- Volume 11 Issue 2
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Protective effects of an ethanol extract of Angelica keiskei against acetaminophen-induced hepatotoxicity in HepG2 and HepaRG cells
- Choi, Yoon-Hee (Department of Food Science and Nutrition, Hallym University) ;
- Lee, Hyun Sook (Department of Food Science and Nutrition, Dongseo University) ;
- Chung, Cha-Kwon (Department of Food Science and Nutrition, Hallym University) ;
- Kim, Eun Ji (Center for Efficacy Assessment and Development of Functional Food and Drugs, Hallym University) ;
- Kang, Il-Jun (Department of Food Science and Nutrition, Hallym University)
- Received : 2016.09.27
- Accepted : 2017.01.05
- Published : 2017.04.01
BACKGROUND/OBJECTIVE: Although Angelica keiskei (AK) has widely been utilized for the purpose of general health improvement among Asian, its functionality and mechanism of action. The aim of this study was to determine the protective effect of ethanol extract of AK (AK-Ex) on acute hepatotoxicity induced by acetaminophen (AAP) in HepG2 human hepatocellular liver carcinoma cells and HepaRG human hepatic progenitor cells. MATERIALS/METHODS: AK-Ex was prepared HepG2 and HepaRG cells were cultured with various concentrations and 30 mM AAP. The protective effects of AK-Ex against AAP-induced hepatotoxicity in HepG2 and HepaRG cells were evaluated using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide, lactate dehydrogenase (LDH) assay, flow cytometry, and Western blotting. RESULTS: AK-Ex, when administered prior to AAP, increased cell growth and decreased leakage of LDH in a dose-dependent manner in HepG2 and HepaRG cells against AAP-induced hepatotoxicity. AK-Ex increased the level of Bcl-2 and decreased the levels of Bax, Bok and Bik decreased the permeability of the mitochondrial membrane in HepG2 cells intoxicated with AAP. AK-Ex decreased the cleavage of poly (ADP-ribose) polymerase (PARP) and the activation of caspase-9, -7, and -3. CONCLUSIONS: These results demonstrate that AK-Ex downregulates apoptosis via intrinsic and extrinsic pathways against AAP-induced hepatotoxicity. We suggest that AK could be a useful preventive agent against AAP-induced apoptosis in hepatocytes.
Supported by : Ministry of Trade, Industry and Energy (MOTIE), Korea Institute for Advancement of Technology (KIAT), Hallym University
- Maronpot RR. Toxicological assessment of Ashitaba Chalcone. Food Chem Toxicol 2015;77:111-9. https://doi.org/10.1016/j.fct.2014.12.021
- Chang HR, Lee HJ, Ryu JH. Chalcones from Angelica keiskei attenuate the inflammatory responses by suppressing nuclear translocation of NF-kappaB. J Med Food 2014;17:1306-13. https://doi.org/10.1089/jmf.2013.3037
- Yasuda M, Kawabata K, Miyashita M, Okumura M, Yamamoto N, Takahashi M, Ashida H, Ohigashi H. Inhibitory effects of 4-hydroxyderricin and xanthoangelol on lipopolysaccharide-induced inflammatory responses in RAW264 macrophages. J Agric Food Chem 2014;62:462-7. https://doi.org/10.1021/jf404175t
- Zhang T, Yamashita Y, Yasuda M, Yamamoto N, Ashida H. Ashitaba (Angelica keiskei) extract prevents adiposity in high-fat diet-fed C57BL/6 mice. Food Funct 2015;6:135-45.
- Ogawa H, Okada Y, Kamisako T, Baba K. Beneficial effect of xanthoangelol, a chalcone compound from Angelica keiskei, on lipid metabolism in stroke-prone spontaneously hypertensive rats. Clin Exp Pharmacol Physiol 2007;34:238-43. https://doi.org/10.1111/j.1440-1681.2007.04578.x
- Kim E, Choi J, Yeo I. The effects of Angelica keiskei Koidz on the expression of antioxidant enzymes related to lipid profiles in rats fed a high fat diet. Nutr Res Pract 2012;6:9-15. https://doi.org/10.4162/nrp.2012.6.1.9
- Akihisa T, Kikuchi T, Nagai H, Ishii K, Tabata K, Suzuki T. 4-Hydroxyderricin from Angelica keiskei roots induces caspasedependent apoptotic cell death in HL60 human leukemia cells. J Oleo Sci 2011;60:71-7. https://doi.org/10.5650/jos.60.71
- Noh HM, Ahn EM, Yun JM, Cho BL, Paek YJ. Angelica keiskei Koidzumi extracts improve some markers of liver function in habitual alcohol drinkers: a randomized double-blind clinical trial. J Med Food 2015;18:166-72. https://doi.org/10.1089/jmf.2014.3222
- Ni HM, Bockus A, Boggess N, Jaeschke H, Ding WX. Activation of autophagy protects against acetaminophen-induced hepatotoxicity. Hepatology 2012;55:222-32. https://doi.org/10.1002/hep.24690
- Labbe G, Pessayre D, Fromenty B. Drug-induced liver injury through mitochondrial dysfunction: mechanisms and detection during preclinical safety studies. Fundam Clin Pharmacol 2008;22:335-53. https://doi.org/10.1111/j.1472-8206.2008.00608.x
- Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiodt FV, Ostapowicz G, Shakil AO, Lee WM; Acute Liver Failure Study Group. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005;42:1364-72. https://doi.org/10.1002/hep.20948
- Jaeschke H. Glutathione disulfide formation and oxidant stress during acetaminophen-induced hepatotoxicity in mice in vivo: the protective effect of allopurinol. J Pharmacol Exp Ther 1990;255:935-41.
- Holownia A, Braszko JJ. Acetaminophen alters microsomal ryanodine Ca2+ channel in HepG2 cells overexpressing CYP2E1. Biochem Pharmacol 2004;68:513-21. https://doi.org/10.1016/j.bcp.2004.04.007
- 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. https://doi.org/10.1002/hep.20437
- Kim EJ, Holthuizen PE, Park HS, Ha YL, Jung KC, Park JH. Trans-10, cis-12-conjugated linoleic acid inhibits Caco-2 colon cancer cell growth. Am J Physiol Gastrointest Liver Physiol 2002;283:G357-67. https://doi.org/10.1152/ajpgi.00495.2001
- Thomas JP, Geiger PG, Girotti AW. Lethal damage to endothelial cells by oxidized low density lipoprotein: role of selenoperoxidases in cytoprotection against lipid hydroperoxide- and iron-mediated reactions. J Lipid Res 1993;34:479-90.
- Jung JI, Lim SS, Choi HJ, Cho HJ, Shin HK, Kim EJ, Chung WY, Park KK, Park JH. Isoliquiritigenin induces apoptosis by depolarizing mitochondrial membranes in prostate cancer cells. J Nutr Biochem 2006;17:689-96. https://doi.org/10.1016/j.jnutbio.2005.11.006
- Cho HJ, Kim WK, Kim EJ, Jung KC, Park S, Lee HS, Tyner AL, Park JH. Conjugated linoleic acid inhibits cell proliferation and ErbB3 signaling in HT-29 human colon cell line. Am J Physiol Gastrointest Liver Physiol 2003;284:G996-1005. https://doi.org/10.1152/ajpgi.00347.2002
- Jetten MJ, Kleinjans JC, Claessen SM, Chesne C, van Delft JH. Baseline and genotoxic compound induced gene expression profiles in HepG2 and HepaRG compared to primary human hepatocytes. Toxicol In Vitro 2013;27:2031-40. https://doi.org/10.1016/j.tiv.2013.07.010
- Jennen DG, Magkoufopoulou C, Ketelslegers HB, van Herwijnen MH, Kleinjans JC, van Delft JH. Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci 2010;115:66-79. https://doi.org/10.1093/toxsci/kfq026
- Liguori MJ, Blomme EA, Waring JF. Trovafloxacin-induced gene expression changes in liver-derived in vitro systems: comparison of primary human hepatocytes to HepG2 cells. Drug Metab Dispos 2008;36:223-33. https://doi.org/10.1124/dmd.107.017608
- Guo L, Dial S, Shi L, Branham W, Liu J, Fang JL, Green B, Deng H, Kaput J, Ning B. Similarities and differences in the expression of drug-metabolizing enzymes between human hepatic cell lines and primary human hepatocytes. Drug Metab Dispos 2011;39:528-38. https://doi.org/10.1124/dmd.110.035873
- Aninat C, Piton A, Glaise D, Le Charpentier T, Langouet S, Morel F, Guguen-Guillouzo C, Guillouzo A. Expression of cytochromes P450, conjugating enzymes and nuclear receptors in human hepatoma HepaRG cells. Drug Metab Dispos 2006;34:75-83.
- Andersson TB. The application of HepRG cells in evaluation of cytochrome P450 induction properties of drug compounds. Methods Mol Biol 2010;640:375-87.
- Ferreira A, Rodrigues M, Silvestre S, Falcao A, Alves G. HepaRG cell line as an in vitro model for screening drug-drug interactions mediated by metabolic induction: amiodarone used as a model substance. Toxicol In Vitro 2014;28:1531-5. https://doi.org/10.1016/j.tiv.2014.08.004
- Danpure CJ. Lactate dehydrogenase and cell injury. Cell Biochem Funct 1984;2:144-8. https://doi.org/10.1002/cbf.290020305
- Cory S, Huang DC, Adams JM. The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 2003;22:8590-607. https://doi.org/10.1038/sj.onc.1207102
- Ohkura N, Nakakuki Y, Taniguchi M, Kanai S, Nakayama A, Ohnishi K, Sakata T, Nohira T, Matsuda J, Baba K, Atsumi G. Xanthoangelols isolated from Angelica keiskei inhibit inflammatory-induced plasminogen activator inhibitor 1 (PAI-1) production. Biofactors 2011;37:455-61. https://doi.org/10.1002/biof.187
- Nagata J, Morino T, Saito M. Effects of dietary Angelica keiskei on serum and liver lipid profiles, and body fat accumulations in rats. J Nutr Sci Vitaminol (Tokyo) 2007;53:133-7. https://doi.org/10.3177/jnsv.53.133
- Aoki N, Muko M, Ohta E, Ohta S. C-geranylated chalcones from the stems of Angelica keiskei with superoxide-scavenging activity. J Nat Prod 2008;71:1308-10. https://doi.org/10.1021/np800187f
- Ohnogi H, Hayami S, Kudo Y, Deguchi S, Mizutani S, Enoki T, Tanimura Y, Aoi W, Naito Y, Kato I, Yoshikawa T. Angelica keiskei extract improves insulin resistance and hypertriglyceridemia in rats fed a high-fructose drink. Biosci Biotechnol Biochem 2012;76:928-32. https://doi.org/10.1271/bbb.110927
- Kawabata K, Sawada K, Ikeda K, Fukuda I, Kawasaki K, Yamamoto N, Ashida H. Prenylated chalcones 4-hydroxyderricin and xanthoangelol stimulate glucose uptake in skeletal muscle cells by inducing GLUT4 translocation. Mol Nutr Food Res 2011;55:467-75. https://doi.org/10.1002/mnfr.201000267
- Oh SR, Kim SJ, Kim DH, Ryu JH, Ahn EM, Jung JW. Angelica keiskei ameliorates scopolamine-induced memory impairments in mice. Biol Pharm Bull 2013;36:82-8.
- Choi SH, Park KH. Protective effects of Angelica keiskei extracts against D-galactosamine(GalN)-induced hepatotoxicity in rats. J Food Hyg Saf 2011;26:235-41.
- Huerta S, Goulet EJ, Huerta-Yepez S, Livingston EH. Screening and detection of apoptosis. J Surg Res 2007;139:143-56. https://doi.org/10.1016/j.jss.2006.07.034
- Thomadaki H, Scorilas A. BCL2 family of apoptosis-related genes: functions and clinical implications in cancer. Crit Rev Clin Lab Sci 2006;43:1-67. https://doi.org/10.1080/10408360500295626
- Boise LH, Gonzalez-Garcia M, Postema CE, Ding L, Lindsten T, Turka LA, Mao X, Nunez G, Thompson CB. bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 1993;74:597-608. https://doi.org/10.1016/0092-8674(93)90508-N
- Nicholson DW. Caspase structure, proteolytic substrates, and function during apoptotic cell death. Cell Death Differ 1999;6:1028-42. https://doi.org/10.1038/sj.cdd.4400598
- Burkle A, Brabeck C, Diefenbach J, Beneke S. The emerging role of poly(ADP-ribose) polymerase-1 in longevity. Int J Biochem Cell Biol 2005;37:1043-53. https://doi.org/10.1016/j.biocel.2004.10.006
- Andrabi SA, Kim NS, Yu SW, Wang H, Koh DW, Sasaki M, Klaus JA, Otsuka T, Zhang Z, Koehler RC, Hurn PD, Poirier GG, Dawson VL, Dawson TM. Poly(ADP-ribose) (PAR) polymer is a death signal. Proc Natl Acad Sci U S A 2006;103:18308-13. https://doi.org/10.1073/pnas.0606526103
- Isabelle M, Moreel X, Gagne JP, Rouleau M, Ethier C, Gagne P, Hendzel MJ, Poirier GG. Investigation of PARP-1, PARP-2, and PARG interactomes by affinity-purification mass spectrometry. Proteome Sci 2010;8:22. https://doi.org/10.1186/1477-5956-8-22