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Protective Effects of Akebia quinata Fruit Extract on Acute Alcohol-induced Hepatotoxicity in Mice

급성 알코올 간독성을 유발한 생쥐에 있어서 으름 열매 추출물의 간 기능 보호효과

  • Lee, Sang Hoon (Department of Nutritional Science and Food Management, College of Health Science, Ewha Womans University) ;
  • Song, Young Sun (Department of Nutritional Science and Food Management, College of Health Science, Ewha Womans University) ;
  • Lee, Seo Yeon (Department of Nutritional Science and Food Management, College of Health Science, Ewha Womans University) ;
  • Kim, So Young (Department of Nutritional Science and Food Management, College of Health Science, Ewha Womans University) ;
  • Ko, Kwang Suk (Department of Nutritional Science and Food Management, College of Health Science, Ewha Womans University)
  • 이상훈 (이화여자대학교 건강과학대학 식품영양학과) ;
  • 송영선 (이화여자대학교 건강과학대학 식품영양학과) ;
  • 이서연 (이화여자대학교 건강과학대학 식품영양학과) ;
  • 김소영 (이화여자대학교 건강과학대학 식품영양학과) ;
  • 고광석 (이화여자대학교 건강과학대학 식품영양학과)
  • Received : 2014.04.07
  • Accepted : 2014.08.29
  • Published : 2014.10.31

Abstract

We studied the effects of Akebia quinata fruit extract (AQ) on acute alcohol-induced hepatotoxicity in mice. AQ (30-1,000 mg/kg body weight (BW) per day) was orally administered to the study group, once daily for 1 week. On the last day of AQ treatment, ethanol (6 mg/kg BW) was orally administered to induce acute liver injury. The AQ-treated group showed significantly lower levels of alanine aminotransferase and aspartate aminotransferase, compared to the only ethanol-treated group (ETG). The glutathione level in the AQ-treated group elevated up to 20.6%, compared to that observed in the ETG. The mRNA expression of glutathione synthetic enzymes was also higher in the AQ-treated group, compared to the ETG. The AQ-treated group also exhibited lower levels of expression of NADPH oxidase 4 and tumor necrosis factor alpha mRNA. Thus, these results show that AQ treatment can be a potential method to reduce oxidative stress and inflammation in ethanol-treated mouse liver and also that AQ can be a useful therapeutic agent for acute alcohol-induced hepatotoxicity.

생쥐에서의 으름의 열매 추출물의 경구 투여가 알코올로 인한 급성 간독성 상태에서 간보호 효과에 대한 영향을 조사 하였다. 즉, 생쥐 (C57BL/6)에게 1주간 으름 열매 추출물을 투여 하고 희생 전 알코올의 경구 투여를 통해 급성 알코올 간독성을 유발한 후 간 조직 형상, 간 기능 지표(ALT, AST), 간 세포내 GSH 합성 효소(GCLM, GCLC, GSS)의 mRNA 발현량, GSH 농도의 측정, 산화 스트레스 지표인 NOX4의 mRNA 발현량과 염증 반응 지표인 TNF-${\alpha}$의 mRNA 발현량을 조사 하였다. 그 결과, 으름 열매 추출물의 경구 투여는 알코올로 유발된 급성 간독성 상태에서 간 조직내 지방의 축적을 완화 하였고, 혈청 AST, ALT 수치를 개선하였으며, 간조직 내 항산화 물질인 GSH의 농도를 증가시켰다. 더불어 활성산소기를 생성하는 NOX4의 mRNA 발현을 억제 하는 것으로 분석되었으며 염증 반응 지표인 TNF-의 mRNA 발현도 억제 하는 것으로 분석되었다. 따라서 으름의 열매 추출물은 알코올로 유발된 산화 스트레스, 염증 반응에 대한 간보호 효과 가능성을 나타내는 것으로 판단된다.

Keywords

References

  1. Ramchandani VA, Bosron WF, Li TK. Research advances in ethanol metabolism. Pathol. Biol. 49: 676-682 (2001) https://doi.org/10.1016/S0369-8114(01)00232-2
  2. Rouach H, Clement M, Ofanelli MT, Janvier B, Nordmann J, Nordmann R. Hepatic lipid peroxidation and mitochondrial susceptibility to peroxidative attacks during ethanol inhalation and withdrawal. Biochem. Biophys. Acta. 753: 439-444 (1983) https://doi.org/10.1016/0005-2760(83)90068-1
  3. Wheeler MD, Nakagami M, Bradford BU, Uesugi T, Mason RP, Connor HD, Dikalova A, Kadiiska M, Thurman RG. Overexpression of manganese superoxide dismutase prevents alcohol-induced liver injury in the rat. J. Biol. Chem. 276: 36664-36672 (2001) https://doi.org/10.1074/jbc.M105352200
  4. Moncade C, Torres V, Varghese G, Albano E, Israsel Y. Ethanol derived immuno reactive species formed by radical mechanisms. Mol. Phaemacol. 46: 786-791 (1994)
  5. Simic MG. Mechanisms of inhibition of free-radical processes in mutagenesis and carcinogensis. Mutat. Res. 202: 377-386 (1988) https://doi.org/10.1016/0027-5107(88)90199-6
  6. Lu SC, Mato JM. S-Adenosylmethionine in cell growth, apoptosis and liver cancer. J. Gastroenterol. Hepatol. 23: s73-s77 (2008) https://doi.org/10.1111/j.1440-1746.2007.05289.x
  7. McClain CJ, Song Z, Barve SS, Hill DB, Deaciuc I. Recent advances in alcoholic liver disease IV. dysregulated cytokine metabolism in alcoholic liver disease. Am. J. Physiol. Gastrointest. Liver Physiol. 287: 497-502 (2004) https://doi.org/10.1152/ajpgi.00171.2004
  8. Camandola S, Scavazza A, Leonarduzzi G, Biasi F, Chiarpotto E, Azzi A, Poli G. Biogenic 4-hydroxy-2-nonenal activates transcription factor AP-1 but not NF-kappa B in cells of the macrophage lineage. Biofactors 6: 173-179 (1997) https://doi.org/10.1002/biof.5520060211
  9. Ohshima H, Tazawa H, Sylla BS, Sawa T. Prevention of human cancer by modulation of chronicinflammatory processes. Mutat. Res. 591: 110-122 (2005) https://doi.org/10.1016/j.mrfmmm.2005.03.030
  10. Ikuta A. Saponins and triterpenes from callus tissues of Akebia trifoliate and comparision with the constituents of other Lardizabalaceous callus tissues. J. Nat. Prod. 58: 1378-1383 (1995) https://doi.org/10.1021/np50123a007
  11. Choi JW, Jung HJ, Lee KT, Park HJ. Antinociceptive and antiinflammatory effects of the saponin and sapogenins obtained from the stem of Akebia quinata. J. Med. Food 8: 78-85 (2005) https://doi.org/10.1089/jmf.2005.8.78
  12. Higuchi R, Kawasaki T. Pericarp saponins of Akebia quinata Decne. I. Glycosides of hederagenin and oleanolic acid. Chem. Pharm. Bull. 24: 1021-1032 (1976) https://doi.org/10.1248/cpb.24.1021
  13. Ikuta A, Itokawa H. A triterpene from Akebia quinata callus tissue. Phytochemistry 27: 3809-3810 (1988) https://doi.org/10.1016/0031-9422(88)83022-X
  14. Jung HJ, Lee CO, Lee TK, Choi JW, Park HJ. Structure - activity relationship of oleanane disaccharides isolated from Akebia quinata versus cytotoxicity against cancer cells and NO inhibition. Biol. Pharm. Bull. 27: 744-747 (2004) https://doi.org/10.1248/bpb.27.744
  15. Kang SH, Kang JS, Jeong WS. Cytotoxic and apoptotic effects of saponins from Akebia quinata on HepG2 hepatocarcinoma cells. Korean. J. Food. Preserv. 17: 311-319 (2010)
  16. Ellman GL. Tissue sulthydryl groups. Arch. Biochem. Biophys. 82: 70-77 (1959) https://doi.org/10.1016/0003-9861(59)90090-6
  17. Tietze F. Disulfide reduction in rat liver. I. Evidence for the presence of nonspecific nucleotide-dependent disulfide reductase and GSH-disulfide transhydrogenase activities in the high-speed supernatant fraction. Arch. Biochem. Biophys. 138: 177-188 (1970) https://doi.org/10.1016/0003-9861(70)90297-3
  18. Bradford M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of proteindye binding. Anal. Biochem. 72: 248-254 (1976) https://doi.org/10.1016/0003-2697(76)90527-3
  19. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Methods 25: 402-408 (2001) https://doi.org/10.1006/meth.2001.1262
  20. Umulis DM, Gurmen NM, Singh P, Fogler HS. A physiologically based model for ethanol and acetaldehyde metabolism in human beings. Alcohol 35: 3-12 (2005) https://doi.org/10.1016/j.alcohol.2004.11.004
  21. Cha YS, Sachan DS. Acetylcarnitine-mediated inhibition of ethanol oxidation in hepatocytes. Alcohol 12: 289-294 (1995) https://doi.org/10.1016/0741-8329(95)00007-E
  22. Israel Y, Robert SB, Hector O. Liver cell enlargement induced by chronic alcohol consumption: studies on its causes and consequences. Clin. Biochem.15: 189-192 (1982)
  23. Kwo PY, Ramchandani VA, O'connor S, Amann D, Carr LG, Sandrasegaran K, Kopecky KK, Li TK. Gender differences in alcohol metabolism: Relationship to liver volume and effect of adjusting for body mass. Gastroenterology 115: 1552-1557 (1998) https://doi.org/10.1016/S0016-5085(98)70035-6
  24. Degracea P, Demizieuxa L, Gresti J, Chardigny JM, Sbdio JL, Clouet P. Association of liver steatosis with lipid oversecretion and hypotriglyceridaemia in C57BL/6j mice fed trans-10, cis-12- linoleic acid. FEBS. Lett. 546: 335-339 (2003) https://doi.org/10.1016/S0014-5793(03)00610-0
  25. Campbell JS, Hughes SD, Gilbertson DG, Palmer TE, Holdren MS, Haran AC, Odell MM, Bauer RL, Ren HP, Haugen HS, Yeh MM, Fausto N. Platelet-derived growth factor C induces liver fibrosis, steatosis, and hepatocellular carcinoma. P. Natl. Acad. Sci. USA 102: 3389-3394 (2005) https://doi.org/10.1073/pnas.0409722102
  26. Gao B, Bataller R, Gastroent. Alcoholic liver disease: Pathogenesis and new therapeutic targets. Gastroenterology. 141: 1572-1585 (2011) https://doi.org/10.1053/j.gastro.2011.09.002
  27. Stickel F, Seitz HK. Alcoholic steatohepatitis. Best. Pract. Res. Clin. Gastroenterol. 24: 683-693 (2010)
  28. Beier JL, McClain CJ, Mechanisms and cell signaling in alcoholic liver disease. J. Biol. Chem. 39: 1249-1264 (2010)
  29. Zeng T, Xie KQ. Ethanol and liver: recent advances in the mechanisms of ethanol-induced hepatosteatosis. Arch. Toxicol. 83: 1075-1081 (2009) https://doi.org/10.1007/s00204-009-0457-4
  30. Espin N, Lima, V, Lieber CS, Garro AJ. In vitro and in vivo inhibitory effect of ethanol and acetaldehyde on O6-methylguanine transferase. Carcinogenesis 9: 761-766 (1988) https://doi.org/10.1093/carcin/9.5.761
  31. Wondergem R, Davis J. Ethanol increases hepatocyte water volume. Alcohol. Clin. Exp. Res. 18: 1230-1236 (1994) https://doi.org/10.1111/j.1530-0277.1994.tb00110.x
  32. Lettron P, Fromenty B, Terris B, Degott C, Pessayre D. Acute and chronic hepatic steatosis lead to in vivo lipid peroxidation in mice. J. Hepatol. 24: 200-208(1996) https://doi.org/10.1016/S0168-8278(96)80030-4
  33. Yin M, Wheeler MD, Kono H, Bradford BU, Gallucc RM, Luster MI, Thurman RG. Essential role of tumor necrosis factor alpha in alcohol-induced liver injury in mice. Gastroenterology 117: 942-952 (1999) https://doi.org/10.1016/S0016-5085(99)70354-9
  34. Abdellah M, Demelliers C, Amsellem S, Pessayre D, Fromenty B. Acute ethanol administration oxidatively damages and depletes mitochondrial DNA in mouse liver, brain, heart, and skeletal muscles: protective effects of antioxidants. J. Pharmacol. Exp. Ther. 298: 737-743 (2001)
  35. Ko KS, Yang H, Noureddin M, Iglesia-Ara A, Xia M, Wagner C, Luka Z, Mato JM, Lu SC. Changes in S-adenosylmethionine and GSH homeostasis during endotoxemia in mice. Lab Invest. 88: 1121-1129 (2008) https://doi.org/10.1038/labinvest.2008.69
  36. Liu H, Wang H, Shenvi S, Hagen TM, Liu RM. Glutathione metabolism during aging and in Alzheimer disease. Ann. N. Y. Acad. Sci. 1019: 346-349 (2004) https://doi.org/10.1196/annals.1297.059
  37. Videla LA, Valenzuela A. Alcohol ingestion, liver glutathione and lipoperoxidation: metabolic interrelations and pathological implications. Life Sci. 31: 2395-2407 (1982) https://doi.org/10.1016/0024-3205(82)90743-3
  38. Sun S, Zhaing H, Xue B, Wu Y, Wang J, Yin Z, Luo L. Protective effect of glutathione against lipopolysaccharide-induced inflammation and mortality in rats. Inflamm. Res. 55: 504-510 (2006) https://doi.org/10.1007/s00011-006-6037-7
  39. Dalton TP, Dieter MZ, Yang Y, Shertzer HG, Nebert DW. Knockout of the mouse glutamate cysteine ligase catalytic subunit (Gclc) gene: embryonic lethal when homozygous, and proposed model for moderate glutathione deficiency when heterozygous. Biochem. Biophys. Res. Commun. 279: 324-329 (2000) https://doi.org/10.1006/bbrc.2000.3930
  40. Lu SC. Regulation of hepatic glutathione synthesis: current concepts and controversies. Faseb. J. 13: 1169-1183 (1999)
  41. Vogt BL, Richie JP Jr. Glutathione depletion and recovery after acute ethanol administration in the aging mouse. Biochem. Pharmacol. 73: 1613-1621 (2007) https://doi.org/10.1016/j.bcp.2007.01.033
  42. Medina J, Moreno-Otero R. Pathophysiological basis for antioxidant therapy in chronic liver disease. Drugs 65: 2445-2461 (2005) https://doi.org/10.2165/00003495-200565170-00003
  43. Roskams T, Yang SQ, Koteish A, Durnez A, DeVos R, Huang X, Achten R, Verslype C, Diehl AM. Oxidative stress and oval cell accumulation in mice and humans with alcoholic and nonalcoholic fatty liver disease. Am. J. Pathol. 163: 1301-1311 (2003) https://doi.org/10.1016/S0002-9440(10)63489-X
  44. Vendemiale G, Altomare E, Trizio T, Grazie CL, Padova CD. Salemo MT, Carrieri V, Albano O. Effects of oral S-adenosyl-Lmethionine on hepatic glutathione in patients with liver disease. Scand. J. Gastroenterol. 24: 407-415 (1989) https://doi.org/10.3109/00365528909093067
  45. Mato JM, Cmara J, Fernndez de Paz J, Caballera L, Coll S, Caballero A, Garca-Buey L, Beltrn J, Benita V, Caballera J, Sol R, Moreno-Otero R, Barrao F, Martn-Duce A, Correa JA, Pars A, Barrao E, Garca-Magaz I, Puerta JL, Moreno J, Boissard G, Ortiz P, Rods J. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo- controlled, double-blind, multicenter clinical trial. J. Hepatol. 30: 1081-1089 (1999) https://doi.org/10.1016/S0168-8278(99)80263-3
  46. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol. Rev. 87: 245-313 (2007) https://doi.org/10.1152/physrev.00044.2005
  47. Jiang JX, Chen X, Serizawa N, Szyndralewiez C, Page P, Schrder K, Brandes RP, Devaraj S, Trk NJ. Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. Free Radic. Biol. Med. 53: 289-296 (2012) https://doi.org/10.1016/j.freeradbiomed.2012.05.007
  48. Bataller R, Schwabe RF, Choi YH, Yang L, Paik YH, Lindquist J, Qian T, Schoonhoven R, Hagedorn CH, Lemasters JJ, Brenner DA. NADPH oxidase signal transduces angiotensin II in hepatic stellate cells and is critical in hepatic fibrosis. J. Clin. Invest. 112: 1383-1394 (2003) https://doi.org/10.1172/JCI18212
  49. Adachi Y, Moore LE, Bradford BU, Gao W, Thurman RG. Antibiotics prevent liver injury in rats following long-term exposure to ethanol. Gastroenterology 108: 218-224 (1995) https://doi.org/10.1016/0016-5085(95)90027-6
  50. Thurman RG, Bradford BU, Iimuro Y, Knecht KT, Arteel GE, Yin M, Connor HD, Wall C, Raleigh JA, Frankenberg MV, Adachi Y, Forman DT, Brenner D, Kadiiska M, Mason RP. The role of gut-derived bacterial toxins and free radicals in alcoholinduced liver injury. J. Gastroenterol. Hepatol. 13: S39-S50 (1998)
  51. Ji C, Deng Q, Kaplowitz N. Role of TNF-alpha in ethanolinduced hyperhomocysteinemia and murine alcoholic liver injury. Hepatology 40: 442-451 (2004) https://doi.org/10.1002/hep.20309
  52. Zhao XJ, Dong Q, Bindas J, Piganelli JD, Magill A, Reiser J, Kolls JK. TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol. J. Immunol. 181: 3049-3056 (2008) https://doi.org/10.4049/jimmunol.181.5.3049
  53. Petrasek J, Dolganiuc A, Csak T, Nath B, Hritz I, Kodys K, Catalano D, Kurt-Jones E, Mandrekar P, Szabo G. Interferon regulatory factor 3 and type I interferons are protective in alcoholic liver injury in mice by way of crosstalk of parenchymal and myeloid cells. Hepatology 53: 649-660 (2011) https://doi.org/10.1002/hep.24059

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