MDR3 (ABCB4) Defects: A Paradigm for the Genetics of Adult Cholestatic Syndromes

ABSTRACT

Because ATP-binding cassette (ABC) transporters are important for normal bile secretion, hereditary and acquired ABC transporter defects play a central role in the pathogenesis of cholestasis. Defects of the phospholipid export pump MDR3 (ABCC4) result in impaired biliary excretion of phosphatidylcholine and a variety of cholestatic syndromes ranging from progressive familial intrahepatic cholestasis in neonates to biliary cirrhosis in adults. Moreover, MDR3 mutations predispose to cholestasis of pregnancy and drug-induced cholestasis. Because Mdr2 (rodent orthologue of human MDR3) knockout mice develop sclerosing cholangitis, it is attractive to speculate that MDR3 defects could also play an important role in cholangiopathies in humans. Indeed, MDR3 variants could play a role as modifier gene in primary biliary cirrhosis and primary sclerosing cholangitis, but their exact role needs further clarification. Impaired biliary phosphatidylcholine excretion has also been reported in total parenteral nutrition-induced cholestasis and bile duct injury following liver transplantation, but a genetic basis for these findings remains to be explored. Several drugs for the treatment of cholestatic liver diseases target MDR3 expression and function, further underscoring the clinical significance of this transport system.

KEYWORDS

ABC transporters - bile acids - phospholipids - cholangitis - vanishing bile duct syndrome

REFERENCES

• 1 Jansen P L, Muller M. The molecular genetics of familial intrahepatic cholestasis.  Gut. 2000;  47 1-5
• 2 Thompson R, Jansen P L. 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 P L, Muller M, Sturm E. Genes and cholestasis.  Hepatology. 2001;  34 1067-1074
• 5 Elferink R O, Groen A K. Genetic defects in hepatobiliary transport.  Biochim Biophys Acta. 2002;  1586 129-145
• 6 Jansen P L, Sturm E. Genetic cholestasis, causes and consequences for hepatobiliary transport.  Liver Int. 2003;  23 315-322
• 7 Oude Elferink R P, Paulusma C C, Groen A K. Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases.  Gastroenterology. 2006;  130 908-925
• 8 Pauli-Magnus C, Meier P J. 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 U M 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 R P, Groen A K. 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 C C, Oude Elferink R P. Diseases of intramembranous lipid transport.  FEBS Lett. 2006;  580 5500-5509
• 16 Oude Elferink R P, Paulusma C C. Function and pathophysiological importance of ABCB4 (MDR3 P-glycoprotein).  Pflugers Arch. 2006;  , April 19 (Epub ahead of print)
• 17 Trauner M, Boyer J L. Bile salt transporters: molecular characterization, function, and regulation.  Physiol Rev. 2003;  83 633-671
• 18 Smit J J, Schinkel A H, Oude Elferink R P 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 A J, Timmermans-Hereijgers J L, 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 M C, Cohen D E. 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 H U, 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 C G et al.. Principles of hepatic organic anion transporter regulation during cholestasis, inflammation and liver regeneration. BBA - MCR 2006 In press
• 26 Karpen S J. Nuclear receptor regulation of hepatic function.  J Hepatol. 2002;  36 832-850
• 27 Boyer J L. Nuclear receptor ligands: rational and effective therapy for chronic cholestatic liver disease?.  Gastroenterology. 2005;  129 735-740
• 28 Kok T, Wolters H, Bloks V W 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 J L et al.. Farnesoid X receptor activates transcription of the phospholipid pump MDR3.  J Biol Chem. 2003;  278 51085-51090
• 30 Bhushan A, Slapak C A, Levy S B 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 P J, Boyer J L. 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 S W, Klomp L W, Bull L N et al.. FIC1 disease: a spectrum of intrahepatic cholestatic disorders.  Semin Liver Dis. 2001;  21 535-544
• 34 Paulusma C C, Oude Elferink R P. 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 S W, van der Woerd W L, 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 G A, 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 J M, 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 H L, Chang P S, Hsu H C et al.. Progressive familial intrahepatic cholestasis with high gamma-glutamyltranspeptidase levels in Taiwanese infants: role of MDR3 gene defect?.  Pediatr Res. 2001;  50 50-55
• 41 Feranchak A P, Sokol R J. 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 D Q, 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 T H, van Nieuwkerk C M, Dingemans K P 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 R M, 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 H U 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 I M et al.. Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis.  Proc Natl Acad Sci USA. 2001;  98 2011-2016
• 48 de Vree J M, Romijn J A, Mok K S 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 H U, Glantz A et al.. Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management.  J Hepatol. 2000;  33 1012-1021
• 52 Riely C A, 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 J F, Herrero J I, 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 D M, 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 J F, Herrero J I, 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 M C 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 J M, Jacquemin E, Sturm E et al.. Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.  Proc Natl Acad Sci USA. 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 P H, Weerasekera N, Linton K J 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 M C et al.. A second heterozygous MDR3 nonsense mutation associated with intrahepatic cholestasis of pregnancy.  J Med Genet. 2003;  40 e32
• 67 Mullenbach R, Linton K J, 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 H E, 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 M L, Heiskanen J T, Hiltunen M J 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 E A, Neklason D W 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 P Y 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 P L, Strautnieks S S, Jacquemin E et al.. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis.  Gastroenterology. 1999;  117 1370-1379
• 79 Eloranta M L, 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 W C. 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 V J, Senior J R. Drug-related hepatotoxicity.  N Engl J Med. 2006;  354 731-739
• 85 Pauli-Magnus C, Meier P J. 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 A J, 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 N F 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 K A, Donner M G, 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 J A, Lindor K D. Primary sclerosing cholangitis.  Inflamm Bowel Dis. 2005;  11 62-72
• 95 O'Mahony C A, Vierling J M. Etiopathogenesis of primary sclerosing cholangitis.  Semin Liver Dis. 2006;  26 3-21
• 96 Levy C, Lindor K D. Primary sclerosing cholangitis: epidemiology, natural history, and prognosis.  Semin Liver Dis. 2006;  26 22-30
• 97 Lazaridis K N, Strazzabosco M, LaRusso N F. 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 H E, 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 P Y et al.. ABCB4 gene mutations and primary sclerosing cholangitis.  Gastroenterology. 2004;  126 1220-1222
• 101 de Vree J M. 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 W B, 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 T H, Lie B A, Frey Froslie K et al.. Polymorphisms in the steroid and xenobiotic receptor gene influence survival in primary sclerosing 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 P M. Liver involvement in cystic fibrosis: primary organ damage or innocent bystander?.  J Hepatol. 2004;  41 1041-1044
• 109 Waters D L, Dorney S F, Gruca M A 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 P G, Zaman M M, 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 M H, 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 M M, 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 V W, Wolters H et al.. Peroxisome proliferator-activated 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 H U 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 J C, Bishop M D et al.. Increased prevalence of CFTR mutations and variants and decreased chloride secretion in primary sclerosing cholangitis.  Hum Genet. 2003;  113 286-292
• 118 McGill J M, Williams D M, Hunt C M. 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 sclerosing cholangitis.  J Hepatol. 2002;  37 192-197
• 120 Gallegos-Orozco J F, 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 B D, Lazaridis K N. Genetics of hepatobiliary diseases.  Clin Gastroenterol Hepatol. 2006;  4 548-557
• 122 Kaplan M M, Gershwin M E. Primary biliary cirrhosis.  N Engl J Med. 2005;  353 1261-1273
• 123 Oude Elferink RP, Groen A K. 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 F L, Reichel C, Sauerbruch T et al.. Semiquantitation 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 E J et al.. Antimitochondrial antibody profiles: are they valid prognostic indicators in primary biliary cirrhosis?.  Am J Gastroenterol. 2002;  97 999-1002
• 128 Graziadei I W. 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 R J, 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 W R, Ludwig J, Lindor K D. 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 J L. 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 I S, Jarvis C, Everson G T. Total parenteral nutrition and cholestasis.  Clin Liver Dis. 1999;  3 489-508
• 139 Tazuke Y, Kiristioglu I, Heidelberger K P 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 parenteral nutrition in infant rats.  Drug Metab Pharmacokinet. 2005;  20 46-54
• 141 Trauner M, Fickert P, Stauber R E. 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 T A, Hooiveld G J, 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 C B, Muller M K 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 A A, Angulo P, Lindor K D. 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 R P, Ottenhoff R, van Marle 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 W D, 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 I W. 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 H U, 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 Y B, Hagey L R, Hofmann A F et al.. Effect of side-chain shortening on the physiologic properties of bile acids: hepatic transport and effect on biliary secretion of 23-nor-ursodeoxycholate in rodents.  Gastroenterology. 1986;  90 837-852
• 159 Hofmann A F, Zakko S F, 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 M J 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 PPARalpha-mediated redistribution of ABCB4.  J Lipid Res. 2004;  45 1813-1825
• 167 Miranda S, Vollrath V, Wielandt A M 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 A M 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 G J, Vos T A, Scheffer G L 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 J K. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors.  Arterioscler Thromb Vasc Biol. 2001;  21 1712-1719
• 178 Hansson G K. Inflammation, atherosclerosis, and coronary artery disease.  N Engl J Med. 2005;  352 1685-1695
• 179 de Vree J M, Ottenhoff R, Bosma P J 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 A J, de Vree J M, 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 R P. Manipulation of biliary lipids by gene therapy: potential consequences for patients with progressive familial intrahepatic cholestasis.  Curr 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