J. R. (2009). Acetaminophen hepatotoxicity and acute liver failure. Journal of Clinical Gastroenterology, 43(4), 342-349.
• [10] Dong, V., Nanchal, R., & Karvellas, C. J. (2020). Pathophysiology of Acute Liver Failure. Nutrition in Clinical Practice, 35(1), 24-29.
• [11] Yoon, E., Babar, A., Choudhary, M., Kutner, M., & Pyrsopoulos, N. (2016). Acetaminophen-induced hepatotoxicity: A comprehensive update. Journal of Clinical and Translational Hepatology, 4(2), 131-142.
• [12] Lv, H., Hong, L., Tian, Y., Yin, C., Zhu, C., & Feng, H. (2019). Corilagin alleviates acetaminophen-induced hepatotoxicity via enhancing the AMPK/GSK3β-Nrf2 signaling pathway. Cell communication and signaling, 17(1), 2-2.
• [13] Maes, M., Vinken, M., & Jaeschke, H. (2016). Experimental models of hepatotoxicity related to acute liver failure. Toxicology and Applied Pharmacology, 290, 86-97.
• [14] Boulares, A. H., Zoltoski, A. J., Stoica, B. A., Cuvillier, O., & Smulson, M. E. (2002). Acetaminophen Induces a Caspase-Dependent and Bcl-XL Sensitive Apoptosis in Human Hepatoma Cells and Lymphocytes. Pharmacology & Toxicology, 90(1), 38-50.
• [15] Manov, I., Hirsh, M., & Iancu, T. C. (2004). N-acetylcysteine does not protect HepG2 cells against acetaminophen-induced apoptosis. Basic & Clinical Pharmacology & Toxicology, 94(5), 213-225.
• [16] Bai, J., & Cederbaum, A. I. (2004). Adenovirus mediated overexpression of CYP2E1 increases sensitivity of HepG2 cells to acetaminophen induced cytotoxicity. Molecular and Cellular Biochemistry, 262(1), 165-176.
• [17] Bolanos, L., Lukaszewski, K., Bonilla, I., & Blevins, D. (2004). Why boron?. Plant Physiology and Biochemistry, 42(11), 907-912.
• [18] Hunt, C. D. (2003). Dietary Boron: An Overview of the Evidence for Its Role in Immune Function. The Journal of Trace Elements in Experimental Medicine, 16(4), 291-306.
• [19] Tanaka, M., & Fujiwara, T. (2008). Physiological roles and transport mechanisms of boron: perspectives from plants. Pflugers Archiv, 456(4), 671-677.
• [20] Demircan, B., & Velioğlu, Y. S. (2020). Gıda ve Çevreden Alınan Bor Bileşiklerinin Toksikolojik Değerlendirmesi [Toxicological Evaluation of Boron Compounds Taken from Food and Environment]. Akademik Gıda, 18(3), 312-322.
• [21] Hunt, C. D. (2012). Dietary boron: progress in establishing essential roles in human physiology. Journal of Trace Elements in Medicine and Biology, 26(2-3), 157-160.
• [22] Lang, P. A., Parkova, A., Leissing, T. M., Calvopiña, K., Cain, R., Krajnc, A., Panduwawala, T. D., Philippe, J., Fishwick, C. W., & Trapencieris, P. (2020). Bicyclic Boronates as Potent Inhibitors of AmpC, the Class C β-Lactamase from Escherichia coli . Biomolecules, 10(6), 899.
• [23] Beer, L. C., Vuong, C. N., Barros, T. L., Latorre, J. D., Tellez, G., Fuller, A. K., & Hargis, B. M. (2020). Research Note: Evaluation of boric acid as a chemoprophylaxis candidate to prevent histomoniasis. Poultry Science, 99(4), 1978-1982.
• [24] Çelikezen, F. Ç., Turkez, H., Togar, B., & Izgi, M. S. (2014). DNA damaging and biochemical effects of potassium tetraborate. EXCLI journal, 13, 446-450.
• [25] Acaroz, U., Ince, S., Arslan-Acaroz, D., Gurler, Z., Demirel, H. H., Kucukkurt, I., Eryavuz, A., Kara, R., Varol, N., & 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.
• [26] Hu, Q., Li, S., Qiao, E., Tang, Z., Jin, E., Jin, G., & Gu, Y. (2014). Effects of boron on structure and antioxidative activities of spleen in rats. Biological Trace Element Research, 158(1), 73-80.
• [27] Yang, W., Gao, X., & Wang, B. (2003). Boronic acid compounds as potential pharmaceutical agents. Medicinal Research Reviews, 23(3), 346-368.
• [28] Cambre, J. N., & Sumerlin, B. S. (2011). Biomedical applications of boronic acid polymers. Polymer, 52(21), 4631-4643.
• [29] Kiener, P. A., & Waley, S. G. (1978). Reversible inhibitors of penicillinases. Biochemical Journal, 169(1), 197-204.
• [30] Lőrincz, T., Deák, V., Makk-Merczel, K., Varga, D., Hajdinák, P., & Szarka, A. (2021). The Performance of HepG2 and HepaRG Systems through the Glass of Acetaminophen-Induced Toxicity. Life (Basel), 11(8), 856.
• [31] Duan, L., Ramachandran, A., Akakpo, J. Y., Weemhoff, J. L., Curry, S. C., & Jaeschke, H. (2019). Role of extracellular vesicles in release of protein adducts after acetaminophen-induced liver injury in mice and humans. Toxicology Letters, 301, 125-132.
• [32] Ayaz, G., Halici, Z., Albayrak, A., Karakus, E., & Cadirci, E. (2017). Evaluation of 5-HT7 receptor trafficking on in vivo and in vitro model of lipopolysaccharide (LPS)-induced inflammatory cell injury in rats and LPS-treated A549 cells. Biochemical genetics, 55(1), 34-47.
• [33] Kumar, P., Nagarajan, A., & Uchil, P. (2018). Analysis of Cell Viability by the MTT Assay. Cold Spring Harbor Protocols, 2018(6).
• [34] Bilen, A., Calik, I., Yayla, M., Dincer, B., Tavaci, T., Cinar, I., Bilen, H., Cadirci, E., Halici, Z., & Mercantepe, F. (2021). Does daily fasting shielding kidney on hyperglycemia-related inflammatory cytokine via TNF-α, NLRP3, TGF-β1 and VCAM-1 mRNA expression. International Journal of Biological Macromolecules, 190, 911-918.
• [35] Dai, G., He, L., Chou, N., & Wan, Y.-J. Y. (2006). Acetaminophen metabolism does not contribute to gender difference in its hepatotoxicity in mouse. Toxicological Sciences, 92(1), 33-41.
• [36] James, L. P., Mayeux, P. R., & Hinson, J. A. (2003). Acetaminophen-induced hepatotoxicity. Drug metabolism and disposition, 31(12), 1499-1506.
• [37] Singh, D., Cho, W. C., & Upadhyay, G. (2016). Drug-induced liver toxicity and prevention by herbal antioxidants: an overview. Frontiers in physiology, 6, 363.
• [38] Woolbright, B. L., & Jaeschke, H. (2017). Role of the inflammasome in acetaminophen-induced liver injury and acute liver failure. Journal of hepatology, 66(4), 836-848.
• [39] Donato, M. T., Lahoz, A., Castell, J. V., & Gomez-Lechon, M. J. (2008). Cell lines: a tool for in vitro drug metabolism studies. Current drug metabolism, 9(1), 1-11.
• [40] Nicod, L., Viollon, C., Regnier, A., Jacqueson, A., & Richert, L. (1997). Rifampicin and isoniazid increase acetaminophen and isoniazid cytotoxicity in human HepG2 hepatoma cells. Human & Experimental Toxicology, 16(1), 28-34.
• [41] Balabanlı, B., & Balaban, T. (2015). Investigation into the Effects of Boron on Liver Tissue Protein Carbonyl, MDA, and Glutathione Levels in Endotoxemia. Biological Trace Element Research, 167(2), 259-263.
• [42] Mohora, M., Boghianu, L., Muscurel, C., Duta, C., & Dumitrache, C. (2002). Effects of boric acid on redox status in the rat liver. Romanian Journal Biophysics, 12(3-4), 77-82.
• [43] Kot, F. S. (2009). Boron sources, speciation and its potential impact on health. Reviews Environmental Science Biotechnology, 8(1), 3–28.
• [44] Smith, R. A., & McBroom, R. B. (2000). Boron oxides, boric acid, and borates. Kirk‐Othmer Encyclopedia of Chemical Technology.
• [45] Khaliq, H., Juming, Z., & Ke-Mei, P. (2018). The Physiological Role of Boron on Health. Biological Trace Element Research, 186(1), 31-51.
• [46] Mogoşanu, G. D., Biţă, A., Bejenaru, L. E., Bejenaru, C., Croitoru, O., Rău, G., Rogoveanu, O. C., Florescu, D. N., Neamţu, J., Scorei, I. D., & Scorei, R. I. (2016). Calcium Fructoborate for Bone and Cardiovascular Health. Biological Trace Element Research, 172(2), 277-281.