熊脱氧胆酸在慢性肝病中应用及机制的再认识

摘要/Abstract

摘要：

熊脱氧胆酸（ursodeoxycholic acid，UDCA）具有“保肝作用”，广泛应用于治疗各种慢性肝病，包括原发性胆汁性肝硬化（primary biliary cirrhosis，PBC）、原发性硬化性胆管炎（primary sclerosing cholangitis，PSC）、囊性纤维化（cystic fibrosis,CF）等，缺乏阳性药物对照，故对UDCA治疗慢性肝病的临床疗效机制尚不十分明确。近年来，由于UDCA不良事件报道日益增多，尤其在高剂量下，UDCA已表现出显著毒性。本文对UDCA在慢性肝病的临床应用及其机制进行探讨，为临床合理应用UDCA治疗肝病提供参考。

关键词: 熊脱氧胆酸, 肝病, 利胆剂, 毒性

Abstract:

Ursodeoxycholic acid （UDCA）has been widely used in clinical treatment of liver disease due to its hepato-protective effect, including primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and cystic fibrosis (CF), etc. Lack of effective drug as control, UDCA's clinical effect and mechanism of action remain unclear. Recently, the reports about adverse events caused by UDCA, especially at high dosage have been increasing. This review summarizes the clinical application and mechanism of UDCA in treatment of liver diseases, which is referential for its clinical application.

Key words: ursodeoxycholic acid, liver disease, cholagogue, toxicity

中图分类号:

R575

张林林，樊玉娟，谭波，李玥，蒋健，裘福荣. 熊脱氧胆酸在慢性肝病中应用及机制的再认识[J]. 中国临床药理学与治疗学, 2017, 22(2): 233-240.

ZHANG Linlin, FAN Yujuan, TAN Bo, LI Yue, JIANG Jian, QIU Furong. Recognition of the clinical application and biological mechanism of ursodeoxycholic acid in liver diseases[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2017, 22(2): 233-240.

参考文献

［1］Hammarsten O. Untersuchungen über die Gallen einiger Polarthiere［J］.Phys chem, 1901, 32( 5) : 435-466.
［2］Shoda M. Uber die Ursodeoxycholsaure aus Barengallen und ihre physiologische wirkung［J］. J Biochem, 1927, 42( 7) : 505-507.
［3］日本药局方编辑委员会编纂.《日本药局方》［M］. 第八改正版, 1971.
［4］Okumura M. Clinical studies on dissolution of gallstones using ursodeoxycholic acid［J］. Gastroterol Jpn, 1977, 12( 6) : 469-475.
［5］钟岚, 范建高. 熊去氧胆酸在慢性肝病中的应用及机制［J］.国外医学·消化系疾病分册, 1999, 19( 2) : 91-94.
［6］Rudic JS, Poropat G, Krstic MN, et al. Ursodeoxycholic acid for primary biliary cirrhosis［J］. Lancet, 2000, 355( 9204) : 657-658.
［7］Poropat G, Giljaca V, Stimac D, et al. Bile acids for liver-transplanted patients［J］. Cochrane Database Syst Rev, 2005, 5(3):85-86.
［8］Cheng K, Ashby D, Smyth RL.Ursodeoxycholic acid for cystic fibrosis-related liver disease［J］. Cochrane Database Syst Rev, 2000, 10( 2) : CD000222.
［9］Sinakos E, Marschall HU, Kowdley KV, et al. Bile acid changes after high-dose ursodeoxycholic acid treatment in primary sclerosing cholangitis : relation to disease progression［J］. Hepatology,2010,52( 1) : 197-203.
［10］Kotb MA. Ursodeoxycholic acid in neonatal hepatitis and infantile paucity of intrahepatic bile ducts : Review of a historical cohort［J］. Dig Dis Sci, 2009, 54(10) : 2231-2241.
［11］Burnat G, Majka J, Konturek PC. Bile acids are multifunctional modulators of the Barrett's carcinogenesis［J］. J Physiol Pharmacol, 2010, 61( 2) : 185-192.
［12］Anabela P, Rolo, Carlos M, Palmeira, et al.Wallace.Mitochondrially mediated synergistic cell killing by bile acids［J］. Biochim Biophys Acta, 2003, 1637( 1) : 127-132.
［13］Magd A, Kotb. Molecular Mechanisms of Ursodeoxycholic Acid Toxicity & Side Effects : Ursodeoxycholic Acid Freezes Regeneration & Induces Hibernation Mode［J］. Int J Mol Sci, 2012, 13( 7) : 8882-8914.
［14］Carey EJ, Ali AH, Lindor KD. Primary biliary cirrhosis［J］.Lancet, 2015, 386(10003) : 1565-1575.
［15］European Association for the Study of the Liver. EASL Clinical Practice Guidelines : management of cholestatic liver diseases［J］. J Hepatol 2009, 51(2) : 237-267.
［16］胆汁淤积性肝病诊断治疗专家共识：2015年更新［J］.中国肝脏病杂志（电子版）, 2015, 7(2) : 1-11.
［17］Zhang LN, Shi TY, Shi XH, et al.Eady biochemical response to ursodeoxycholic acid and long-term prognosis of primary biliary cirrhosis : results of a 14 year cohort study［J］. Hepatology, 2013, 58(1) : 264-272.
［18］Lammers WJ, van Buuren HR, Hirschfield GM, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study［J］. Gastroenterology, 2014, 147(16) : 1338-1349.
［19］Ali AH, Lindor KD.Obeticholic acid for the treatment of primary biliary cholangitis［J］.Expert Opin Pharmacother, 2016 , 17(13): 1809-1815.
［20］Jones DE.Obeticholic acid for the treatment ofprimary biliary cirrhosis［J］.Expert Rev Gastroenterol Hepatol, 2016, 10 (10): 1091-1099.
［21］Dyson JK, Hirschfield GM, Adams DH, et al. Novel therapeutic targets in primary biliary cirrhosis［J］.Nat Rev Gastroenterol Hepatol, 2015, 12(3): 147-158.
［22］Czul F, Levy C. Novel Therapies on Primary Biliary Cirrhosis［J］.Clin Liver Dis,2016, 20 (1): 113-130.
［23］Kuiper EM, Hansen BE, Adang RP, et al. Relatively high risk for hepatocellular carcinoma in patients with primary biliary cirrhosis not responding to ursodeoxycholic acid［J］. Eur J Gastroenterol Hepatol, 2010, 22(12) : 1495-1502.
［24］Christophe C. Primary Biliary Cirrhosis Beyond Ursodeoxycholic Acid［J］. Semin Liver Dis, 2016, 36(1) : 15-26.
［25］Sclair SN, Little E, Levy C. Current Concepts in Primary Biliary Cirrhosis and Primary Sclerosing Cholangitis［J］. Clin Transl Gastroenterol, 2015, 6(8) : e109.
［26］Lindor K, Kowdley K, Luketic V, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis［J］. Hepatology, 2009,50(3): 808-814.
［27］Lindstrom L, Hultcrantz R, Boberg KM, et al. Association between reduced levels of alkaline phosphatase and survival times of patients with primary sclerosing cholangitisp［J］.Clin Gastroenterol Hepatol , 2013, 11 (7) : 841-846.
［28］Othman MO, Dunkelberg J, Roy PK. Urosdeoxycholic acid in primary sclerosing cholangitis: A meta-analysis and systematic review［J］. Arab J Gastroenterol, 2012, 13(3) : 103-110.
［29］Hansen JD, Kumar S, Lo WK, et al.Ursodiol and colorectal cancer or dysplasia risk in primary sclerosing cholangitis and inflammatory bowel disease: a meta-analysis［J］. Dig Dis Sci, 2013, 58(11) : 3079-3087.
［30］Wunsch E, Trottier J, Milkiewicz M, et al. Prospective evaluation of ursodeoxycholic acid withdrawal in patients with primary sclerosing cholangitis［J］.Hepatology, 2014, 60 (3): 931-940.
［31］Chazouillères O. Primary sclerosing cholangitis and bile acids［J］. Clin Res Hepatol Gastroenterol, 2012, 36(36S1) : S21-S25.
［32］Triantos CK, Koukias NM, Nikolopoulou VN, et al. Meta-analysis: ursodeoxycholic acid for primary sclerosing cholangitis［J］. Aliment Pharmacol Ther, 2011, 34(8) : 901-910.
［33］Ali AH, Carey EJ, Lindor KD.Current research on the treatment of primary sclerosing cholangitis［J］. Intractable Rare Dis Res, 2015, 4(1): 1-6.
［34］Halilbasic E, Fuchs C, Hofer H, et al. Therapyof Primary Sclerosing Cholangitis-Today and Tomorrow［J］.Dig Dis,2015, 33(2): 149-163.
［35］Costa PC, Barreto CC, Pereira L, et al. Cystic fibrosis-related liver disease: a single-center experience［J］.Pediatr Rep, 2011, 3(21):87-90.
［36］Flass T, Narkewicz MR.Cirrhosis and other liver disease in cystic fibrosis［J］. J Cyst Fibr2013, 12(2) : 116-124.
［37］Sokol RJ, Durie PR. Recommendations for management of liver and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group［J］. J Pediatr Gastroenterol Nutr, 1999, 28(1) : S1-S13.
［38］Debray D, Kelly D, Houwen R, et al. Best practice guidance for the diagnosis and management of cystic fibrosis-associated liver disease［J］.J Cyst Fibros, 2011,10 (2) :S29-36.
［39］Colombo C, Crosignani A, Alicandro G, et al. Long-Term Ursodeoxycholic Acid Therapy Does Not Alter Lithocholic Acid Levels in Patients with Cystic Fibrosis with Associated Liver Disease［J］. J Pediatr,2016, 177 : 59-65.
［40］Joutsiniemi T, Timonen S, Linden M, et al. Intrahepatic cholestasis of pregnancy: observational study of the treatment with low-dose ursodeoxycholic acid［J］. BMC Gastroenterology, 2015, 15(1) : 1-7.
［41］Zhang Y, Lu L, Victor DW, et al. Ursodeoxycholic Acidand S-adenosylmethionine for the Treatment of IntrahepaticCholestasisof Pregnancy: A Meta-analysis［J］.Hepat Mon, 2016, 16(8):e38558.
［42］Xiang Z, Chen YP, Ma KF, et al. The role of Ursodeoxycholic acid in non-alcoholic steatohepatitis: a systematic review［J］. BMC Gastroenterology, 2013, 13(1) : 6125-6126.
［43］Orlando R., Azzalini L, Orando S, et al. Bile acids for non-alcoholic fatty liver disease and/or steatohepatitis［DB/OL］. Cochrane Database Syst Rev, 2007, 1(1) : CD005160.
［44］Leuschner UF, Lindenthal B, Herrmann G, et al. High-dose ursodeoxycholic acid therapy for nonalcoholic steatohepatitis: A double-blind, randomized, placebo-controlled trial［J］. Hepatology, 2010, 52(2): 472-479.
［45］Vlad Ratziu.Treatment of NASH with ursodeoxycholic acid: Pro［J］.Clin Res Hepatol Gastroenterol, 2012, 36 (1): S41-S45.
［46］Liechti F，Dufour JF.Treatment of NASH with ursodeoxycholic acid: cons［J］.Clin Res Hepatol Gastroenterol, 2012, 36(1): S46-S52.
［47］Pelletier G, Roulot D, Davion T, et al. A randomized controlled trial of ursodeoxycholic acid in patients with alcohol-induced cirrhosis and jaundice［J］.Hepatology, 2003, 37(4): 887-892.
［48］Jacquemin E. Progressive familial intrahepatic cholestasis［J］. Clin Res Hepatol Gastroenterol, 2012, 36 (1): S26-S35.
［49］Srivastava A. Progressive Familial Intrahepatic Cholestasis［J］.J Clin Exp Hepatol, 2014, 9(6) : 594-599.
［50］Devarbhavi H. An Update on Drug-induced Liver Injury［J］.J Clin Exp Hepatol, 2012, 2 (3): 247-259.
［51］Venneman NG, Besselink MG, Keulemans YC, et al. Ursodeoxycholic Acid Exerts No Beneficial Effect in Patients With Symptomatic Gallstones Awaiting Cholecystectomy［J］. Hepatology, 2006,43(6) : 1276-1283.
［52］Reichen J. Review: Ursodeoxycholic acid does not reduce risk for mortality or liver transplantation in primary cirrhosis［J］. ACP J Club, 2008, 148(1) : 17.
［53］Vang S, Longley K, Steer CJ, et al. The Unexpected Uses of Urso-and Tauroursodeoxycholic Acid in the Treatment of Non-liver Diseases［J］.Glob Adv Health Med, 2014, 3(3):58-69.
［54］Festi D, Montagnani M, Azzaroli F, et al. Clinical efficacy and effectiveness of ursodeoxycholic acid in cholestatic liver diseases［J］.Curr Clin Pharmacol, 2007, 2 (2) :155-177.
［55］Proctor WR, Ming X, Bourdet D, et al. Why Does the Intestine Lack Basolateral Efflux Transporters for Cationic Compounds? A Provocative Hypothesis［J］. J Pharm Sci, 2016 105(2) : 484-496.
［56］Sies H. Oxidative stress: Oxidants and antioxidants［J］. Exp Physiol, 1997, 82(2) : 291-295.
［57］Angulo P. Use of ursodeoxycholic acid in patients with liver disease［J］. Curr Gastroenterol Rep, 2002, 4(1) : 37-44.
［58］Gaus OV, Akhmedov VA.Dynamic of clinical, laboratory and sonographic parameters after successful litholitic therapy at patients with gallstone disease in association with metabolic syndrome［J］.Eksp Klin Gastroenterol, 2015, (7) :18-23.
［59］Fiorotto R, Spirlì C, Fabris L, et al. Ursodeoxycholic Acid Stimulates Cholangiocyte Fluid Secretion in Mice via CFTR-Dependent ATP Secretion［J］. Gastroenterology, 2007, 133(5) :1603-1613.
［60］Zollner G, Marschall HU, Wagner M, et al. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: Pathogenetic and therapeutic considerations［J］. Mol Pharm, 2006, 3(3) : 231-251.
［61］Fickert P, Pollheimer MJ, Silbert D, et al. Differential effects of norUDCA and UDCA in obstructive cholestasis in mice［J］. J Hepatol,2013, 58(6) : 1201-1208.
［62］Castro RE, Amaral JD, Sola S, et al. Differential regulation of cyclin D1 and cell death by bile acids in primary rat hepatocytes［J］. Am J Physiol Gastrointest Liver Physiol, 2007, 293(1): G327-G334.
［63］Amaral JD, Castro RE, Solá S, et al. p53 is a key molecular target of ursodeoxycholic acid in regulating apoptosis［J］. J Biol Chem, 2007, 282(47) :34250-34259.
［64］Rodrigues CM, Fan G, Wong PY, et al. Ursodeoxycholic acid may inhibit deoxycholic acid-induced apoptosis by modulating mitochondrial transmembrane potential and reactive oxygen species production［J］. Mol Med, 1998, 4(3) : 165-178.
［65］Utanohara S, Tsuji M, Momma S, et al. The effect of ursodeoxycholic acid on glycochenodeoxycholic acid-induced apoptosis in rat hepatocytes［J］.Toxicology, 2005, 214(2) :77-86.
［66］Fimognari C, Lenzi M, Cantelli-Forti G, et al. Apoptosis and modulation of cell cycle control by bile acids in human leukemia T cells［J］. Ann N Y Acad Sci, 2009, 1171(1) : 264-269.
［67］Hiramatsu K, Matsumoto Y, Miyazaki M, et al. Inhibition of hepatocyte growth factor production in human fibroblasts by ursodeoxycholic acid［J］. Biol Pharm Bull, 2005, 28(4) : 619-624.
［68］Tsagarakis NJ, Drygiannakis I, Batistakis AG, et al. A concentration-dependent effect of ursodeoxycholate on apoptosis and caspases activities of HepG2 hepatocellular carcinoma cells［J］. Eur J Pharmacol, 2010, 640(3) : 1-7.
［69］Schiedermaier P, Hansen S, Asdonk D, et al. Effects of ursodeoxycholic acid on splanchnic and systemic hemodynamics. A double-blind, cross-over, placebo-controlled study in healthy volunteers［J］. Digestion, 2000, 61(2) : 107-112.
［70］Hirano S, Masuda N, Oda H.In vitro transformation of chenodeoxycholic acid and ursodeoxycholic acid by human intestinal flora, with particular reference to the mutual conversion between the two bile acids［J］. J Lipid Res, 1981, 22(5) : 735-743.
［71］ Dubreuil M,Ruiz-Gaspà S, Guaabens N, et al. Ursodeoxycholic acid increases differentiation and mineralization and neutralizes the damaging effects of bilirubin on osteoblastic cells［J］. Liver Int, 2013, 33(7) : 1029-1038 .
［72］Kelly OB, Mroz MS, Ward JB, et al. Ursodeoxycholic acid attenuates colonic epithelial secretory function［J］.J Physiol, 2013, 591(9): 2307-2318.
［73］Solá S, Amaral JD, Aranha MM, et al. Modulation of hepatocyte apoptosis: Cross-talk between bile acids and nuclear steroid receptors［J］. Curr Med Chem, 2006, 13(25) : 3039-3051.
［74］Halilbasic E, Baghdasaryan A.Trauner M.Nuclear Receptors as Drug Targets in Cholestatic Liver Diseases［J］. Clin Liver Dis, 2013, 17(2) : 161-189.
［75］Huang J, Plass C, Gerhauser C. Cancer chemoprevention by targeting the epigenome［J］. Curr Drug Targets, 2011, 12(13):1925-1956.
［76］Oike T, Ogiwara H, Torikai K, et al. Garcinol, a histone acetyltransferase inhibitor, radiosensitizes cancer cells by inhibiting non-homologous end joining［J］. Int J Radiat Oncol Biol Phys, 2012, 84(3):815-821.
［77］Takigawa T, Miyazaki H, Kinoshita M, et al. Glucocorticoid receptor-dependent immunomodulatory effect of ursodeoxycholic acid on liver lymphocytes in mice［J］. Am J Physiol Gastrointest Liver Physiol, 2013, 305(6) : G427-G438.
［78］Rodrigues CM, Ma X, Linehan-Stieers C, et al. Ursodeoxycholic acid prevents cytochrome c release in apoptosis by inhibiting mitochondrial membrane depolarization and channel formation［J］. Cell Death Differ, 1999, 6(9) : 842-854.
［79］Rolo AP, Palmeira CM, Holy JM, et al. Role of mitochondrial dysfunction in combined bile acid-induced cytotoxicity: The switch between apoptosis and necrosis［J］. Toxicol Sci, 2004, 79(1) : 196-204.
［80］Abate N, Carubbi F, Bozzoli M, et al. Effect of chenodeoxycholic acid and ursodeoxycholic acid administration on acyl-CoA: Cholesterol acyltransferase activity in human liver［J］. Ital J Gastroenterol, 1994, 26(6) : 287-293.
［81］Weber P, Wagner M,Schneckenburger H. Fluorescence imaging of membrane dynamics in living cells［J］. J Biomed Opt, 2010, 15(15) : 046017.
［82］Sombetzki M, Fuchs CD, Fickert P, et al. 24-nor-ursodeoxycholic acid ameliorates inflammatory response and liver fibrosisin a murine model of hepatic schistosomiasis［J］.J Hepatol, 2015, 62(4): 871-878.
［83］He H, Mennone A, Boyer JL, et al. Combination of retinoic acid and ursodeoxycholic acid attenuates liver in jury in bile duct-ligated rats and human hepatic cells［J］.Hepatology, 2011, 53(2): 548-557.

[1]	马言, 田高鹏, 石兴文, 孙婷, 谢晶晶, 甄东户. 探讨T2DM人群中25（OH）D与代谢相关性脂肪肝的相关性[J]. 中国临床药理学与治疗学, 2023, 28(9): 1018-1026.
[2]	王安婧, 王亚亚, 梁轩, 闫雅婕, 苏静, 李彩东. 基于PPAR治疗胆汁淤积性肝病的机制与药物研究进展[J]. 中国临床药理学与治疗学, 2023, 28(7): 796-808.
[3]	汪东辉, 蒋素文, 胡爱荣, 朱波, 何哲耘, 张露侃, 王家岚, 范莹, 林恳. 桑葚改善大鼠非酒精性脂肪性肝病的氧化应激损伤[J]. 中国临床药理学与治疗学, 2023, 28(6): 609-616.
[4]	石明珠, 叶田香, 刘逸轩, 李会芳. 栀子苷代谢产物京尼平对HK-2细胞损伤及NLRP3通路的影响[J]. 中国临床药理学与治疗学, 2023, 28(5): 481-488.
[5]	李艳阳, 王云姣, 吕仕超. 中药注射液防治抗肿瘤药物心脏毒性的效应和机制[J]. 中国临床药理学与治疗学, 2023, 28(5): 572-577.
[6]	戚林玲, 刘寿荣. 丙酚替诺福韦在乙肝母婴阻断中的研究进展[J]. 中国临床药理学与治疗学, 2023, 28(5): 578-582.
[7]	马申, 刘玉硕, 唐辉, 陈文斌, 高聆. 改善非酒精性脂肪性肝病药物的药代动力学及其临床意义[J]. 中国临床药理学与治疗学, 2022, 27(8): 908-918.
[8]	王新丽, 许霞青, 方寒冰, 郭玉忠. 佛波酯增强顺铂的抗肿瘤活性及降低其肾毒性的作用研究[J]. 中国临床药理学与治疗学, 2022, 27(5): 535-543.
[9]	樊迪, 史翠娜, 杨青青, 纪木火. 七氟烷麻醉对发育期大脑影响的研究进展[J]. 中国临床药理学与治疗学, 2022, 27(12): 1333-1339.
[10]	姚依婷, 刘寒玉, 吴仔峰, 王娣, 杨春, 黄朝理. 麻醉药对发育期神经系统的毒性作用及机制研究进展[J]. 中国临床药理学与治疗学, 2022, 27(12): 1354-1364.
[11]	杨柳, 罗爱林, 李世勇. 全麻药物损伤发育期大脑的研究进展[J]. 中国临床药理学与治疗学, 2022, 27(12): 1381-1390.
[12]	刘文静, 武之涛, 潘国宇. 肝毒性风险的体外早期发现和预测[J]. 中国临床药理学与治疗学, 2021, 26(8): 923-930.
[13]	宋如铮, 彭英, 王广基, 孙建国. 定量蛋白质组学常用研究技术及其在肝源性疾病发病机制中的应用进展[J]. 中国临床药理学与治疗学, 2021, 26(5): 570-578.
[14]	丁雪明, 陈天鹏, 徐强, 何欢, 何明. 川芎嗪通过14-3-3γ/Bcl-2减轻阿霉素引起的心肌毒性[J]. 中国临床药理学与治疗学, 2021, 26(4): 361-367.
[15]	赵芳卿, 杨雯雯, 殷玉杰, 张斌, 王邦才, 窦晓兵, 李松涛, 朱林文思. 丹酚酸A激活AMPK及SIRT1减轻棕榈酸诱导的肝细胞脂毒性[J]. 中国临床药理学与治疗学, 2021, 26(3): 241-249.