MDR3 (ABCB4) defects: A paradigm for the genetics of adult cholestatic syndromes

Seminars in Liver Disease

Volumn 27, Issue 1, 2007, Pages 77-98

  Trauner, Michael ^a   Fickert, Peter ^a   Wagner, Martin ^a  

^a MEDICAL UNIVERSITY OF GRAZ   (Austria)

Author keywords

ABC transporters; Bile acids; Cholangitis; Phospholipids; Vanishing bile duct syndrome

Indexed keywords

3 [2 [2 CHLORO 4 [3 (2,6 DICHLOROPHENYL) 5 ISOPROPYL 4 ISOXAZOLYLMETHOXY]PHENYL]VINYL]BENZOIC ACID; ABC TRANSPORTER; AMOXICILLIN PLUS CLAVULANIC ACID; BILE ACID; BOSENTAN; CYCLOSPORIN; FIBRIC ACID DERIVATIVE; FUSIDIC ACID; GLIBENCLAMIDE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; MULTIDRUG RESISTANCE PROTEIN 3; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA AGONIST; PHOSPHATIDYLCHOLINE; PHOSPHOLIPID; RAPAMYCIN; RIFAMPICIN; RISPERIDONE; TROGLITAZONE; URSODEOXYCHOLIC ACID; VERAPAMIL; VINBLASTINE;

ADULT; BILE DUCT INJURY; BILIARY EXCRETION; CHOLESTATIC HEPATITIS; DIAGNOSTIC APPROACH ROUTE; GENE MUTATION; GENETIC PREDISPOSITION; GENETICS; GENOTYPE PHENOTYPE CORRELATION; HUMAN; HYPERBILIRUBINEMIA; INTRAHEPATIC CHOLESTASIS; JAUNDICE; LIVER INJURY; NONHUMAN; PATHOGENESIS; PRIMARY SCLEROSING CHOLANGITIS; PRIORITY JOURNAL; PROGNOSIS; PROTEIN EXPRESSION; REVIEW; TOTAL PARENTERAL NUTRITION; VANISHING BILE DUCT SYNDROME;

ADULT; ANIMALS; ATP-BINDING CASSETTE TRANSPORTERS; BILE; BIOLOGICAL TRANSPORT; CHOLESTASIS; GENE THERAPY; HUMANS; LIVER; LIVER TRANSPLANTATION; MUTATION; P-GLYCOPROTEINS; PROGNOSIS; SEPSIS;

EID: 33847064667     PISSN: 02728087     EISSN: None     Source Type: Journal    
DOI: 10.1055/s-2006-960172     Document Type: Review

References (182)

1. Jansen PL, Muller M. The molecular genetics of familial intrahepatic cholestasis. Gut 2000;47:1-5
2. Thompson R, Jansen PL. Genetic defects in hepatocanalicular transport. Semin Liver Dis 2000;20:365-372
3. Jacquemin E. Progressive familial intrahepatic cholestasis: genetic basis and treatment. Clin Liver Dis 2000;4:753-763
4. Jansen PL, Muller M, Sturm E. Genes and cholestasis. Hepatology 2001;34:1067-1074
5. Elferink RO, Groen AK. Genetic defects in hepatobiliary transport. Biochim Biophys Acta 2002;1586:129-145
6. Jansen PL, Sturm E. Genetic cholestasis, causes and consequences for hepatobiliary transport. Liver Int 2003; 23:315-322
7. Oude Elferink RP, Paulusma CC, Groen AK. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases. Gastroenterology 2006;130: 908-925
8. Pauli-Magnus C, Meier PJ. Hepatocellular transporters and cholestasis. J Clin Gastroenterol 2005;39:S103-S110
9. Pauli-Magnus C, Stieger B, Meier Y, et al. Enterohepatic transport of bile salts and genetics of cholestasis. J Hepatol 2005;43:342-357
10. Saito S, Iida A, Sekine A, et al. Three hundred twenty-six genetic variations in genes encoding nine members of ATP-binding cassette, subfamily B (ABCB/MDR/TAP), in the Japanese population. J Hum Genet 2002;47:38-50
11. Meier Y, Pauli-Magnus C, Zanger UM, et al. Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver. Hepatology 2006;44:62-74
12. Lang T, Haberl M, Jung D, et al. Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11). Drug Metab Dispos 2006;34:1582-1599
13. Oude Elferink RP, Groen AK. Mechanisms of biliary lipid secretion and their role in lipid homeostasis. Semin Liver Dis 2000;20:293-305
14. Fickert P, Fuchsbichler A, Wagner M, et al. Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2004;127:261-274
15. Paulusma CC, Oude Elferink RP. Diseases of intramembranous lipid transport. FEBS Lett 2006;580:5500-5509
16. Oude Elferink RP, Paulusma CC. Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein). Pflugers Arch 2006; April 19 (Epub ahead of print)
17. Trauner M, Boyer JL. Bile salt transporters: molecular characterization, function, and regulation. Physiol Rev 2003;83:633-671
18. Smit JJ, Schinkel AH, Oude Elferink RP, et al. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 1993;75:451-462
19. Ruetz S, Gros P. Phosphatidylcholine translocase: a physiological role for the mdr2 gene. Cell 1994;77:1071-1081
20. Smith AJ, Timmermans-Hereijgers JL, Roelofsen B, et al. The human MDR3 P-glycoprotein promotes translocation of phosphatidylcholine through the plasma membrane of fibroblasts from transgenic mice. FEBS Lett 1994;354:263-266
21. Fuchs M, Carey MC, Cohen DE. Evidence for an ATP-independent long-chain phosphatidylcholine translocator in hepatocyte membranes. Am J Physiol 1997;273:G1312-G1319
22. Strazzabosco M, Fabris L, Spirli C. Pathophysiology of cholangiopathies. J Clin Gastroenterol 2005;39:S90-S102
23. 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. Mol Pharm 2006;3:231-251
24. Wagner M, Trauner M. Transcriptional regulation of hepatobiliary transport systems in health and disease: implications for a rationale approach to the treatment of intrahepatic cholestasis. Ann Hepatol 2005;4:77-99
25. Geier A, Wagner M, Dietrich CG, et al. Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. BBA - MCR 2006. In press
26. Karpen SJ. Nuclear receptor regulation of hepatic function. J Hepatol 2002;36:832-850
27. Boyer JL. Nuclear receptor ligands: rational and effective therapy for chronic cholestatic liver disease? Gastroenterology 2005;129:735-740
28. Kok T, Wolters H, Bloks VW, et al. Induction of hepatic ABC transporter expression is part of the PPARalpha-mediated fasting response in the mouse. Gastroenterology 2003;124:160-171
29. Huang L, Zhao A, Lew JL, et al. Farnesoid X receptor activates transcription of the phospholipid pump MDR3. J Biol Chem 2003;278:51085-51090
30. Bhushan A, Slapak CA, Levy SB, et al. Expression of c-fos precedes MDR3 in vincristine and adriamycin selected multidrug resistant murine erythroleukemia cells. Biochem Biophys Res Commun 1996;226:819-821
31. Trauner M, Meier PJ, Boyer JL. Molecular pathogenesis of cholestasis. N Engl J Med 1998;339:1217-1227
32. Trauner M, Wagner M, Fickert P, et al. Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis. J Clin Gastroenterol 2005;39:S111-S124
33. van Mil SW, Klomp LW, Bull LN, et al. FIC1 disease: a spectrum of intrahepatic cholestatic disorders. Semin Liver Dis 2001;21:535-544
34. Paulusma CC, Oude Elferink RP. The type 4 subfamily of P-type ATPases, putative aminophospholipid translocases with a role in human disease. Biochim Biophys Acta 2005; 1741:11-24
35. Thompson R, Strautnieks S. BSEP: function and role in progressive familial intrahepatic cholestasis. Semin Liver Dis 2001;21:545-550
36. van Mil SW, van der Woerd WL, van der Brugge G, et al. Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11. Gastroenterology 2004;127:379-384
37. Noe J, Kullak-Ublick GA, Jochum W, et al. Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis. J Hepatol 2005;43:536-543
38. Jacquemin E. Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. Semin Liver Dis 2001;21:551-562
39. Jacquemin E, de Vree JM, Cresteil D, et al. The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 2001; 120:1448-1458
40. Chen HL, Chang PS, Hsu HC, et al. Progressive familial intrahepatic cholestasis with high gamma-glutamyltrans-peptidase levels in Taiwanese infants: role of MDR3 gene defect? Pediatr Res 2001;50:50-55
41. Feranchak AP, Sokol RJ. Cholangiocyte biology and cystic fibrosis liver disease. Semin Liver Dis 2001;21:471-488
42. Fickert P, Zollner G, Fuchsbichler A, et al. Ursodeoxycholic acid aggravates bile infarcts in bile duct-ligated and Mdr2 knockout mice via disruption of cholangioles. Gastroenterology 2002;123:1238-1251
43. Lammert F, Wang DQ, Hillebrandt S, et al. Spontaneous cholecysto- and hepatolithiasis in Mdr2 -/- mice: a model for low phospholipid-associated cholelithiasis. Hepatology 2004;39:117-128
44. Mauad TH, van Nieuwkerk CM, Dingemans KP, et al. Mice with homozygous disruption of the mdr2 P-glycoprotein gene: a novel animal model for studies of nonsuppurative inflammatory cholangitis and hepatocarcinogenesis. Am J Pathol 1994;145:1237-1245
45. Pikarsky E, Porat RM, Stein I, et al. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature 2004;431:461-466
46. Fickert P, Wagner M, Marschall HU, et al. 24-norUrsodeoxycholic acid is superior to ursodeoxycholic acid in the treatment of sclerosing cholangitis in Mdr2 (Abcb4) knockout mice. Gastroenterology 2006;130:465-481
47. Wang R, Salem M, Yousef IM, et al. Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis. Proc Natl Acad Sci U S A 2001;98:2011-2016
48. de Vree JM, Romijn JA, Mok KS, et al. Lack of enteral nutrition during critical illness is associated with profound decrements in biliary lipid concentrations. Am J Clin Nutr 1999;70:70-77
49. Shoda J, Oda K, Suzuki H, et al. Etiologic significance of defects in cholesterol, phospholipid, and bile acid metabolism in the liver of patients with intrahepatic calculi. Hepatology 2001;33:1194-1205
50. Geuken E, Visser D, Kuipers F, et al. Rapid increase of bile salt secretion is associated with bile duct injury after human liver transplantation. J Hepatol 2004;41:1017-1025
51. Lammert F, Marschall HU, Glantz A, et al. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J Hepatol 2000;33:1012-1021
52. Riely CA, Bacq Y. Intrahepatic cholestasis of pregnancy. Clin Liver Dis 2004;8:167-176
53. Poupon R. Intrahepatic cholestasis of pregnancy: from bedside to bench to bedside. Liver Int 2005;25:467-468
54. Lucena JF, Herrero JI, Quiroga J, et al. A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis. Gastroenterology 2003;124:1037-1042
55. Ropponen A, Sund R, Riikonen S, et al. Intrahepatic cholestasis of pregnancy as an indicator of liver and biliary diseases: a population-based study. Hepatology 2006;43: 723-728
56. Beuers U, Pusl T. Intrahepatic cholestasis of pregnancy: a heterogeneous group of pregnancy-related disorders? Hepatology 2006;43:647-649
57. Locatelli A, Roncaglia N, Arreghini A, et al. Hepatitis C virus infection is associated with a higher incidence of cholestasis of pregnancy. Br J Obstet Gynaecol 1999;106: 498-500
58. Paternoster DM, Fabris F, Palu G, et al. Intra-hepatic cholestasis of pregnancy in hepatitis C virus infection. Acta Obstet Gynecol Scand 2002;81:99-103
59. Reyes H, Zapata R, Hernandez I, et al. Is a leaky gut involved in the pathogenesis of intrahepatic cholestasis of pregnancy? Hepatology 2006;43:715-722
60. Lucena JF, Herrero JI, Quiroga J, et al. Reply to "Is intrahepatic cholestasis of pregnancy an MDR3-related disease?" Gastroenterology 2003;125:1923-1924
61. Bacq Y, Sapey T, Brechot MC, et al. Intrahepatic cholestasis of pregnancy: a French prospective study. Hepatology 1997; 26:358-364
62. Milkiewicz P, Gallagher R, Chambers J, et al. Obstetric cholestasis with elevated gamma glutamyl transpeptidase: incidence, presentation and treatment. J Gastroenterol Hepatol 2003;18:1283-1286
63. de Vree JM, Jacquemin E, Sturm E, et al. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc Natl Acad Sci U S A 1998;95:282-287
64. Jacquemin E, Cresteil D, Manouvrier S, et al. Heterozygous non-sense mutation of the MDR3 gene in familial intrahepatic cholestasis of pregnancy [letter]. Lancet 1999;353: 210-211
65. Dixon PH, Weerasekera N, Linton KJ, et al. Heterozygous MDR3 missense mutation associated with intrahepatic cholestasis of pregnancy: evidence for a defect in protein trafficking. Hum Mol Genet 2000;9:1209-1217
66. Gendrot C, Bacq Y, Brechot MC, et al. A second heterozygous MDR3 nonsense mutation associated with intrahepatic cholestasis of pregnancy. J Med Genet 2003; 40:e32
67. Mullenbach R, Linton KJ, Wiltshire S, et al. ABCB4 gene sequence variation in women with intrahepatic cholestasis of pregnancy. J Med Genet 2003;40:e70
68. 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. Pharmacogenetics 2004;14: 91-102
69. Floreani A, Carderi I, Paternoster D, et al. Intrahepatic cholestasis of pregnancy: three novel MDR3 gene mutations. Aliment Pharmacol Ther 2006;23:1649-1653
70. Wasmuth HE, Glantz A, Keppeler H, et al. Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter gene ABCB4. Gut 2006; August 4 (Epub ahead of print)
71. Eloranta ML, Heiskanen JT, Hiltunen MJ, et al. Multidrug resistance 3 gene mutation 1712delT and estrogen receptor alpha gene polymorphisms in Finnish women with obstetric cholestasis. Eur J Obstet Gynecol Reprod Biol 2002;105: 132-135
72. Savander M, Ropponen A, Avela K, et al. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy. Gut 2003;52:1025-1029
73. Debry P, Nash EA, Neklason DW, et al. Role of multidrug resistance P-glycoproteins in cholesterol esterification. J Biol Chem 1997;272:1026-1031
74. Rosmorduc O, Hermelin B, Poupon R. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Gastroenterology 2001;120:1459-1467
75. Rosmorduc O, Hermelin B, Boelle PY, et al. ABCB4 gene mutation-associated cholelithiasis in adults. Gastroenterology 2003;125:452-459
76. Arrese M, Accatino L. Is intrahepatic cholestasis of pregnancy an MDR3-related disease? Gastroenterology 2003;125:1922-1923
77. Ganne-Carrie N, Baussan C, Grando V, et al. Progressive familial intrahepatic cholestasis type 3 revealed by oral contraceptive pills. J Hepatol 2003;38:693-694
78. Jansen PL, Strautnieks SS, Jacquemin E, et al. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis. Gastroenterology 1999;117:1370-1379
79. 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. Scand J Gastroenterol 2003;38:648-652
80. Hinoshita E, Taguchi K, Inokuchi A, et al. Decreased expression of an ATP-binding cassette transporter, MRP2, in human livers with hepatitis C virus infection. J Hepatol 2001;35:765-773
81. Stieger B, Fattinger K, Madon J, et al. Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 2000;118:422-430
82. Maddrey WC. Drug-induced hepatotoxicity: 2005. J Clin Gastroenterol 2005;39:S83-S89
83. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov 2005;4:489-499
84. Navarro VJ, Senior JR. Drug-related hepatotoxicity. N Engl J Med 2006;354:731-739
85. Pauli-Magnus C, Meier PJ. Pharmacogenetics of hepatocellular transporters. Pharmacogenetics 2003;13:189-198
86. Meier Y, Stieger B, Zodan-Marin T, et al. ABCB11 polymorphism 1457T > C (V444A) of the bile salt export pump (BSEP) associates with drug-induced cholestasis and intrahepatic cholestasis of pregnancy. Hepatology 2005;42 (suppl.1):513A
87. 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. Pharmacogenet Genomics 2006. In press
88. Smith AJ, van Helvoort A, van Meer G, et al. MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. J Biol Chem 2000;275:23530-23539
89. Bramow S, Ott P, Thomsen NF, et al. Cholestasis and regulation of genes related to drug metabolism and biliary transport in rat liver following treatment with cyclosporine A and sirolimus (rapamycin). Pharmacol Toxicol 2001;89: 133-139
90. Elamiri A, Perwaiz S, Tuchweber B, et al. Effect of mdr2 mutation with combined tandem disruption of canalicular glycoprotein transporters by cyclosporine A on bile formation in mice. Pharmacol Res 2003;48:467-472
91. Fattinger K, Funk C, Pantze M, et al. The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: a potential mechanism for hepatic adverse reactions. Clin Pharmacol Ther 2001;69:223-231
92. Bode KA, Donner MG, Leier I, et al. Inhibition of transport across the hepatocyte canalicular membrane by the antibiotic fusidate. Biochem Pharmacol 2002;64:151-158
93. Fouassier L, Kinnman N, Lefevre G, et al. Contribution of mrp2 in alterations of canalicular bile formation by the endothelin antagonist bosentan. J Hepatol 2002;37:184-191
94. Talwalkar JA, Lindor KD. Primary sclerosing cholangitis. Inflamm Bowel Dis 2005;11:62-72
95. O'Mahony CA, Vierling JM. Etiopathogenesis of primary sclerosing cholangitis. Semin Liver Dis 2006;26:3-21
96. Levy C, Lindor KD. Primary sclerosing cholangitis: epidemiology, natural history, and prognosis. Semin Liver Dis 2006;26:22-30
97. Lazaridis KN, Strazzabosco M, LaRusso NF. The cholangiopathies: disorders of biliary epithelia. Gastroenterology 2004;127:1565-1577
98. Pauli-Magnus C, Kerb R, Fattinger K, et al. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Hepatology 2004;39:779-791
99. Wasmuth HE, Matern S, Lammert F. From genotypes to haplotypes in hepatobiliary diseases: one plus one equals (sometimes) more than two. Hepatology 2004;39:604-607
100. Rosmorduc O, Hermelin B, Boelle PY, et al. ABCB4 gene mutations and primary sclerosing cholangitis. Gastroenterology 2004;126:1220-1222
101. de Vree JM. Defects in Hepatobiliary Transport: Genetics and Therapy of Progressive Familial Intrahepatic Cholestasis Type 3 [thesis]. Amsterdam: University of Amsterdam; 1999:32
102. Kaw M, Silverman WB, Rabinovitz M, et al. Biliary tract calculi in primary sclerosing cholangitis. Am J Gastroenterol 1995;90:72-75
103. Hartmann G, Kim H, Piquette-Miller M. Regulation of the hepatic multidrug resistance gene expression by endotoxin and inflammatory cytokines in mice. Int Immunopharmacol 2001;1:189-199
104. Tygstrup N, Bangert K, Ott P, et al. Messenger RNA profiles in liver injury and stress: a comparison of lethal and nonlethal rat models. Biochem Biophys Res Commun 2002;290:518-525
105. Teng S, Piquette-Miller M. The involvement of the pregnane X receptor in hepatic gene regulation during inflammation in mice. J Pharmacol Exp Ther 2005;312: 841-848
106. Karlsen TH, Lie BA, Frey Froslie K, et al. Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sderosing cholangitis. Gastroenterology 2006;131: 781-787
107. Durieu I, Pellet O, Simonot L, et al. Sclerosing cholangitis in adults with cystic fibrosis: a magnetic resonance cholangiographic prospective study. J Hepatol 1999;30:1052-1056
108. Colombo C, Battezzati PM. Liver involvement in cystic fibrosis: primary organ damage or innocent bystander? J Hepatol 2004;41:1041-1044
109. Waters DL, Dorney SF, Gruca MA, et al. Hepatobiliary disease in cystic fibrosis patients with pancreatic sufficiency. Hepatology 1995;21:963-969
110. Strandvik B, Bronnegard M, Gilljam H, et al. Relation between defective regulation of arachidonic acid release and symptoms in cystic fibrosis. Scand J Gastroenterol Suppl 1988;143:1-4
111. Blanco PG, Zaman MM, Junaidi O, et al. Induction of colitis in cftr -/- mice results in bile duct injury. Am J Physiol Gastrointest Liver Physiol 2004;287:G491-G496
112. Spirli C, Nathanson MH, Fiorotto R, et al. Proinflammatory cytokines inhibit secretion in rat bile duct epithelium. Gastroenterology 2001;121:156-169
113. Spirli C, Fabris L, Duner E, et al. Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology 2003;124:737-753
114. Pall H, Zaman MM, Andersson C, et al. Decreased peroxisome proliferator activated receptor alpha is associated with bile duct injury in cystic fibrosis transmembrane conductance regulator -/- mice. J Pediatr Gastroenterol Nutr 2006;42:275-281
115. Kok T, Bloks VW, Wolters H, et al. Peroxisome proliferator-activa ted receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice. Biochem J 2003;369:539-547
116. Wagner M, Halilbasic E, Marschall HU, et al. CAR and PXR agonists stimulate hepatic bile acid and bilirubin detoxification and elimination pathways in mice. Hepatology 2005;42:420-430
117. Sheth S, Shea JC, Bishop MD, et al. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sderosing cholangitis. Hum Genet 2003;113:286-292
118. McGill JM, Williams DM, Hunt CM. Survey of cystic fibrosis transmembrane conductance regulator genotypes in primary sclerosing cholangitis. Dig Dis Sci 1996;41:540-542
119. Girodon E, Sternberg D, Chazouilleres O, et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene defects in patients with primary sderosing cholangitis. J Hepatol 2002;37:192-197
120. Gallegos-Orozco JF, Yurk E, Wang N, et al. Lack of association of common cystic fibrosis transmembrane conductance regulator gene mutations with primary sclerosing cholangitis. Am J Gastroenterol 2005;100:874-878
121. Juran BD, Lazaridis KN. Genetics of hepatobiliary diseases. Clin Gastroenterol Hepatol 2006;4:548-557
122. Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med 2005;353:1261-1273
123. Oude Elferink RP, Groen AK. The role of mdr2 P-glycoprotein in biliary lipid secretion: cross-talk between cancer research and biliary physiology. J Hepatol 1995;23: 617-625
124. Dumoulin FL, Reichel C, Sauerbruch T, et al. Semi-quantitation of intrahepatic MDR3 mRNA levels by reverse transcription/competitive polymerase chain reaction. J Hepatol 1997;26:852-856
125. Zollner G, Fickert P, Zenz R, et al. Hepatobiliary transporter expression in percutaneous liver biopsies of patients with cholestatic liver diseases. Hepatology 2001;33: 633-646
126. Zollner G, Fickert P, Silbert D, et al. Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 2003;38:717-727
127. Joshi S, Cauch-Dudek K, Heathcote EJ, et al. Antimitochondrial antibody profiles: are they valid prognostic indicators in primary biliary cirrhosis? Am J Gastroenterol 2002;97:999-1002
128. Graziadei IW. Recurrence of primary sclerosing cholangitis after liver transplantation. Liver Transpl 2002;8:575-581
129. Neuberger J. Recurrent primary biliary cirrhosis. Liver Transpl 2003;9:539-546
130. Hoekstra H, Porte RJ, Tian Y, et al. Bile salt toxicity aggravates cold ischemic injury of bile ducts after liver transplantation in Mdr2 +/- mice. Hepatology 2006;43: 1022-1031
131. Shoda J, Inada Y, Osuga T. Molecular pathogenesis of hepatolithiasis: a type of low phospholipid-associated cholelithiasis. Front Biosci 2006;11:669-675
132. Kano M, Shoda J, Sumazaki R, et al. Mutations identified in the human multidrug resistance P-glycoprotein 3 (ABCB4) gene in patients with primary hepatolithiasis. Hepatol Res 2004;29:160-166
133. Kim WR, Ludwig J, Lindor KD. Variant forms of cholestatic diseases involving small bile ducts in adults. Am J Gastroenterol 2000;95:1130-1138
134. Bruguera M, Llach J, Rodes J. Nonsyndromic paucity of intrahepatic bile ducts in infancy and idiopathic ductopenia in adulthood: the same syndrome? Hepatology 1992;15: 830-834
135. Ludwig J. Idiopathic adulthood ductopenia: an update. Mayo Clin Proc 1998;73:285-291
136. Trauner M, Boyer JL. Cholestatic syndromes. Curr Opin Gastroenterol 2001;17:242-256
137. Ziol M, Frassati-Biaggi A, Hermelin B, et al. Liver histology in multidrug-resistance-3P-glycoprotein heterozygous gene mutations adult carriers: high prevalence of fibrosis. Hepatology 2005;42:461A
138. Sandhu IS, Jarvis C, Everson GT. Total parenteral nutrition and cholestasis. Clin Liver Dis 1999;3:489-508
139. Tazuke Y, Kiristioglu I, Heidelberger KP, et al. Hepatic P-glycoprotein changes with total parenteral nutrition administration. JPEN J Parenter Enteral Nutr 2004;28:1-6
140. Nishimura M, Yamaguchi M, Yamauchi A, et al. Role of soybean oil fat emulsion in the prevention of hepatic xenobiotic transporter mRNA up- and down-regulation induced by overdose of fat-free total patenteral nutrition in infant rats. Drug Metab Pharmacokinet 2005;20:46-54
141. Trauner M, Fickert P, Stauber RE. Inflammation-induced cholestasis. J Gastroenterol Hepatol 1999;14:946-959
142. Geier A, Fickert P, Trauner M. Mechanisms of disease: mechanisms and clinical implications of cholestasis in sepsis. Nat Clin Pract Gastroenterol Hepatol 2006;3:574-585
143. Vos TA, Hooiveld GJ, Koning H, et al. Up-regulation of the multidrug resistance genes, Mrp1 and Mdr1b, and down-regulation of the organic anion transporter, Mrp2, and the bile salt transporter, Spgp, in endotoxemic rat liver. Hepatology 1998;28:1637-1644
144. Schmitt M, Kolbel CB, Muller MK, et al. [Sclerosing cholangitis after burn injury]. Z Gastroenterol 1997;35:929-934
145. Scheppach W, Druge G, Wittenberg G, et al. Sclerosing cholangitis and liver cirrhosis after extrabiliary infections: report on three cases. Crit Care Med 2001;29:438-441
146. Engler S, Elsing C, Flechtenmacher C, et al. Progressive sclerosing cholangitis after septic shock: a new variant of vanishing bile duct disorders. Gut 2003;52:688-693
147. Benninger J, Grobholz R, Oeztuerk Y, et al. Sclerosing cholangitis following severe trauma: description of a remarkable disease entity with emphasis on possible pathophysiologic mechanisms. World J Gastroenterol 2005;11:4199-4205
148. Gossard AA, Angulo P, Lindor KD. Secondary sclerosing cholangitis: a comparison to primary sclerosing cholangitis. Am J Gastroenterol 2005;100:1330-1333
149. Jaeger C, Mayer G, Henrich R, et al. Secondary sclerosing cholangitis after long-term treatment in an intensive care unit: clinical presentation, endoscopic findings, treatment, and follow-up. Endoscopy 2006;38:730-734
150. Elferink RP, Ottenhoff R, van Marie J, et al. Class III P-glycoproteins mediate the formation of lipoprotein X in the mouse. J Clin Invest 1998;102:1749-1757
151. Barbu WD, Corpechot C, Ping C, et al. Allelic variations of hepatobiliary transporters and nuclear receptors genes determine disease behavior in primary biliary cirrhosis. Hepatology 2005;42:208A-209A
152. Paumgartner G, Beuers U. Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 2002;36:525-531
153. Beuers U. Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 2006;3:318-328
154. Paumgartner G, Beuers U. Mechanisms of action and therapeutic efficacy of ursodeoxycholic acid in cholestatic liver disease. Clin Liver Dis 2004;8:67-81
155. Trauner M, Graziadei IW. Review article: mechanisms of action and therapeutic applications of ursodeoxycholic acid in chronic liver diseases. Aliment Pharmacol Ther 1999;13: 979-996
156. Stiehl A, Rudolph G, Sauer P, et al. Biliary secretion of bile acids and lipids in primary sclerosing cholangitis: influence of cholestasis and effect of ursodeoxycholic acid treatment. J Hepatol 1995;23:283-289
157. Marschall HU, Wagner M, Zollner G, et al. Complementary stimulation of hepatobiliary transport and detoxification systems by rifampicin and ursodeoxycholic acid in humans. Gastroenterology 2005;129:476-485
158. Yoon YB, Hagey LR, Hofmann AF, et al. Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-norursodeoxycholate in rodents. Gastroenterology 1986;90: 837-852
159. Hofmann AF, Zakko SF, Lira M, et al. Novel biotransformation and physiological properties of norursodeoxycholic acid in humans. Hepatology 2005;42:1391-1398
160. Liu Y, Binz J, Numerick MJ, et al. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. J Clin Invest 2003;112: 1678-1687
161. Fiorucci S, Clerici C, Antonelli E, et al. Protective effects of 6-ethyl chenodeoxycholic acid, a farnesoid X receptor (FXR) ligand, in estrogen-induced cholestasis. J Pharmacol Exp Ther 2005;313:604-612
162. Pellicciari R, Fiorucci S, Camaioni E, et al. 6alpha-ethyl- chenodeoxycholic acid (6-ECDCA), a potent and selective FXR agonist endowed with anticholestatic activity. J Med Chem 2002;45:3569-3572
163. Wagner M, Fickert P, Zollner G, et al. Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice. Gastroenterology 2003;125:825-838
164. Stedman C, Liddle C, Coulter S, et al. Benefit of farnesoid X receptor inhibition in obstructive cholestasis. Proc Natl Acad Sci USA 2006;103:11323-11328
165. Trauner M. The nuclear bile acid receptor FXR as a novel therapeutic target in cholestatic liver diseases: hype or hope? Hepatology 2004;40:260-263
166. Shoda J, Inada Y, Tsuji A, et al. Bezafibrate stimulates canalicular localization of NBD-labeled PC in HepG2 cells by PP ARalpha-media ted redistribution of ABCB4. J Lipid Res 2004;45:1813-1825
167. Miranda S, Vollrath V, Wielandt AM, et al. Overexpression of mdr2 gene by peroxisome proliferators in the mouse liver. J Hepatol 1997;26:1331-1339
168. Chianale J, Vollrath V, Wielandt AM, et al. Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse. Biochem J 1996;314:781-786
169. Kurihara T, Niimi A, Maeda A, et al. Bezafibrate in the treatment of primary biliary cirrhosis: comparison with ursodeoxycholic acid. Am J Gastroenterol 2000;95:2990-2992
170. Nakai S, Masaki T, Kurokohchi K, et al. Combination therapy of bezafibrate and ursodeoxycholic acid in primary biliary cirrhosis: a preliminary study. Am J Gastroenterol 2000;95:326-327
171. Ohmoto K, Mitsui Y, Yamamoto S. Effect of bezafibrate in primary biliary cirrhosis: a pilot study. Liver 2001;21:223-224
172. Kurihara T, Maeda A, Shigemoto M, et al. Investigation into the efficacy of bezafibrate against primary biliary cirrhosis, with histological references from cases receiving long term monotherapy. Am J Gastroenterol 2002;97:212-214
173. Yano K, Kato H, Morita S, et al. Is bezafibrate histologically effective for primary biliary cirrhosis? Am J Gastroenterol 2002;97:1075-1077
174. Ritzel U, Leonhardt U, Nather M, et al. Simvastatin in primary biliary cirrhosis: effects on serum lipids and distinct disease markers. J Hepatol 2002;36:454-458
175. Hooiveld GJ, Vos TA, Scheffer GL, et al. 3-Hydroxy-3-methylglutaryl- coenzyme A reductase inhibitors (statins) induce hepatic expression of the phospholipid translocase mdr2 in rats. Gastroenterology 1999;117:678-687
176. Carrella M, Feldman D, Cogoi S, et al. Enhancement of mdr2 gene transcription mediates the biliary transfer of phosphatidylcholine supplied by an. increased biosynthesis in the pravastatin-treated rat. Hepatology 1999;29:1825-1832
177. Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol 2001;21:1712-1719
178. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685-1695
179. de Vree JM, Ottenhoff R, Bosma PJ, et al. Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis. Gastroenterology 2000;119:1720-1730
180. Smith AJ, de Vree JM, Ottenhoff R, et al. Hepatocyte-specific expression of the human MDR3 P-glycoprotein gene restores the biliary phosphatidylcholine excretion absent in Mdr2 (-/-) mice. Hepatology 1998;28:530-536
181. Oude Elferink RP. Manipulation of biliary lipids by gene therapy: potential consequences for patients with progressive familial intrahepatic cholestasis. Cuir Drug Targets Immune Endocr Metabol Disord 2005;5:199-202
182. Keitel V, Vogt C, Haussinger D, Kubitz R. Combined mutations of canalicular transporter proteins cause severe intrahepatic cholestasis of pregnancy. Gastroenterology 2006;131:624-629