胆盐输出泵基因突变在特发性婴儿肝炎肝内胆汁淤积中的意义
|
摘要
目的：对特发性婴儿肝炎肝内胆汁淤积患儿的BSEP基因进行筛查,初步探讨胆盐输出泵基因与特发性婴儿肝炎肝内胆汁淤积的关系。
方法：收集2009年10月至2011年02月于广西医科大学第一附属医院儿科住院的特发性婴儿肝炎肝内胆汁淤积的患儿115例作为病例组,60例无胆汁淤积婴儿作为对照组,应用聚合酶链反应-单链构象多态性分析(PCR-SSCP)方法对BSEP基因上的7、8、11、12、14、15、18、21、26外显子进行检测。对有异常条带的外显子进行测序,结果在Genbank基因库上进行序列比较。
结果：在2例患儿BSEP基因的第7外显子上检测到相同未报道的杂合突变c.499G>T,导致基因编码的BSEP蛋白的第167位丙氨酸(Ala)被丝氨酸(Ser)所替代(p.A167S)。该位点的突变未在其余病人与对照组中检测出。
结论：本研究在特发性婴儿肝炎胆汁淤积患儿的BSEP基因第7外显子上发现一个新的错义突变A167S。A167S可能在婴儿特发性肝炎肝内胆汁淤积的发生机制中发挥一定的作用,并可能对突变相关类型的肝内胆汁淤积的预后有一定的指导意义。
Objective:To screen the BSEP gene in intrahepatic cholestasis of idiopathic infantile hepatitis patients. And investigate the relationship between intrahepatic cholestasis of idiopathic infantile hepatitis and bile salt export pump gene.
Methods:A total of115cases of idiopathic infantile hepatitis with intrahepatic cholestasis in case group and60idiopathic infantile hepatitis persons who had no intrahepatic cholestasis in the control group were collected in paediatrics department of the First Affiliated Hospital of Guangxi Medical University from Oct.2009to Feb.2011. The exons of BSEP gene7,8,11,12,14,15,18,21were screening by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), The PCR products which had abnormal bands in SSCP were sequenced by DNA sequencer. The sequenced results were comared with the normal gen in the Genbank database.
Results:Two new cases of heterozygous mutation c.499G>T were detected in the exon7of BSEP gene. This mutation caused genetic code of BSEP protein167th alanine (Ala) be serine (Ser) replacement (p.A167S). There were not mutation found in the other patients and the control group.
Conclusions:A167S is a heterozygous nonsense mutation in exon7of BSEP. Which show that A167S maybe play an important role in cholestasis in idiopathic infantile hepatitis and it will give some useful information for the prognosis of cholestasis in the future.
方法：收集2009年10月至2011年02月于广西医科大学第一附属医院儿科住院的特发性婴儿肝炎肝内胆汁淤积的患儿115例作为病例组,60例无胆汁淤积婴儿作为对照组,应用聚合酶链反应-单链构象多态性分析(PCR-SSCP)方法对BSEP基因上的7、8、11、12、14、15、18、21、26外显子进行检测。对有异常条带的外显子进行测序,结果在Genbank基因库上进行序列比较。
结果：在2例患儿BSEP基因的第7外显子上检测到相同未报道的杂合突变c.499G>T,导致基因编码的BSEP蛋白的第167位丙氨酸(Ala)被丝氨酸(Ser)所替代(p.A167S)。该位点的突变未在其余病人与对照组中检测出。
结论：本研究在特发性婴儿肝炎胆汁淤积患儿的BSEP基因第7外显子上发现一个新的错义突变A167S。A167S可能在婴儿特发性肝炎肝内胆汁淤积的发生机制中发挥一定的作用,并可能对突变相关类型的肝内胆汁淤积的预后有一定的指导意义。
Objective:To screen the BSEP gene in intrahepatic cholestasis of idiopathic infantile hepatitis patients. And investigate the relationship between intrahepatic cholestasis of idiopathic infantile hepatitis and bile salt export pump gene.
Methods:A total of115cases of idiopathic infantile hepatitis with intrahepatic cholestasis in case group and60idiopathic infantile hepatitis persons who had no intrahepatic cholestasis in the control group were collected in paediatrics department of the First Affiliated Hospital of Guangxi Medical University from Oct.2009to Feb.2011. The exons of BSEP gene7,8,11,12,14,15,18,21were screening by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP), The PCR products which had abnormal bands in SSCP were sequenced by DNA sequencer. The sequenced results were comared with the normal gen in the Genbank database.
Results:Two new cases of heterozygous mutation c.499G>T were detected in the exon7of BSEP gene. This mutation caused genetic code of BSEP protein167th alanine (Ala) be serine (Ser) replacement (p.A167S). There were not mutation found in the other patients and the control group.
Conclusions:A167S is a heterozygous nonsense mutation in exon7of BSEP. Which show that A167S maybe play an important role in cholestasis in idiopathic infantile hepatitis and it will give some useful information for the prognosis of cholestasis in the future.
引文
[1]. Benchimol EI, Walsh CM, Ling SC. Early diagnosis of neonatal cholestatic jaundice:test at 2 weeks[J]. Can Fam Physician,2009, 55(12):1184-1192.
[2]. Noe J, Stieger B, PJ Meier. Functional expression of the canalicular bile salt export pump of human liver[J]. Gastroenterology,2002, 123(5):1659-1666.
[3]. Stieger B. Role of the bile salt export pump, BSEP, in acquired forms of cholestasis[J]. Drug Metab Rev,2010,42(3):437-445.
[4]. Bull LN, van Eijk MJ,Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis[J]. Nat Genet,1998,18(3):219-224.
[5]. Strautnieks SS, Bull LN, Knisely AS, et al. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis[J]. Nat Genet,1998,20(3):233-238.
[6]. Pauli-Magnus, Lang CT, Meier Y, et al. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy [J]. Pharmacogenetics,2004,14(2): 91-102.
[7]. Zollner GP, Fickert, Silbert D, et al. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis[J]. J Hepatol,2003,38(6):717-727.
[8]. Zollner GP, Fickert, Fuchsbichler A, et al. Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver, kidney and intestine[J]. J Hepatol,2003,39(4):480-488.
[9]. 曹云海,陈熙,张程,等.利福平对小鼠肝细胞胆汁酸转运体Bsep和Mrp2表达与定位的影响[J].中国药理学通报,2010,26(12)：1581-1586.
[10]. Plass JR, Mol O, Heegsma J, et al. Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump[J]. Hepatology,2002,35(3): 589-596.
[11]. Maggiore GE, Gonzales, Sciveres M, et al. Relapsing features of bile salt export pump deficiency after liver transplantation in two patients with progressive familial intrahepatic cholestasis type 2[J]. Journal of hepatology,2010,53(5):981-986.
[12]. Ben-Ari, Pappo ZO, Mor E. Intrahepatic cholestasis after liver transplantation [J]. Liver transplantation,2003,9(10):1005-1018.
[13]. Kamath BM, Schwarz KB, Hadzic N. Alagille syndrome and liver transplantation [J]. Journal of pediatric gastroenterology and nutrition,2010,50(1):11.
[14]. 刘丽艳.ABCB11和ATP8B1基因突变在低GGT进行性肝内胆汁淤积症中的意义[学位论文]上海,复旦大学,2007.
[15]. Takahashi AM, Hasegawa R, Sumazaki, et al. Gradual improvement of liver function after administration of ursodeoxycholic acid in an infant with a novel ABCB11 gene mutation with phenotypic continuum between BRIC2 and PFIC2[J]. Eur J Gastroenterol Hepatol,2007,19(11):942-946.
[16]. SS Strautnieks, Kagalwalla AF, Tanner MS, et al. Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24[J]. Am J Hum Genet,1997.61(3):630-633.
[17]. Stieger B, Meier Y, Meier PJ. The bile salt export pump[J]. Pflugers Arch,2007,453(5).611-620.
[18]. Stieger B, Beuers U. The canalicular bile salt export pump BSEP (ABCB11) as a potential therapeutic target[J]. Curr Drug Targets, 2011,12(5).661-670.
[19]. Thompson R, Strautnieks S. BSEP:function and role in progressive familial intrahepatic cholestasis[J]. Semin Liver Dis, 2001,21(4):545-550.
[20]. Lang TM, Haberl, Jung D, et al., Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11)[J]. Drug metabolism and disposition,2006,34(9):1582-1599.
[21]. Chen HL, Liu YJ, Su YN, et al. Diagnosis of BSEP/ABCB11 mutations in Asian patients with cholestasis using denaturing high performance liquid chromatography[J]. J Pediatr,2008, 153(6):825-832.
[22].王中林.婴儿进行性肝内胆汁淤积症及BSEP基因突变研究[学位论文]上海,复旦大学,2007.
[23].邓亚楠,王琳琳,唐清,等.胆盐输出泵基因V444A与特发性婴儿肝炎肝内胆汁淤积的关系[J].世界华人消化杂志,2011,19(1)：38-43.
[24]. Byrne JA, Strautnieks SS, Ihrke G, et al. Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNAsplicing[J]. Hepatology,2009,49(2):553-567.
[25]. Jansen PL, Strautnieks SS, Jacquemin E, et al. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis [J]. Gastroenterology,1999.117(6): 1370-1379.
[26]. Perez LM, Milkiewicz P, Elias E, et al. Oxidative stress induces internalization of the bile salt export pump, Bsep, and bile salt secretory failure in isolated rat hepatocyte couplets:a role for protein kinase C and prevention by protein kinase A[J]. Toxicol Sci, 2006,91(1):150-158.
[27]. Chen XQ, Wang LL, Shan QW, et al. Multidrug resistance protein 3 R652G may reduce susceptibility to idiopathic infant cholestasis[J]. World J Gastroenterol,2009,15(46):5855-5858.
[28]. Kovacs P, Kress R, Rocha J, et al. Variation of the gene encoding the nuclear bile salt receptor FXR and gallstone susceptibility in mice and humans[J]. J Hepatol,2008.48(1):116-124.
[1]. Langmann, TR. Mauerer, Zahn A, et al. Real-time reverse transcription-PCR expression profiling of the complete human ATP-binding cassette transporter superfamily in various tissues[J]. Clinical chemistry,2003.49(2):230.
[2]. Childs S, RL Yeh, Hui D, et al. Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein[J]. Cancer research,1998.58(18):4160.
[3]. 王吉耀,涂传涛.重视胆汁淤积的分子机制和药物治疗研究[J].《胃肠病学》,2005,10(4)：195-197.
[4]. Lam P, Soroka CJ, Boyer JL. The bile salt export pump:clinical and experimental aspects of genetic and acquired cholestatic liver disease[J]. Semin Liver Dis,2010,30(2):125-133.
[5]. Davit-Spraul, Fabre AM, Branchereau S, et al. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history[J], Hepatology,2010,51(5):1645-155.
[6]. Sugiyama Y, Hayashi H. Regulation of the cell surface expression and transport capacity of BSEP by small chemical molecules[J]. Bile Acid Biology and Therapeutic Actions,2008,45:32.
[7]. Strautnieks SS, Byrne JA, Pawlikowska L, et al. Severe bile salt export pump deficiency:82 different ABCB11 mutations in 109 families[J]. Gastroenterology,2008,134(4):1203-1214.
[8]. Hayashi H, Sugiyama Y. phenylbutyrate enhances the cell surface expression and the transport capacity of wild type and mutated bile salt export pumps[J]. Hepatology,2007,45(6):1506-1516.
[9]. Strautnieks SS, JA Byrne, Pawlikowska L, et al. Severe bile salt export pump deficiency:82 different ABCB11 mutations in 109 families[J]. Gastroenterology,2008,134(4):1203-1214.
[10]. Kim SR, Saito Y, Itoda, et al. Genetic variations of the ABC transporter gene ABCB11 encoding the human bile salt export pump (BSEP) in a Japanese population[J]. Drug Metab Pharmacokinet,2009,24(3):277-81.
[11]. Chen HL, Liu YJ, Su YN, et al. Diagnosis of BSEP/ABCB11 mutations in Asian patients with cholestasis using denaturing high performance liquid chromatography[J]. The Journal of pediatrics, 2008,153(6):825-832
[12]. Oude Elferink R, van Berge Henegouwen GP. Cracking the genetic code for benign recurrent and progressive familial intrahepatic cholestasis[J]. Journal of hepatology,1998,29(2):317.
[13]. Summerskill W, Walshe J. Benign recurrent intrahepatic obstructive jaundice[J]. Lancet,1959,2(7105):686.
[14]. Mil van, SWC WL, van der Woerd G, et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11[J]. Gastroenterology,2004,127(2):379-384.
[15]. Takahashi A, Hasegawa M, Sumazaki R, et al. Gradual improvement of liver function after administration of ursodeoxycholic acid in an infant with a novel ABCB11 gene mutation with phenotypic continuum between BRIC2 and PFIC2[J]. Eur J Gastroenterol Hepatol,2007,19(11):942-946.
[16]. Dixon P, Williamson C. The molecular genetics of intrahepatic cholestasis of pregnancy [J]. Obstetric Medicine,2008,1(2):65.
[17]. Oude Elferink RP, Paulusma CC. Function and pathohysiol ogical importance of ABCB4 (MDR3 P-glycoprotein)[J]. Pflugers Arch,2007,453(5):601-610.
[18]. Pauli-Magnus C, Meier PJ, Stieger B, Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy[J]. Semin Liver Dis,2010,30(2):145-157.
[19]. Eloranta ML, Hakli T, Hiltunen M, et al. Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy [J]. Scandinavian journal of gastroenterology,2003,38(6):648-652.
[20]. Meier Y, Zodan T, Lang C, et al. Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T> C polymorphism in the bile salt export pump[J]. World Journal of Gastroenterology:WJG, 2008,14(1):38.
[21]. Dixon PH, van Mil S, Chambers J, et al. Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy [J]. Gut,2009,58(4):537.
[22]. Pauli-Magnus C, Lang T, Meier Y, et al. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy[J]. Pharmacogenetics and Genomics, 2004,14(2):91.
[23].刘玉凌.胆汁淤积基因在妊娠期肝内胆汁淤积症发病机制和在异常胎盘胆汁酸排泌机制中作用的研究, [学位论文],武汉,华中科技大学,2006.
[24]. Pauli-Magnus C, Stieger B, Meier Y, et al. Enterohepatic transport of bile salts and genetics of cholestasis [J]. J Hepatol,2005,43(2): 342-357.
[25].曹云海.利福平对小鼠肝细胞胆汁酸转运体Bsep和Mrp2表达与定位的影响[J].中国药理学通报,2010,26(12)：1581-1586.
[26]. Lang C, Meier Y, Stieger B, et al. Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury[J]. Pharmacogenetics and Genomics,2007,17(1):47.
[27]. Nguyen DL, Juran BD, Lazaridis KN. Primary biliary cirrhosis[J]. Best Pract Res Clin Gastroenterol,2010,24(5):647-654.
[28]. Takeyama Y, Kanegae K, Inomata S, et al. Sustained upregulation of sodium taurocholate cotransporting polypeptide and bile salt export pump and downregulation of cholesterol 7alpha-hydroxylase in the liver of patients with end-stage primary biliary cirrhosis[J]. Med Mol Morphol,2010,43(3):134-138.
[29]. Pauli-Magnus C, Kerb R, Fattinger K, et al. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis[J]. Hepatology,2004,39(3): 779-791.
[30]. Ardesj B, Portela Gomes GM, Rorsman F, et al. Identification of a novel staining pattern of bile duct epithelial cells in primary sclerosing cholangitis[J]. Inflammatory bowel diseases,2010, 16(2):305-311.
[31]. Zen Y, Quaglia A, Portmann B. Immunoglobulin G4-positive plasma cell infiltration in explanted livers for primary sclerosing cholangitis[J]. Histopathology,2011,58(3):414-422.
[2]. Noe J, Stieger B, PJ Meier. Functional expression of the canalicular bile salt export pump of human liver[J]. Gastroenterology,2002, 123(5):1659-1666.
[3]. Stieger B. Role of the bile salt export pump, BSEP, in acquired forms of cholestasis[J]. Drug Metab Rev,2010,42(3):437-445.
[4]. Bull LN, van Eijk MJ,Pawlikowska L, et al. A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis[J]. Nat Genet,1998,18(3):219-224.
[5]. Strautnieks SS, Bull LN, Knisely AS, et al. A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis[J]. Nat Genet,1998,20(3):233-238.
[6]. Pauli-Magnus, Lang CT, Meier Y, et al. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy [J]. Pharmacogenetics,2004,14(2): 91-102.
[7]. Zollner GP, Fickert, Silbert D, et al. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis[J]. J Hepatol,2003,38(6):717-727.
[8]. Zollner GP, Fickert, Fuchsbichler A, et al. Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver, kidney and intestine[J]. J Hepatol,2003,39(4):480-488.
[9]. 曹云海,陈熙,张程,等.利福平对小鼠肝细胞胆汁酸转运体Bsep和Mrp2表达与定位的影响[J].中国药理学通报,2010,26(12)：1581-1586.
[10]. Plass JR, Mol O, Heegsma J, et al. Farnesoid X receptor and bile salts are involved in transcriptional regulation of the gene encoding the human bile salt export pump[J]. Hepatology,2002,35(3): 589-596.
[11]. Maggiore GE, Gonzales, Sciveres M, et al. Relapsing features of bile salt export pump deficiency after liver transplantation in two patients with progressive familial intrahepatic cholestasis type 2[J]. Journal of hepatology,2010,53(5):981-986.
[12]. Ben-Ari, Pappo ZO, Mor E. Intrahepatic cholestasis after liver transplantation [J]. Liver transplantation,2003,9(10):1005-1018.
[13]. Kamath BM, Schwarz KB, Hadzic N. Alagille syndrome and liver transplantation [J]. Journal of pediatric gastroenterology and nutrition,2010,50(1):11.
[14]. 刘丽艳.ABCB11和ATP8B1基因突变在低GGT进行性肝内胆汁淤积症中的意义[学位论文]上海,复旦大学,2007.
[15]. Takahashi AM, Hasegawa R, Sumazaki, et al. Gradual improvement of liver function after administration of ursodeoxycholic acid in an infant with a novel ABCB11 gene mutation with phenotypic continuum between BRIC2 and PFIC2[J]. Eur J Gastroenterol Hepatol,2007,19(11):942-946.
[16]. SS Strautnieks, Kagalwalla AF, Tanner MS, et al. Identification of a locus for progressive familial intrahepatic cholestasis PFIC2 on chromosome 2q24[J]. Am J Hum Genet,1997.61(3):630-633.
[17]. Stieger B, Meier Y, Meier PJ. The bile salt export pump[J]. Pflugers Arch,2007,453(5).611-620.
[18]. Stieger B, Beuers U. The canalicular bile salt export pump BSEP (ABCB11) as a potential therapeutic target[J]. Curr Drug Targets, 2011,12(5).661-670.
[19]. Thompson R, Strautnieks S. BSEP:function and role in progressive familial intrahepatic cholestasis[J]. Semin Liver Dis, 2001,21(4):545-550.
[20]. Lang TM, Haberl, Jung D, et al., Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11)[J]. Drug metabolism and disposition,2006,34(9):1582-1599.
[21]. Chen HL, Liu YJ, Su YN, et al. Diagnosis of BSEP/ABCB11 mutations in Asian patients with cholestasis using denaturing high performance liquid chromatography[J]. J Pediatr,2008, 153(6):825-832.
[22].王中林.婴儿进行性肝内胆汁淤积症及BSEP基因突变研究[学位论文]上海,复旦大学,2007.
[23].邓亚楠,王琳琳,唐清,等.胆盐输出泵基因V444A与特发性婴儿肝炎肝内胆汁淤积的关系[J].世界华人消化杂志,2011,19(1)：38-43.
[24]. Byrne JA, Strautnieks SS, Ihrke G, et al. Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNAsplicing[J]. Hepatology,2009,49(2):553-567.
[25]. Jansen PL, Strautnieks SS, Jacquemin E, et al. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis [J]. Gastroenterology,1999.117(6): 1370-1379.
[26]. Perez LM, Milkiewicz P, Elias E, et al. Oxidative stress induces internalization of the bile salt export pump, Bsep, and bile salt secretory failure in isolated rat hepatocyte couplets:a role for protein kinase C and prevention by protein kinase A[J]. Toxicol Sci, 2006,91(1):150-158.
[27]. Chen XQ, Wang LL, Shan QW, et al. Multidrug resistance protein 3 R652G may reduce susceptibility to idiopathic infant cholestasis[J]. World J Gastroenterol,2009,15(46):5855-5858.
[28]. Kovacs P, Kress R, Rocha J, et al. Variation of the gene encoding the nuclear bile salt receptor FXR and gallstone susceptibility in mice and humans[J]. J Hepatol,2008.48(1):116-124.
[1]. Langmann, TR. Mauerer, Zahn A, et al. Real-time reverse transcription-PCR expression profiling of the complete human ATP-binding cassette transporter superfamily in various tissues[J]. Clinical chemistry,2003.49(2):230.
[2]. Childs S, RL Yeh, Hui D, et al. Taxol resistance mediated by transfection of the liver-specific sister gene of P-glycoprotein[J]. Cancer research,1998.58(18):4160.
[3]. 王吉耀,涂传涛.重视胆汁淤积的分子机制和药物治疗研究[J].《胃肠病学》,2005,10(4)：195-197.
[4]. Lam P, Soroka CJ, Boyer JL. The bile salt export pump:clinical and experimental aspects of genetic and acquired cholestatic liver disease[J]. Semin Liver Dis,2010,30(2):125-133.
[5]. Davit-Spraul, Fabre AM, Branchereau S, et al. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history[J], Hepatology,2010,51(5):1645-155.
[6]. Sugiyama Y, Hayashi H. Regulation of the cell surface expression and transport capacity of BSEP by small chemical molecules[J]. Bile Acid Biology and Therapeutic Actions,2008,45:32.
[7]. Strautnieks SS, Byrne JA, Pawlikowska L, et al. Severe bile salt export pump deficiency:82 different ABCB11 mutations in 109 families[J]. Gastroenterology,2008,134(4):1203-1214.
[8]. Hayashi H, Sugiyama Y. phenylbutyrate enhances the cell surface expression and the transport capacity of wild type and mutated bile salt export pumps[J]. Hepatology,2007,45(6):1506-1516.
[9]. Strautnieks SS, JA Byrne, Pawlikowska L, et al. Severe bile salt export pump deficiency:82 different ABCB11 mutations in 109 families[J]. Gastroenterology,2008,134(4):1203-1214.
[10]. Kim SR, Saito Y, Itoda, et al. Genetic variations of the ABC transporter gene ABCB11 encoding the human bile salt export pump (BSEP) in a Japanese population[J]. Drug Metab Pharmacokinet,2009,24(3):277-81.
[11]. Chen HL, Liu YJ, Su YN, et al. Diagnosis of BSEP/ABCB11 mutations in Asian patients with cholestasis using denaturing high performance liquid chromatography[J]. The Journal of pediatrics, 2008,153(6):825-832
[12]. Oude Elferink R, van Berge Henegouwen GP. Cracking the genetic code for benign recurrent and progressive familial intrahepatic cholestasis[J]. Journal of hepatology,1998,29(2):317.
[13]. Summerskill W, Walshe J. Benign recurrent intrahepatic obstructive jaundice[J]. Lancet,1959,2(7105):686.
[14]. Mil van, SWC WL, van der Woerd G, et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11[J]. Gastroenterology,2004,127(2):379-384.
[15]. Takahashi A, Hasegawa M, Sumazaki R, et al. Gradual improvement of liver function after administration of ursodeoxycholic acid in an infant with a novel ABCB11 gene mutation with phenotypic continuum between BRIC2 and PFIC2[J]. Eur J Gastroenterol Hepatol,2007,19(11):942-946.
[16]. Dixon P, Williamson C. The molecular genetics of intrahepatic cholestasis of pregnancy [J]. Obstetric Medicine,2008,1(2):65.
[17]. Oude Elferink RP, Paulusma CC. Function and pathohysiol ogical importance of ABCB4 (MDR3 P-glycoprotein)[J]. Pflugers Arch,2007,453(5):601-610.
[18]. Pauli-Magnus C, Meier PJ, Stieger B, Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy[J]. Semin Liver Dis,2010,30(2):145-157.
[19]. Eloranta ML, Hakli T, Hiltunen M, et al. Association of single nucleotide polymorphisms of the bile salt export pump gene with intrahepatic cholestasis of pregnancy [J]. Scandinavian journal of gastroenterology,2003,38(6):648-652.
[20]. Meier Y, Zodan T, Lang C, et al. Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T> C polymorphism in the bile salt export pump[J]. World Journal of Gastroenterology:WJG, 2008,14(1):38.
[21]. Dixon PH, van Mil S, Chambers J, et al. Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy [J]. Gut,2009,58(4):537.
[22]. Pauli-Magnus C, Lang T, Meier Y, et al. Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy[J]. Pharmacogenetics and Genomics, 2004,14(2):91.
[23].刘玉凌.胆汁淤积基因在妊娠期肝内胆汁淤积症发病机制和在异常胎盘胆汁酸排泌机制中作用的研究, [学位论文],武汉,华中科技大学,2006.
[24]. Pauli-Magnus C, Stieger B, Meier Y, et al. Enterohepatic transport of bile salts and genetics of cholestasis [J]. J Hepatol,2005,43(2): 342-357.
[25].曹云海.利福平对小鼠肝细胞胆汁酸转运体Bsep和Mrp2表达与定位的影响[J].中国药理学通报,2010,26(12)：1581-1586.
[26]. Lang C, Meier Y, Stieger B, et al. Mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug-induced liver injury[J]. Pharmacogenetics and Genomics,2007,17(1):47.
[27]. Nguyen DL, Juran BD, Lazaridis KN. Primary biliary cirrhosis[J]. Best Pract Res Clin Gastroenterol,2010,24(5):647-654.
[28]. Takeyama Y, Kanegae K, Inomata S, et al. Sustained upregulation of sodium taurocholate cotransporting polypeptide and bile salt export pump and downregulation of cholesterol 7alpha-hydroxylase in the liver of patients with end-stage primary biliary cirrhosis[J]. Med Mol Morphol,2010,43(3):134-138.
[29]. Pauli-Magnus C, Kerb R, Fattinger K, et al. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis[J]. Hepatology,2004,39(3): 779-791.
[30]. Ardesj B, Portela Gomes GM, Rorsman F, et al. Identification of a novel staining pattern of bile duct epithelial cells in primary sclerosing cholangitis[J]. Inflammatory bowel diseases,2010, 16(2):305-311.
[31]. Zen Y, Quaglia A, Portmann B. Immunoglobulin G4-positive plasma cell infiltration in explanted livers for primary sclerosing cholangitis[J]. Histopathology,2011,58(3):414-422.