Abstract
This study aims to investigate the protective effects of silymarin (Sm) in thioacetamide (TAA)-related liver damage. What makes this study special is that it attempts to determine the expression of changes in the liver at the level of gene expression. Routine liver damage markers were compared with changes in the levels of microRNA (miRNA) known as new biomarkers. With this in mind, we divided the rats into four groups including control, TAA, Sm + TAA (50 + 50 mg/kg), and Sm + TAA (100 + 50 mg/kg). Blood and tissue samples belonging to the rats were collected in consideration of morphological, immunohistochemistry, miRNAs levels, and biochemical evaluations. Our study results showed that miR-122, miR-192, and miR-194 levels had decreased in the experimental groups given TAA, whereas miR-122, miR-192, and miR-194 levels had increased in the doses of Sm + TAA-given group. Therefore, Sm treatment undertaken before exposure to the toxin successfully altered its effects upon the study animals.
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Mangipudy, R. S., Chanda, S., & Mehendale, H. M. (1995). Tissue repair response as a function of dose in thioacetamide hepatotoxicity. Environmental Health Perspectives, 103(3), 260–267. https://doi.org/10.1289/ehp.95103260.
Nozu, F., Takeyama, N., & Tanaka, T. (1992). Changes of hepatic fatty acid metabolism produced by chronic thioacetamide administration in rats.J. Hepatol., 15, 1099–1106. https://doi.org/10.1002/hep.1840150621.
Ledda-Columbano, G. M., Coni, P., Curto, M., Giacomini, L., Faa, G., Oliverio, S., Piacentini, M., & Columbano, A. (1991). Induction of two different modes of cell death, apoptosis and necrosis, in rat liver after a single dose of thioacetamide. The American Journal of Pathology, 39, 1099–1109.
Siemionow, K., Teul, J., Drągowski, P., Pałka, J., & Miltyk, W. (2016). New potential biomarkers of acetaminophen-induced hepatotoxicity. Advances in Medical Sciences, 61(2), 325–330.
Hunter, A. L., Holscher, M. A., & Neal, R. A. (1977). Thioacetamide induced hepatic necrosis. I. Involvement of the mixed-function oxidase enzyme system. J. Pharmacol. Exp. Ther, 200(2), 439–448.
Wang, K., Zhang, S., Marzolf, B., Troisch, P., Brightman, A., Hu, Z., Hood, L.E., Galas, D.J. (2009). Circulating microRNAs, potential biomarkers for drug-induced liver injury.ProcNatl Acad. Sci. 106.
Ramaiah, S. K., Apte, U., & Mehendale, H. M. (2001). Cytochrome P4502E1 induction increases thioacetamide liver injury in diet restricted rats. DrugMetabDispos., 29, 1088–1095.
Chilakapati, J., Korrapati, M.C., Shankar, K., Hill, R.A., Warbritton, A., Latendresse, J. R., Mehendale, H.M. (2007). Role of CYP2E1 and saturation kinetics in the bioactivation of thioacetamide: effects of diet restriction and phenobarbital. Toxicol.Appl. Pharmacol., 15;219(1):72-84.
Van Beijnum, J. R., Giovannetti, E., Poel, D., Nowak-Sliwinska, P., & Griffioen, A. W. (2017). miRNAs: micro-managers of anticancer combination therapies. Angiogenesis., 20, 269–285.
Chang, J., Nicolas, E., Marks, D., Sander, C., Lerro, A., Buendia, M. A., Xu, C., Mason, W. S., Moloshok, T., Bort, R., Zaret, K. S., & Taylor, J. M. (2004). miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biology, 1(2), 106–113.
Coulouarn, C., Factor, V. M., Andersen, J. B., Durkin, M. E., & Thorgeirsson, S. S. (2009). Loss of miR-122 expression in liver cancer correlates with suppression of the hepatic phenotype and gain of metastatic properties. Oncogene., 28(40), 3526–3536.
Szabo, G., & Bala, S. (2013). MicroRNAs in liver disease. Nature Reviews. Gastroenterology & Hepatology, 10(9), 542–552.
Krauskopf, J., Caiment, F., Claessen, S. M., Johnson, K. J., Warner, R. L., Schomaker, S. J., Burt, D. A., Aubrecht, J., & Kleinjans, J. C. (2015). Application of high-throughput sequencing to circulating microRNAs reveals novel biomarkers for drug-induced liver injury. Toxicol.Sci., 143(2), 268–276.
Starkey, L. P. J., Dear, J., Platt, V., Simpson, K. J., Craig, D. G., Antoine, D. J., French, N. S., Dhaun, N., Webb, D. J., Costello, E. M., Neoptolemos, J. P., Moggs, J., Goldring, C. E., & Park, B. K. (2011). Circulating microRNAs as potential markers of human drug-induced liver injury. Journal of Hepatology, 54, 1767–1776.
Laterza, O. F., Scott, M. G., Garrett-Engele, P. W., Korenblat, K. M., & Lockwood, C. M. (2013). Circulating miR-122 as a potential biomarker of liver disease. Biomarkers in Medicine, 7(2), 205–210.
Van der Meer, A. J., Farid, W. R., Sonneveld, M. J., de Ruiter, P. E., Boonstra, A., van Vuuren, A. J., Verheij, J., Hansen, B. E., de Knegt, R. J., van der Laan, L. J., & Janssen, H. L. (2013). Sensitive detection of hepatocellular injury in chronic hepatitis C patients with circulating hepatocyte-derived microRNA-122. Journal of Viral Hepatitis, 20(3), 158–166.
Hu, J., Wang, Z., Tan, C. J., Liao, B. Y., Zhang, X., Xu, M., Dai, Z., Qiu, S. J., Huang, X. W., Sun, J., Sun, Q. M., He, Y. F., Song, K., Pan, Q., Wu, Y., Fan, J., & Zhou, J. (2013). Plasma microRNA, a potential biomarker for acute rejection after liver transplantation. Transplantation., 95(8), 991–999.
Silakit, R., Loilome, W., Yongvanit, P., Chusorn, P., Techasen, A., Boonmars, T., Khuntikeo, N., Chamadol, N., Pairojkul, C. And Namwat, N. (2014). Circulating miR-192 in liver fluke-associated cholangiocarcinoma patients: a prospective prognostic indicator. Journal of Hepato-Biliary-Pancreatic Sciences 21, 864–872, 12.
Meng, Z., Fu, X., Chen, X., Zeng, S., Tian, Y., Jove, R., Xu, R., & Huang, W. (2010). miR-194 is a marker of hepatic epithelial cells and suppresses metastasis of liver cancer cells in mice. Hepatology, 52(6), 2148–2157.
Bruck, R., Aeed, H., Shirin, H., Matas, Z., Zaidel, L., Avni, Y., & Halpern, Z. (1999). The hydroxyl radical scavengers dimethyl sulfoxide and dimethyl thio urea protect rats against thioacetamide-induced fulminant hepatic failure. Journal of Hepatology, 31, 27–38.
Zahir, A., Haider, B., Abbasi, B. H., Adil, M., Anjum, S., Zia, M., & Ul-haq, I. (2014). Synergistic effects of drought stress and photoperiods on phenology and secondary metabolism of Silybum marianum. Applied Biochemistry and Biotechnology, 174, 693–707.
Natarajan, S. K., Thomas, S., Ramamoorthy, S., Basivireddy, J., Pulimood, A. B., Ramachandran, A., & Balasubramanian, K. A. (2006). Oxidative stress in the development of liver cirrhosis: a comparison of two different experimental models. Journal of Gastroenterology and Hepatology, 21, 947–957.
Duan, L., Carrier, D. J., & Clausen, E. C. (2004). Silymarin extraction from milk thistle using hot water. Applied Biochemistry and Biotechnology, 113-116, 559–568.
Sathyasaikumar, K. V., Swapna, I., Reddy, P. V., Murthy, C. R., Roy, K. R., Dutta Gupta, A., Senthilkumaran, B., & Redanna, P. (2007). Co-administration of C-phycocyanin ameliorates thioacetamide-induced hepatic encephalopathy in Wistar rats. Journal of the Neurological Sciences, 252(1), 67–75.
Anbarasu, C., Rajkapoor, B., & Bhat, K. S. (2012). John Giridharan, A Arul Amuthan, Satish K Protective effect of Pisonia aculeata on thioacetamide induced hepatotoxicity in rats. Asian Pacific Journal of Tropical Biomedicine, 2(7), 511–515.
Nada, S. A., Gowifel, A. M. H., El-Denshary, E. E.-D. S., Salama, A. A., Khalil, M. G., & Ahmed, K. A. (2015). Protective effect of grape seed extract and/or silymarin against thioacetamide-induced hepatic fibrosis in rats. J Liver, 4, 2.
Esterbauer, H., & Cheeseman, K. H. (1990). Determination of aldehydic lipid peroxidation products: malonaldehyde and 4-hydroxynonenal. Methods in Enzymology, 186, 407–421.
Esterbauer, H., Schaur, R.J., Zollner, H. (1991). Chemistry and biochemistry of 4-hydroxynonenal, malonaldehyde and related aldehydes, free radical biology and medicine. 11, 1, 81–128.
Giera, M., Lingeman, H., & Niessen, W. M. A. (2012). Recent advancements in the LC- and GC-based analysis of malondialdehyde (MDA): a brief overview. Chromatographia., 75(9-10), 433–440.
David, C., Raziella, R. G., Silvia, B., et al. (2011). Role of quercetin in preventing thioacetamide-induced liver injury in rats. Toxicologic Pathology, 39(6), 949–957.
Nafees, S., Ahmad, S.T., Arjumand, W., Rashid, S., Ali, N., Sultana, S. (2013). Carvacrol ameliorates thioacetamide-induced hepatotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in liver of Wistar rats. Human and Experimental Toxicology 1–13.
Lim, S., Lee, S. J., Nam, K. W., Kim, K. H., & Mar, W. (2013). Hepatoprotective effects of reynosin against thioacetamide induced apoptosis in primary hepatocytes and mouse liver. Archives of Pharmacal Research, 36, 485–494.
Antoine, D. J., Dear, J. W., Lewis, P. S., Platt, V., Coyle, J., Masson, M., Thanacoody, R. H., Gray, A. J., Webb, D. J., Moggs, J. G., Bateman, D. N., Goldring, C. E., & Park, B. K. (2013). Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital. Journal of Hepatology, 58, 777–787.
Nitatori, T., Sato, N., Waguri, S., Karasawa, Y., Araki, H., Shinabai, K., et al. (1994). Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. The Journal of Neuroscience, 15(2), 1001–1011.
Nitatori, T., Sato, N., Waguri, S., Karasawa, Y., Araki, H., Shinabai, K., Kominani, E., & Uchiyama, Y. (1994). Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. The Journal of Neuroscience, 15, 1001–1011.
Hashimoto, K., Minaga, W., & Yanagi, Y. (2003). Caspase-dependent apoptosis in fulminant hepatic failure induced by herpes simplex virus in mice. Journal of Hepatology, 39, 773–778.
Madani, H., Talebolhosseini, M., Asgary, S., & Naderi, G. H. (2008). Hepatoprotective activity of Silybum marianum and Cichorium intybus against thioacetamide in Rat. Pakistan Journal of Nutrition, 7, 172–176.
Patel, N., Joseph, C., Corcoran, G. B., & Ray, S. D. (2000). Silymarin modulates doxorubicin induced oxidative stress, Bcl-xL and p53 expression while preventing apoptotic and necrotic cell death in the liver. Toxicology and Applied Pharmacology, 245, 143–152.
Santosh, K., Anshu, R., & Manjeshwar, B. (2005). Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release, and caspase activation. Molecular Cancer Therapeutics, 4, 207–216.
Funding
Project with coded 2017-1621 was supported by the scientific research projects of Eskisehir Osmangazi University. This study was made from PhD thesis by Ozgun Teksoy at Eskisehir Osmangazi University.
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Teksoy, O., Sahinturk, V., Cengiz, M. et al. The Protective Effects of Silymarin on Thioacetamide-Induced Liver Damage: Measurement of miR-122, miR-192, and miR-194 Levels. Appl Biochem Biotechnol 191, 528–539 (2020). https://doi.org/10.1007/s12010-019-03177-w
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DOI: https://doi.org/10.1007/s12010-019-03177-w