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http://dx.doi.org/10.1016/j.jgr.2017.07.003

Ginsenoside Rk1 ameliorates paracetamol-induced hepatotoxicity in mice through inhibition of inflammation, oxidative stress, nitrative stress and apoptosis  

Hu, Jun-Nan (College of Chinese Medicinal Materials, Jilin Agricultural University)
Xu, Xing-Yue (College of Chinese Medicinal Materials, Jilin Agricultural University)
Li, Wei (College of Chinese Medicinal Materials, Jilin Agricultural University)
Wang, Yi-Ming (College of Animal Science and Technology, Jilin Agricultural University)
Liu, Ying (College of Chinese Medicinal Materials, Jilin Agricultural University)
Wang, Zi (College of Chinese Medicinal Materials, Jilin Agricultural University)
Wang, Ying-Ping (Institute of Special Wild Economic Animals and Plant, CAAS)
Publication Information
Journal of Ginseng Research / v.43, no.1, 2019 , pp. 10-19 More about this Journal
Abstract
Background: Frequent overdose of paracetamol (APAP) has become the major cause of acute liver injury. The present study was designed to evaluate the potential protective effects of ginsenoside Rk1 on APAP-induced hepatotoxicity and investigate the underlying mechanisms for the first time. Methods: Mice were treated with Rk1 (10 mg/kg or 20 mg/kg) by oral gavage once per d for 7 d. On the 7th d, allmice treated with 250mg/kg APAP exhibited severeliverinjury after 24 h, and hepatotoxicitywas assessed. Results: Our results showed that pretreatment with Rk1 significantly decreased the levels of serum alanine aminotransferase, aspartate aminotransferase, tumor necrosis factor, and interleukin-$1{\beta}$ compared with the APAP group. Meanwhile, hepatic antioxidants, including superoxide dismutase and glutathione, were elevated compared with the APAP group. In contrast, a significant decrease in levels of the lipid peroxidation product malondialdehyde was observed in the ginsenoside Rk1-treated group compared with the APAP group. These effects were associated with a significant increase of cytochrome P450 E1 and 4-hydroxynonenal levels in liver tissues. Moreover, ginsenoside Rk1 supplementation suppressed activation of apoptotic pathways by increasing Bcl-2 and decreasing Bax protein expression levels, which was shown using western blotting analysis. Histopathological observation also revealed that ginsenoside Rk1 pretreatment significantly reversed APAP-induced necrosis and inflammatory infiltration in liver tissues. Biological indicators of nitrative stress, such as 3-nitrotyrosine, were also inhibited after pretreatment with Rk1 compared with the APAP group. Conclusion: The results clearly suggest that the underlying molecular mechanisms in the hepatoprotection of ginsenoside Rk1 in APAP-induced hepatotoxicity may be due to its antioxidation, antiapoptosis, anti-inflammation, and antinitrative effects.
Keywords
anti-inflammation; anti-apoptosis; APAP-induced hepatotoxicity; ginsenoside Rk1; oxidative stress;
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1 Hsu YW, Tsai CF, Chen WK, Lu FJ. Protective effects of seabuckthorn (Hippophae rhamnoides L.) seed oil against carbon tetrachloride-induced hepatotoxicity in mice. Food Chem Toxicol 2009;47:2281-8.   DOI
2 Firuzi O, Miri R, Tavakkoli M, Saso L. Antioxidant therapy: current status and future prospects. Curr Med Chem 2011;18:3871-88.   DOI
3 Weydert CJ, Cullen JJ. Measurement of superoxide dismutase, catalase and glutathione peroxidase in cultured cells and tissue. Nat Protoc 2010;5:51-66.   DOI
4 Hau DK, Gambari R, Wong RS, Yuen MC, Cheng GY, Tong CS, Zhu GY, Leung AK, Lai PB, Lau FY, et al. Phyllanthus urinaria extract attenuates acetaminophen induced hepatotoxicity: involvement of cytochrome P450 CYP2E1. Phytomedicine 2009;16:751-60.   DOI
5 Tai M, Zhang J, Song S, Miao R, Liu S, Pang Q, Wu Q, Liu C. Protective effects of luteolin against acetaminophen-induced acute liver failure in mouse. Int Immunopharmacol 2015;27:164-70.   DOI
6 Saito C, Lemasters JJ, Jaeschke H. c-Jun N-terminal kinase modulates oxidant stressandperoxynitrite formationindependent of inducible nitric oxide synthase in acetaminophen hepatotoxicity. Toxicol Appl Pharmacol 2010;246:8-17.   DOI
7 Jaeschke H, Williams CD, McGill MR, Xie Y, Ramachandran A. Models of druginduced liver injury for evaluation of phytotherapeutics and other natural products. Food Chem Toxicol 2013;55:279-89.   DOI
8 Chung WY, Park JH, Kim MJ, Kim HO, Hwang JK, Lee SK, Park KK. Xanthorrhizol inhibits 12-O-tetradecanoylphorbol-13-acetate-induced acute inflammation and two-stage mouse skin carcinogenesis by blocking the expression of ornithine decarboxylase, cyclooxygenase-2 and inducible nitric oxide synthase through mitogen-activated protein kinases and/or the nuclear factor-kappa B. Carcinogenesis 2007;28:1224-31.   DOI
9 Jiao L, Zhang X, Wang M, Li B, Liu Z, Liu S. Chemical and antihyperglycemic activity changes of ginseng pectin induced by heat processing. Carbohydr Polym 2014;114:567-73.   DOI
10 Jin Y, Piao J, Lee SM. Evaluating the validity of the Braden scale using longitudinal electronic medical records. Res Nurs Health 2015;38:152-61.   DOI
11 Park JH, Cha HY, Seo JJ, Hong JT, Han K, Oh KW. Anxiolytic-like effects of ginseng in the elevated plus-maze model: comparison of red ginseng and sun ginseng. Prog Neuropsychopharmacol Biol Psychiatry 2005;29:895-900.   DOI
12 Park IH, Kim NY, Han SB, Kim JM, Kwon SW, Kim HJ, Park MK, Park JH. Three new dammarane glycosides from heat processed ginseng. Arch Pharm Res 2002;25:428-32.   DOI
13 Lee S, Maharjan S, Kim K, Kim NJ, Choi HJ, Kwon YG, Suh YG. Cholesterolderived novel anti-apoptotic agents on the structural basis of ginsenoside Rk1. Bioorg Med Chem Lett 2010;20:7102-5.   DOI
14 Ko H, Kim YJ, Park JS, Park JH, Yang HO. Autophagy inhibition enhances apoptosis induced by ginsenoside Rk1 in hepatocellular carcinoma cells. Biosci Biotechnol Biochem 2009;73:2183-9.   DOI
15 Li W, Liu Y, Wang Z, Han Y, Tian YH, Zhang GS, Sun YS, Wang YP. Platycodin D isolated from the aerial parts of Platycodon grandiflorum protects alcoholinduced liver injury in mice. Food Funct 2015;6:1418-27.   DOI
16 Zamora Nava LE, Aguirre Valadez J, Chavez-Tapia NC, Torre A. Acute-onchronic liver failure: a review. Ther Clin Risk Manag 2014;10:295-303.   DOI
17 Sun H, Chen L, Zhou W, Hu L, Li L, Tu Q, Chang Y, Liu Q, Sun X, Wu M, et al. The protective role of hydrogen-rich saline in experimental liver injury in mice. J Hepatol 2011;54:471-80.   DOI
18 Dargan P, Jones A. Paracetamol: balancing risk against benefit. QJM 2002;95:831-2.   DOI
19 Ju HK, Lee JG, Park MK, Park SJ, Lee CH, Park JH, Kwon SW. Metabolomic investigation of the anti-platelet aggregation activity of ginsenoside Rk(1) reveals attenuated 12-HETE production. J Proteome Res 2012;11:4939-46.   DOI
20 Li W, Yan MH, Liu Y, Liu Z, Wang Z, Chen C, Zhang J, Sun YS. Ginsenoside Rg5 ameliorates cisplatin-induced nephrotoxicity in mice through inhibition of inflammation, oxidative stress, and apoptosis. Nutrients 2016;8:566.   DOI
21 Dragomir AC, Sun R, Mishin V, Hall LB, Laskin JD, Laskin DL. Role of galectin-3 in acetaminophen-induced hepatotoxicity and inflammatory mediator production. Toxicol Sci 2012;127:609-19.   DOI
22 He M, Zhang S, Jiao Y, Lin X, Huang J, Chen C, Chen Z, Huang R. Effects and mechanisms of rifampin on hepatotoxicity of acetaminophen in mice. Food Chem Toxicol 2012;50:3142-9.   DOI
23 Larson AM. Acetaminophen hepatotoxicity. Clin Liver Dis 2007;11:525-48. vi.   DOI
24 Uzkeser M. Protective effect of Panax ginseng against N-acetyl-p-aminophenolinduced hepatotoxicity in rats. Afr J Pharm Pharmacol 2012;6:2634-42.   DOI
25 Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB. Acetaminopheninduced hepatic necrosis. IV. Protective role of glutathione. J Pharmacol Exp Ther 1973;187:211-7.
26 Kon K, Kim JS, Jaeschke H, Lemasters JJ. Mitochondrial permeability transition in acetaminophen-induced necrosis and apoptosis of cultured mouse hepatocytes. Hepatology 2004;40:1170-9.   DOI
27 Hinson JA, Reid AB, McCullough SS, James LP. Acetaminophen-induced hepatotoxicity: role of metabolic activation, reactive oxygen/nitrogen species, and mitochondrial permeability transition. Drug Metab Rev 2004;36:805-22.   DOI
28 Han Y, Xu Q, Hu JN, Han XY, Li W, Zhao LC. Maltol, a food flavoring agent, attenuates acute alcohol-induced oxidative damage in mice. Nutrients 2015;7:682-96.   DOI
29 Hsu YL, Kuo PL, Liu CF, Lin CC. Acacetin-induced cell cycle arrest and apoptosis in human non-small cell lung cancer A549 cells. Cancer Lett 2004;212:53-60.   DOI
30 Oz HS, Chen TS. Green-tea polyphenols downregulate cyclooxygenase and Bcl-2 activity in acetaminophen-induced hepatotoxicity. Dig Dis Sci 2008;53:2980-8.   DOI
31 Li W, Xu Q, He YF, Liu Y, Yang SB, Wang Z, Zhang J, Zhao LC. Anti-tumor effect of steamed codonopsis lanceolata in H22 tumor-bearing mice and its possible mechanism. Nutrients 2015;7:8294-307.   DOI
32 Xing-yue Xu, Jun-nan Hu, Zhi Liu, Rui Zhang, Yu-fang He, Wei Hou, Zhiqing Wang, Ge Yang, Wei Li. Saponins (ginsenosides) from the leaves of Panax quinquefolius ameliorated acetaminophen-induced hepatotoxicity in mice. J Agric Food Chem 2017;65(18):3684-92.   DOI
33 Mitka M. FDA asks physicians to stop prescribing high-dose acetaminophen products. JAMA 2014;311:563.   DOI
34 Nagi MN, Almakki HA, Sayed-Ahmed MM, Al-Bekairi AM. Thymoquinone supplementation reverses acetaminophen-induced oxidative stress, nitric oxide production and energy decline inmice liver. Food Chem Toxicol 2010;48:2361-5.   DOI
35 Barman PK, Mukherjee R, Prusty BK, Suklabaidya S, Senapati S, Ravindran B. Chitohexaose protects against acetaminophen-induced hepatotoxicity in mice. Cell Death Dis 2016;7:e2224.   DOI
36 Jodynis-Liebert J, Matlawska I, Bylka W, Murias M. Protective effect of Aquilegia vulgaris (L.) on APAP-induced oxidative stress in rats. J Ethnopharmacol 2005;97:351-8.   DOI
37 Ghanem CI, Perez MJ, Manautou JE, Mottino AD. Acetaminophen from liver to brain: new insights into drug pharmacological action and toxicity. Pharmacol Res 2016;109:119-31.   DOI
38 McGill MR, Sharpe MR, Williams CD, Taha M, Curry SC, Jaeschke H. The mechanism underlying acetaminophen-induced hepatotoxicity in humans and mice involves mitochondrial damage and nuclear DNA fragmentation. J Clin Invest 2012;122:1574-83.   DOI
39 Liu J, Li C, Waalkes MP, Clark J, Myers P, Saavedra JE, Keefer LK. The nitric oxide donor, V-PYRRO/NO, protects against acetaminophen-induced hepatotoxicity in mice. Hepatology 2003;37:324-33.   DOI
40 Lee NH, Seo CS, Lee HY, Jung DY, Lee JK, Lee JA, Song KY, Shin HK, Lee MY, Seo YB, et al. Hepatoprotective and antioxidative activities of cornus officinalis against acetaminophen-induced hepatotoxicity in mice. Evid Based Complement Alternat Med 2012;2012, 804924.
41 Zhang Y, Zhang F, Wang K, Liu G, Yang M, Luan Y, Zhao Z. Protective effect of allyl methyl disulfide on acetaminophen-induced hepatotoxicity in mice. Chem Biol Interact 2016;249:71-7.   DOI
42 Wang S, Wang X, Luo F, Tang X, Li K, Hu X, Bai J. Panaxatriol saponin ameliorated liver injury by acetaminophen via restoring thioredoxin-1 and pro-caspase-12. Liver Int 2014;34:1068-73.   DOI
43 Leung KW, Wong AS. Pharmacology of ginsenosides: a literature review. Chin Med 2010;5:20.   DOI
44 Kim SK, Park JH. Trends in ginseng research in 2010. J Ginseng Res2011;35:389-98.   DOI
45 Li W, Zhang M, Gu J, Meng ZJ, Zhao LC, Zheng YN, Chen L, Yang GL. Hypoglycemic effect of protopanaxadiol-type ginsenosides and compound K on Type 2 diabetes mice induced by high-fat diet combining with streptozotocin via suppression of hepatic gluconeogenesis. Fitoterapia 2012;83:192-8.   DOI
46 Nelson SD. Molecular mechanisms of the hepatotoxicity caused by acetaminophen. Semin Liver Dis 1990;10:267-78.   DOI
47 Igami K, Shimojo Y, Ito H, Miyazaki T, Kashiwada Y. Hepatoprotective effect of fermented ginseng and its major constituent compound K in a rat model of paracetamol (acetaminophen)-induced liver injury. J Pharm Pharmacol 2015;67:565-72.   DOI
48 Kim WY, Kim JM, Han SB, Lee SK, Kim ND, Park MK, Kim CK, Park JH. Steaming of ginseng at high temperature enhances biological activity. J Nat Prod 2000;63:1702-4.   DOI
49 Jin Y, Kim YJ, Jeon JN, Wang C, Min JW, Noh HY, Yang DC. Effect of white, red and black ginseng on physicochemical properties and ginsenosides. Plant Foods Hum Nutr 2015;70:141-5.   DOI
50 Baek NI, Kim DS, Lee YH, Park JD, Lee CB, Kim SI. Ginsenoside Rh4, a genuine dammarane glycoside from Korean Red Ginseng. Planta Med 1996;62:86-7.   DOI
51 Hwang IG, Kim HY, Joung EM, Woo KS, Jeong JH, Yu KW, Lee J, Jeong HS. Changes in ginsenosides and antioxidant activity of Korean ginseng (Panax ginseng C.A. Meyer) with heating temperature and pressure. Food Sci Biotechnol 2010;19:941-9.   DOI
52 Song Z, McClain CJ, Chen T. S-Adenosylmethionine protects against acetaminophen-induced hepatotoxicity in mice. Pharmacology 2004;71:199-208.   DOI
53 Hu JN, Liu Z, Wang Z, Li XD, Zhang LX, Li W, Wang YP. Ameliorative effects and possible molecular mechanism of action of black ginseng (Panax ginseng) on acetaminophen-mediated liver injury. Molecules 2017;22:664.   DOI
54 Park IH, Piao LZ, Kwon SW, Lee YJ, Cho SY, Park MK, Park JH. Cytotoxic dammarane glycosides from processed ginseng. Chem Pharm Bull (Tokyo) 2002;50:538-40.   DOI
55 Liu LC, Wang CJ, Lee CC, Su SC, Chen HL, Hsu JD, Lee HJ. Aqueous extract of Hibiscus sabdariffa L. decelerates acetaminophen-induced acute liver damage by reducing cell death and oxidative stress in mouse experimental models. J Sci Food Agric 2010;90:329-37.   DOI
56 Hsu CC, Lin CC, Liao TS, Yin MC. Protective effect of s-allyl cysteine and spropyl cysteine on acetaminophen-induced hepatotoxicity in mice. Food Chem Toxicol 2006;44:393-7.   DOI