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Licensed Unlicensed Requires Authentication Published by De Gruyter February 7, 2019

ABCB4/MDR3 in health and disease – at the crossroads of biochemistry and medicine

  • Martin Prescher , Tim Kroll and Lutz Schmitt EMAIL logo
From the journal Biological Chemistry

Abstract

Several ABC transporters of the human liver are responsible for the secretion of bile salts, lipids and cholesterol. Their interplay protects the biliary tree from the harsh detergent activity of bile salts. Among these transporters, ABCB4 is essential for the translocation of phosphatidylcholine (PC) lipids from the inner to the outer leaflet of the canalicular membrane of hepatocytes. ABCB4 deficiency can result in altered PC to bile salt ratios, which led to intrahepatic cholestasis of pregnancy, low phospholipid associated cholelithiasis, drug induced liver injury or even progressive familial intrahepatic cholestasis type 3. Although PC lipids only account for 30–40% of the lipids in the canalicular membrane, 95% of all phospholipids in bile are PC lipids. We discuss this discrepancy in the light of PC synthesis and bile salts favoring certain lipids. Nevertheless, the in vivo extraction of PC lipids from the outer leaflet of the canalicular membrane by bile salts should be considered as a separate step in bile formation. Therefore, methods to characterize disease causing ABCB4 mutations should be considered carefully, but such an analysis represents a crucial point in understanding the currently unknown transport mechanism of this ABC transporter.

Award Identifier / Grant number: CRC 974

Funding statement: The authors apologize to all their colleagues whose work was not adequately cited due to space limitations. We thank Jan Stindt, Carola Dröge, Michele Bonus, Holger Gohlke, Verena Keitel, Sander Smits, Manuel Wagner, Marcel Lagedroste and all members of the Institute of Biochemistry for fruitful discussions. This work was supported by the Deutsche Forschungsgemeinschaft (Funder Id 10.13039/501100001659, CRC 974 project B03 to L.S.).

  1. Conflict of interest statement: The authors declare that they have no conflicts of interest with the contents of this article.

References

Aleo, M.D., Shah, F., He, K., Bonin, P.D., and Rodrigues, A.D. (2017). Evaluating the role of multidrug resistance protein 3 (MDR3) inhibition in predicting drug-induced liver injury using 125 pharmaceuticals. Chem. Res. Toxicol. 30, 1219–1229.10.1021/acs.chemrestox.7b00048Search in Google Scholar PubMed

Andress, E.J., Nicolaou, M., Romero, M.R., Naik, S., Dixon, P.H., Williamson, C., and Linton, K.J. (2014). Molecular mechanistic explanation for the spectrum of cholestatic disease caused by the S320F variant of ABCB4. Hepatology 59, 1921–1931.10.1002/hep.26970Search in Google Scholar PubMed

Andress, E.J., Nicolaou, M., McGeoghan, F., and Linton, K.J. (2017). ABCB4 missense mutations D243A, K435T, G535D, I490T, R545C, and S978P significantly impair the lipid floppase and likely predispose to secondary pathologies in the human population. Cell Mol. Life Sci. 74, 2513–2524.10.1007/s00018-017-2472-6Search in Google Scholar PubMed PubMed Central

Bacq, Y., le Besco, M., Lecuyer, A.I., Gendrot, C., Potin, J., Andres, C.R., and Aubourg, A. (2017). Ursodeoxycholic acid therapy in intrahepatic cholestasis of pregnancy: Results in real-world conditions and factors predictive of response to treatment. Dig. Liver Dis. 49, 63–69.10.1016/j.dld.2016.10.006Search in Google Scholar PubMed

Beharry, S., Zhong, M., and Molday, R.S. (2004). N-retinylidene-phosphatidylethanolamine is the preferred retinoid substrate for the photoreceptor-specific ABC transporter ABCA4 (ABCR). J. Biol. Chem. 279, 53972–53979.10.1074/jbc.M405216200Search in Google Scholar PubMed

Bhamidimarri, K.R. and Schiff, E. (2013). Drug-induced cholestasis. Clin. Liver Dis. 17, 519–531, vii.10.1016/j.cld.2013.07.015Search in Google Scholar PubMed

Bleibel, W., Kim, S., D’Silva, K., and Lemmer, E.R. (2007). Drug-induced liver injury: review article. Dig. Dis. Sci. 52, 2463–2471.10.1007/s10620-006-9472-ySearch in Google Scholar PubMed

Borst, P., Zelcer, N., and van Helvoort, A. (2000). ABC transporters in lipid transport. Biochim. Biophys. Acta 1486, 128–144.10.1016/B978-012352551-2/50023-8Search in Google Scholar

Boyer, J.L. (1986). Mechanisms of Bile Secretion and Hepatic Transport (Boston, MA: Springer).10.1007/978-1-4613-2097-5_35Search in Google Scholar

Bull, L.N., van Eijk, M.J., Pawlikowska, L., DeYoung, J.A., Juijn, J.A., Liao, M., Klomp, L.W., Lomri, N., Berger, R., Scharschmidt, B.F., et al. (1998). A gene encoding a P-type ATPase mutated in two forms of hereditary cholestasis. Nat. Genet. 18, 219–224.10.1038/ng0398-219Search in Google Scholar PubMed

Bungert, S., Molday, L.L., and Molday, R.S. (2001). Membrane topology of the ATP binding cassette transporter ABCR and its relationship to ABC1 and related ABCA transporters: identification of N-linked glycosylation sites. J. Biol. Chem. 276, 23539–23546.10.1074/jbc.M101902200Search in Google Scholar PubMed

Buschman, E. and Gros, P. (1991). Functional analysis of chimeric genes obtained by exchanging homologous domains of the mouse mdr1 and mdr2 genes. Mol. Cell Biol. 11, 595–603.Search in Google Scholar

Buschman, E. and Gros, P. (1994). The inability of the mouse mdr2 gene to confer multidrug resistance is linked to reduced drug binding to the protein. Cancer Res. 54, 4892–4898.Search in Google Scholar

Carey, C.P. and Carey, M.C. (1998). Sphingomyelins of rat liver-biliary enrichment with molecular species containing 16-0 fatty acids as compared to canalicular-enriched plasma membranes. J. Membr. Biol. 167, 165–171.10.1007/s002329900480Search in Google Scholar PubMed

Carlton, V.E., Knisely, A.S., and Freimer, N.B. (1995). Mapping of a locus for progressive familial intrahepatic cholestasis (Byler disease) to 18q21-q22, the benign recurrent intrahepatic cholestasis region. Hum. Mol. Genet. 4, 1049–1053.10.1093/hmg/4.6.1049Search in Google Scholar PubMed

Chan, W., Calderon, G., Swift, A.L., Moseley, J., Li, S., Hosoya, H., Arias, I.M., and Ortiz, D.F. (2005). Myosin II regulatory light chain is required for trafficking of bile salt export protein to the apical membrane in Madin-Darby canine kidney cells. J. Biol. Chem. 280, 23741–23747.10.1074/jbc.M502767200Search in Google Scholar PubMed

Chappell, L.C., Gurung, V., Seed, P.T., Chambers, J., Williamson, C., Thornton, J.G., and Consortium, P.S. (2012). Ursodeoxycholic acid versus placebo, and early term delivery versus expectant management, in women with intrahepatic cholestasis of pregnancy: semifactorial randomised clinical trial. Br. Med. J. 344, e3799.10.1136/bmj.e3799Search in Google Scholar PubMed PubMed Central

Chen, J., Lu, G., Lin, J., Davidson, A.L., and Quiocho, F.A. (2003). A tweezers-like motion of the ATP-binding cassette dimer in an ABC transport cycle. Mol. Cell. 12, 651–661.10.1016/j.molcel.2003.08.004Search in Google Scholar PubMed

Chen, Z., Shi, T., Zhang, L., Zhu, P., Deng, M., Huang, C., Hu, T., Jiang, L., and Li, J. (2016). Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: a review of the past decade. Cancer Lett. 370, 153–164.10.1016/j.canlet.2015.10.010Search in Google Scholar PubMed

Chen, H.L., Wu, S.H., Hsu, S.H., Liou, B.Y., Chen, H.L., and Chang, M.H. (2018). Jaundice revisited: recent advances in the diagnosis and treatment of inherited cholestatic liver diseases. J. Biomed. Sci. 25, 75.10.1186/s12929-018-0475-8Search in Google Scholar PubMed PubMed Central

Chufan, E.E., Kapoor, K., Sim, H.M., Singh, S., Talele, T.T., Durell, S.R., and Ambudkar, S.V. (2013). Multiple transport-active binding sites are available for a single substrate on human P-glycoprotein (ABCB1). PLoS One 8, e82463.10.1371/journal.pone.0082463Search in Google Scholar PubMed PubMed Central

Cole, S.P. and Deeley, R.G. (2006). Transport of glutathione and glutathione conjugates by MRP1. Trends Pharmacol. Sci. 27, 438–446.10.1016/j.tips.2006.06.008Search in Google Scholar PubMed

Crawford, A.R., Smith, A.J., Hatch, V.C., Oude Elferink, R.P., Borst, P., and Crawford, J.M. (1997). Hepatic secretion of phospholipid vesicles in the mouse critically depends on mdr2 or MDR3 P-glycoprotein expression. Visualization by electron microscopy. J. Clin. Invest. 100, 2562–2567.10.1172/JCI119799Search in Google Scholar

Davit-Spraul, A., Gonzales, E., Baussan, C., and Jacquemin, E. (2010). The spectrum of liver diseases related to ABCB4 gene mutations: pathophysiology and clinical aspects. Semin. Liver Dis. 30, 134–146.10.1055/s-0030-1253223Search in Google Scholar

de Vree, J.M., Jacquemin, E., Sturm, E., Cresteil, D., Bosma, P.J., Aten, J., Deleuze, J.F., Desrochers, M., Burdelski, M., Bernard, O., et al. (1998). Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis. Proc. Natl. Acad. Sci. USA 95, 282–287.10.1073/pnas.95.1.282Search in Google Scholar

Dean, M., Hamon, Y., and Chimini, G. (2001). The human ATP-binding cassette (ABC) transporter superfamily. J. Lipid. Res. 42, 1007–1017.10.1016/S0022-2275(20)31588-1Search in Google Scholar

Deeley, R.G. and Cole, S.P. (2006). Substrate recognition and transport by multidrug resistance protein 1 (ABCC1). FEBS Lett. 580, 1103–1111.10.1016/j.febslet.2005.12.036Search in Google Scholar PubMed

Delaunay, J.L., Durand-Schneider, A.M., Delautier, D., Rada, A., Gautherot, R., Jacquemin, E., Ait-Slimane, T., and Maurice, M. (2009). A missense mutation in ABCB4 gene involved in progressive familial intrahepatic cholestasis type 3 leads to a folding defect that can be rescued by low temperature. Hepatology 49, 1218–1227.10.1002/hep.22775Search in Google Scholar PubMed

Delaunay, J.L., Durand-Schneider, A.M., Dossier, C., Falguières, T., Gautherot, J., Davit-Spraul, A., Aït-Slimane, T., Housset, C., Jacquemin, E., and Maurice, M. (2016). A functional classification of ABCB4 variations causing progressive familial intrahepatic cholestasis type 3. Hepatology 63, 1620–1631.10.1002/hep.28300Search in Google Scholar PubMed

Delaunay, J.L., Bruneau, A., Hoffmann, B., Durand-Schneider, A.M., Barbu, V., Jacquemin, E., Maurice, M., Housset, C., Callebaut, I., and Aït-Slimane, T. (2017). Functional defect of variants in the adenosine triphosphate-binding sites of ABCB4 and their rescue by the cystic fibrosis transmembrane conductance regulator potentiator, ivacaftor (VX-770). Hepatology 65, 560–570.10.1002/hep.28929Search in Google Scholar PubMed

Deleuze, J.F., Jacquemin, E., Dubuisson, C., Cresteil, D., Dumont, M., Erlinger, S., Bernard, O., and Hadchouel, M. (1996). Defect of multidrug-resistance 3 gene expression in a subtype of progressive familial intrahepatic cholestasis. Hepatology 23, 904–908.10.1002/hep.510230435Search in Google Scholar PubMed

DeLong, C.J., Shen, Y.J., Thomas, M.J., and Cui, Z. (1999). Molecular distinction of phosphatidylcholine synthesis between the CDP-choline pathway and phosphatidylethanolamine methylation pathway. J. Biol. Chem. 274, 29683–29688.10.1074/jbc.274.42.29683Search in Google Scholar PubMed

Devault, A. and Gros, P. (1990). Two members of the mouse mdr gene family confer multidrug resistance with overlapping but distinct drug specificities. Mol. Cell. Biol. 10, 1652–1663.Search in Google Scholar

Devaux, P.F. (1991). Static and dynamic lipid asymmetry in cell membranes. Biochemistry 30, 1163–1173.10.1021/bi00219a001Search in Google Scholar PubMed

Dixon, P.H. and Williamson, C. (2016). The pathophysiology of intrahepatic cholestasis of pregnancy. Clin. Res. Hepatol. Gastroenterol. 40, 141–153.10.1016/j.clinre.2015.12.008Search in Google Scholar PubMed

Dixon, P.H., van Mil, S.W., Chambers, J., Strautnieks, S., Thompson, R.J., Lammert, F., Kubitz, R., Keitel, V., Glantz, A., Mattsson, L.A., et al. (2009). Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy. Gut 58, 537–544.10.1136/gut.2008.159541Search in Google Scholar PubMed

Doyle, L. and Ross, D.D. (2003). Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2). Oncogene 22, 7340–7358.10.1038/sj.onc.1206938Search in Google Scholar PubMed

Droge, C., Bonus, M., Baumann, U., Klindt, C., Lainka, E., Kathemann, S., Brinkert, F., Grabhorn, E., Pfister, E.D., Wenning, D., et al. (2017). Sequencing of FIC1, BSEP and MDR3 in a large cohort of patients with cholestasis revealed a high number of different genetic variants. J. Hepatol. 67, 1253–1264.10.1016/j.jhep.2017.07.004Search in Google Scholar PubMed

Dzagania, T., Engelmann, G., Haussinger, D., Schmitt, L., Flechtenmacher, C., Rtskhiladze, I., and Kubitz, R. (2012). The histidine-loop is essential for transport activity of human MDR3. A novel mutation of MDR3 in a patient with progressive familial intrahepatic cholestasis type 3. Gene 506, 141–145.10.1016/j.gene.2012.06.029Search in Google Scholar PubMed

Elferink, R.P., Tytgat, G.N., and Groen, A.K. (1997). Hepatic canalicular membrane 1: the role of mdr2 P-glycoprotein in hepatobiliary lipid transport. FASEB J. 11, 19–28.10.1096/fasebj.11.1.9034162Search in Google Scholar PubMed

Ellinger, P., Kluth, M., Stindt, J., Smits, S.H., and Schmitt, L. (2013). Detergent screening and purification of the human liver ABC transporters BSEP (ABCB11) and MDR3 (ABCB4) expressed in the yeast Pichia pastoris. PLoS One 8, e60620.10.1371/journal.pone.0060620Search in Google Scholar PubMed PubMed Central

Fagerberg, L., Hallström, B.M., Oksvold, P., Kampf, C., Djureinovic, D., Odeberg, J., Habuka, M., Tahmasebpoor, S., Danielsson, A., Edlund, K., et al. (2014). Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol. Cell Proteomics 13, 397–406.10.1074/mcp.M113.035600Search in Google Scholar PubMed PubMed Central

Gautherot, J., Durand-Schneider, A.M., Delautier, D., Delaunay, J.L., Rada, A., Gabillet, J., Housset, C., Maurice, M., and Ait-Slimane, T. (2012). Effects of cellular, chemical, and pharmacological chaperones on the rescue of a trafficking-defective mutant of the ATP-binding cassette transporter proteins ABCB1/ABCB4. J. Biol. Chem. 287, 5070–5078.10.1074/jbc.M111.275438Search in Google Scholar PubMed PubMed Central

Gautherot, J., Delautier, D., Maubert, M.A., Aït-Slimane, T., Bolbach, G., Delaunay, J.L., Durand-Schneider, A.M., Firrincieli, D., Barbu, V., Chignard, N., et al. (2014). Phosphorylation of ABCB4 impacts its function: insights from disease-causing mutations. Hepatology 60, 610–621.10.1002/hep.27170Search in Google Scholar

Gerloff, T., Meier, P.J., and Stieger, B. (1998a). Taurocholate induces preferential release of phosphatidylcholine from rat liver canalicular vesicles. Liver 18, 306–312.10.1111/j.1600-0676.1998.tb00810.xSearch in Google Scholar

Gerloff, T., Stieger, B., Hagenbuch, B., Madon, J., Landmann, L., Roth, J., Hofmann, A.F., and Meier, P.J. (1998b). The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J. Biol. Chem. 273, 10046–10050.10.1074/jbc.273.16.10046Search in Google Scholar

Gordo-Gilart, R., Andueza, S., Hierro, L., Martinez-Fernandez, P., D’Agostino, D., Jara, P., and Alvarez, L. (2015). Functional analysis of ABCB4 mutations relates clinical outcomes of progressive familial intrahepatic cholestasis type 3 to the degree of MDR3 floppase activity. Gut 64, 147–155.10.1136/gutjnl-2014-306896Search in Google Scholar

Gotthardt, D., Runz, H., Keitel, V., Fischer, C., Flechtenmacher, C., Wirtenberger, M., Weiss, K.H., Imparato, S., Braun, A., Hemminki, K., et al. (2008). A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults. Hepatology 48, 1157–1166.10.1002/hep.22485Search in Google Scholar

Graf, G.A., Yu, L.Q., Li, W.P., Gerard, R., Tuma, P.L., Cohen, J.C., and Hobbs, H.H. (2003). ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J. Biol. Chem. 278, 48275–48282.10.1074/jbc.M310223200Search in Google Scholar

Gros, P. and Buschman, E. (1993). The mouse multidrug resistance gene family: structural and functional analysis. Int. Rev. Cytol. 137C, 169–197.Search in Google Scholar

Gudbjartsson, D.F., Helgason, H., Gudjonsson, S.A., Zink, F., Oddson, A., Gylfason, A., Besenbacher, S., Magnusson, G., Halldorsson, B.V., Hjartarson, E., et al. (2015). Large-scale whole-genome sequencing of the Icelandic population. Nat. Genet. 47, 435–444.10.1038/ng.3247Search in Google Scholar

Guyot, C. and Stieger, B. (2011). Interaction of bile salts with rat canalicular membrane vesicles: evidence for bile salt resistant microdomains. J. Hepatol. 55, 1368–1376.10.1016/j.jhep.2011.04.014Search in Google Scholar

Halilbasic, E., Steinacher, D., and Trauner, M. (2017). Nor-ursodeoxycholic acid as a novel therapeutic approach for cholestatic and metabolic liver diseases. Dig. Dis. 35, 288–292.10.1159/000454904Search in Google Scholar

Hegedus, T., Sessler, T., Scott, R., Thelin, W., Bakos, E., Váradi, A., Szabó, K., Homolya, L., Milgram, S.L., and Sarkadi, B. (2003). C-terminal phosphorylation of MRP2 modulates its interaction with PDZ proteins. Biochem. Biophys. Res. Commun. 302, 454–461.10.1016/S0006-291X(03)00196-7Search in Google Scholar

Higgins, C.F. and Gottesman, M.M. (1992). Is the multidrug transporter a flippase? Trends Biochem. Sci. 17, 18–21.10.1016/0968-0004(92)90419-ASearch in Google Scholar

Higgins, C.F. and Linton, K.J. (2004). The ATP switch model for ABC transporters. Nat. Struct. Mol. Biol. 11, 918–926.10.1038/nsmb836Search in Google Scholar PubMed

Hirschfield, G.M., Mason, A., Luketic, V., Lindor, K., Gordon, S.C., Mayo, M., Kowdley, K.V., Vincent, C., Bodhenheimer Jr, H.C., Parés, A., et al. (2015). Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 148, 751–761 e758.10.1053/j.gastro.2014.12.005Search in Google Scholar PubMed

Hochrath, K., Krawczyk, M., Goebel, R., Langhirt, M., Rathkolb, B., Micklich, K., Rozman, J., Horsch, M., Beckers, J., Klingenspor, M., et al. (2012). The hepatic phosphatidylcholine transporter ABCB4 as modulator of glucose homeostasis. FASEB J. 26, 5081–5091.10.1096/fj.12-209379Search in Google Scholar PubMed

Hojjati, M.R. and Jiang, X.C. (2006). Rapid, specific, and sensitive measurements of plasma sphingomyelin and phosphatidylcholine. J. Lipid Res. 47, 673–676.10.1194/jlr.D500040-JLR200Search in Google Scholar PubMed

Honda, A., Ikegami, T., Nakamuta, M., Miyazaki, T., Iwamoto, J., Hirayama, T., Saito, Y., Takikawa, H., Imawari, M., and Matsuzaki, Y. (2013). Anticholestatic effects of bezafibrate in patients with primary biliary cirrhosis treated with ursodeoxycholic acid. Hepatology 57, 1931–1941.10.1002/hep.26018Search in Google Scholar PubMed

Huang, L., Zhao, A., Lew, J.L., Zhang, T., Hrywna, Y., Thompson, J.R., de Pedro, N., Royo, I., Blevins, R.A., Peláez, F., et al. (2003). Farnesoid X receptor activates transcription of the phospholipid pump MDR3. J. Biol. Chem. 278, 51085–51090.10.1074/jbc.M308321200Search in Google Scholar PubMed

Hyde, S.C., Emsley, P., Hartshorn, M.J., Mimmack, M.M., Gileadi, U., Pearce, S.R., Gallagher, M.P., Gill, D.R., Hubbard, R.E., and Higgins, C.F. (1990). Structural model of ATP-binding proteins associated with cystic fibrosis, multidrug resistance and bacterial transport. Nature 346, 362–365.10.1038/346362a0Search in Google Scholar PubMed

Ikebuchi, Y., Takada, T., Ito, K., Yoshikado, T., Anzai, N., Kanai, Y., and Suzuki, H. (2009). Receptor for activated C-kinase 1 regulates the cellular localization and function of ABCB4. Hepatol. Res. 39, 1091–1107.10.1111/j.1872-034X.2009.00544.xSearch in Google Scholar PubMed

Illing, M., Molday, L.L., and Molday, R.S. (1997). The 220-kDa rim protein of retinal rod outer segments is a member of the ABC transporter superfamily. J. Biol. Chem. 272, 10303–10310.10.1074/jbc.272.15.10303Search in Google Scholar PubMed

Ishigami, M., Tominaga, Y., Nagao, K., Kimura, Y., Matsuo, M., Kioka, N., and Ueda, K. (2013). ATPase activity of nucleotide binding domains of human MDR3 in the context of MDR1. Biochim. Biophys. Acta 1831, 683–690.10.1016/j.bbalip.2012.12.016Search in Google Scholar PubMed

Jacquemin, E., De Vree, J.M., Cresteil, D., Sokal, E.M., Sturm, E., Dumont, M., Scheffer, G.L., Paul, M., Burdelski, M., Bosma, P.J., et al. (2001). The wide spectrum of multidrug resistance 3 deficiency: from neonatal cholestasis to cirrhosis of adulthood. Gastroenterology 120, 1448–1458.10.1053/gast.2001.23984Search in Google Scholar PubMed

Kamisako, T., Kobayashi, Y., Takeuchi, K., Ishihara, T., Higuchi, K., Tanaka, Y., Gabazza, E.C., and Adachi, Y. (2000). Recent advances in bilirubin metabolism research: the molecular mechanism of hepatocyte bilirubin transport and its clinical relevance. J. Gastroenterol. 35, 659–664.10.1007/s005350070044Search in Google Scholar PubMed

Kararli, T.T. (1995). Comparison of the gastroitestinal anatomy, physiology, and biochemistry of humans and commonly used laboratory animals. Biopharm. Drug. Dispos. 16, 351–380.10.1002/bdd.2510160502Search in Google Scholar PubMed

Keitel, V., Droge, C., Stepanow, S., Fehm, T., Mayatepek, E., Kohrer, K., and Haussinger, D. (2016). Intrahepatic cholestasis of pregnancy (ICP): case report and review of the literature. Zeitschr. Gastroenterol. 54, 1327–1333.10.1055/s-0042-118388Search in Google Scholar PubMed

Kelley, L.A., Mezulis, S., Yates, C.M., Wass, M.N., and Sternberg, M.J.E. (2015). The Phyre2 web portal for protein modeling, prediction and analysis. Nat. Protoc. 10, 845–858.10.1038/nprot.2015.053Search in Google Scholar PubMed PubMed Central

Kent, C. (1995). Eukaryotic phospholipid biosynthesis. Annu. Rev. Biochem. 64, 315–343.10.1146/annurev.bi.64.070195.001531Search in Google Scholar PubMed

Khabou, B., Durand-Schneider, A.M., Delaunay, J.L., Ait-Slimane, T., Barbu, V., Fakhfakh, F., Housset, C., and Maurice, M. (2017). Comparison of in silico prediction and experimental assessment of ABCB4 variants identified in patients with biliary diseases. Int. J. Biochem. Cell Biol. 89, 101–109.10.1016/j.biocel.2017.05.028Search in Google Scholar PubMed

Kim, Y. and Chen, J. (2018). Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation. Science 359, 915–919.10.1126/science.aar7389Search in Google Scholar PubMed

Kimchi-Sarfaty, C., Oh, J.M., Kim, I.W., Sauna, Z.E., Calcagno, A.M., Ambudkar, S.V., and Gottesman, M.M. (2007). A ‘silent’ polymorphism in the MDR1 gene changes substrate specificity. Science 315, 525–528.10.1126/science.1135308Search in Google Scholar PubMed

Kino, K., Taguchi, Y., Yamada, K., Komano, T., and Ueda, K. (1996). Aureobasidin A, an antifungal cyclic depsipeptide antibiotic, is a substrate for both human MDR1 and MDR2/P-glycoproteins. FEBS Lett. 399, 29–32.10.1016/S0014-5793(96)01265-3Search in Google Scholar

Kipp, H. and Arias, I.M. (2002). Trafficking of canalicular ABC transporters in hepatocytes. Annu. Rev. Physiol. 64, 595–608.10.1146/annurev.physiol.64.081501.155793Search in Google Scholar

Klucken, J., Büchler, C., Orsó, E., Kaminski, W.E., Porsch-Ozcürümez, M., Liebisch, G., Kapinsky, M., Diederich, W., Drobnik, W., Dean, M., et al. (2000). ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport. Proc. Natl. Acad. Sci. USA 97, 817–822.10.1073/pnas.97.2.817Search in Google Scholar

Kluth, M., Stindt, J., Droge, C., Linnemann, D., Kubitz, R., and Schmitt, L. (2015). A mutation within the extended X loop abolished substrate-induced ATPase activity of the human liver ATP-binding cassette (ABC) transporter MDR3. J. Biol. Chem. 290, 4896–4907.10.1074/jbc.M114.588566Search in Google Scholar

Kocher, O., Comella, N., Gilchrist, A., Pal, R., Tognazzi, K., Brown, L.F., and Knoll, J.H. (1999). PDZK1, a novel PDZ domain-containing protein up-regulated in carcinomas and mapped to chromosome 1q21, interacts with cMOAT (MRP2), the multidrug resistance-associated protein. Lab. Invest. 79, 1161–1170.Search in Google Scholar

Krawczyk, M., Mullenbach, R., Weber, S.N., Zimmer, V., and Lammert, F. (2010). Genome-wide association studies and genetic risk assessment of liver diseases. Nat. Rev. Gastro. Hepat. 7, 669–681.10.1038/nrgastro.2010.170Search in Google Scholar

Kruh, G.D. and Belinsky, M.G. (2003). The MRP family of drug efflux pumps. Oncogene 22, 7537–7552.10.1038/sj.onc.1206953Search in Google Scholar

Kubitz, R., Bode, J., Erhardt, A., Graf, D., Kircheis, G., Müller-Stöver, I., Reinehr, R., Reuter, S., Richter, J., Sagir, A., et al. (2011). Cholestatic liver diseases from child to adult: the diversity of MDR3 disease. Z. Gastroenterol. 49, 728–736.10.1055/s-0031-1273427Search in Google Scholar

Lammert, F. and Hochrath, K. (2015). A letter on ABCB4 from Iceland: on the highway to liver disease. Clin. Res. Hepatol. Gas. 39, 655–658.10.1016/j.clinre.2015.08.004Search in Google Scholar

Lammert, F., Marschall, H.U., Glantz, A., and Matern, S. (2000). Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management. J. Hepatol. 33, 1012–1021.10.1016/S0168-8278(00)80139-7Search in Google Scholar

Li, J., Jaimes, K.F., and Aller, S.G. (2014). Refined structures of mouse P-glycoprotein. Protein. Sci. 23, 34–46.10.1002/pro.2387Search in Google Scholar PubMed PubMed Central

Li, W., Zhang, H., Assaraf, Y.G., Zhao, K., Xu, X., Xie, J., Yang, D.H., and Chen, Z.S. (2016). Overcoming ABC transporter-mediated multidrug resistance: molecular mechanisms and novel therapeutic drug strategies. Drug Resist. Updat. 27, 14–29.10.1016/j.drup.2016.05.001Search in Google Scholar

Locher, K.P. (2016). Mechanistic diversity in ATP-binding cassette (ABC) transporters. Nat. Struct. Mol. Biol. 23, 487–493.10.1038/nsmb.3216Search in Google Scholar

Loo, T.W. and Clarke, D.M. (2001). Defining the drug-binding site in the human multidrug resistance P-glycoprotein using a methanethiosulfonate analog of verapamil, MTS-verapamil. J. Biol. Chem. 276, 14972–14979.10.1074/jbc.M100407200Search in Google Scholar

Mahdi, Z.M., Synal-Hermanns, U., Yoker, A., Locher, K.P., and Stieger, B. (2016). Role of multidrug resistance protein 3 in antifungal-induced cholestasis. Mol. Pharmacol. 90, 23.10.1124/mol.116.103390Search in Google Scholar

Marrapodi, M. and Chiang, J.Y.L. (2000). Peroxisome proliferator-activated receptor alpha (PPARα) and agonist inhibit cholesterol 7 alpha-hydroxylase gene (CYP7A1) transcription. J. Lipid Res. 41, 514–520.10.1016/S0022-2275(20)32398-1Search in Google Scholar

McConnell, H.M. and Kornberg, R.D. (2002). Inside-outside transitions of phospholipids in vesicle membranes. Biochemistry 10, 1111–1120.10.1021/bi00783a003Search in Google Scholar PubMed

Meier, P.J., Sztul, E.S., Reuben, A., and Boyer, J.L. (1984). Structural and functional polarity of canalicular and basolateral plasma membrane vesicles isolated in high yield from rat liver. J. Cell Biol. 98, 991–1000.10.1083/jcb.98.3.991Search in Google Scholar PubMed PubMed Central

Meier, Y., Zodan, T., Lang, C., Zimmermann, R., Kullak-Ublick, G.A., Meier, P.J., Stieger, B., and Pauli-Magnus, C. (2008). Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T→C polymorphism in the bile salt export pump. World J. Gastroenterol. 14, 38–45.10.3748/wjg.14.38Search in Google Scholar PubMed PubMed Central

Mi Sun Jin, M.L.O., Zhang, Q., and Chen, J. (2012). Crystal structure of the multidrug transporter P-glycoprotein from C. elegans. Nature 490, 566–569.10.1038/nature11448Search in Google Scholar PubMed PubMed Central

Molday, R.S. (2007). ATP-binding cassette transporter ABCA4: molecular properties and role in vision and macular degeneration. J. Bioenerg. Biomembr. 39, 507–517.10.1007/s10863-007-9118-6Search in Google Scholar PubMed

Morita, S.y., Kobayashi, A., Takanezawa, Y., Kioka, N., Handa, T., Arai, H., Matsuo, M., and Ueda, K. (2007). Bile salt-dependent efflux of cellular phospholipids mediated by ATP binding cassette protein B4. Hepatology 46, 188–199.10.1002/hep.21591Search in Google Scholar

Needleman, P., Turk, J., Jakschik, B.A., Morrison, A.R., and Lefkowith, J.B. (1986). Arachidonic-acid metabolism. Annu. Rev. Biochemi. 55, 69–102.10.1146/annurev.bi.55.070186.000441Search in Google Scholar

Nibbering, C.P., Groen, A.K., Ottenhoff, R., Brouwers, J.F.H.M., vanBerge-Henegouwen, G.P., and van Erpecum, K.J. (2001). Regulation of biliary cholesterol secretion is independent of hepatocyte canalicular membrane lipid composition: a study in the diosgenin-fed rat model. J. Hepatol. 35, 164–169.10.1016/S0168-8278(01)00125-8Search in Google Scholar

Nishimura, M. and Naito, S. (2005). Tissue-speciffic mRNA expression profiles of human ATP-binding cassette and solute transporter superfamilies. Drug Metab. Pharmacokinet. 20, 452–477.10.2133/dmpk.20.452Search in Google Scholar

Oram, J.F. and Lawn, R.M. (2001). ABCA1: the gatekeeper for eliminating excess tissue cholesterol. J. Lipid Res. 42, 1173–1179.10.1016/S0022-2275(20)31566-2Search in Google Scholar

Ortiz, D.F., Moseley, J., Calderon, G., Swift, A.L., Li, S., and Arias, I.M. (2004). Identification of HAX-1 as a protein that binds bile salt export protein and regulates its abundance in the apical membrane of Madin-Darby canine kidney cells. J. Biol. Chem. 279, 32761–32770.10.1074/jbc.M404337200Search in Google Scholar PubMed

Park, H.J., Kim, T.H., Kim, S.W., Noh, S.H., Cho, K.J., Choi, C., Kwon, E.Y., Choi, Y.J., Gee, H.Y., and Choi, J.H. (2016). Functional characterization of ABCB4 mutations found in progressive familial intrahepatic cholestasis type 3. Sci. Rep. 6, 26872.10.1038/srep26872Search in Google Scholar PubMed PubMed Central

Pauli-Magnus, C., Lang, T., Meier, Y., Zodan-Marin, T., Jung, D., Breymann, C., Zimmermann, R., Kenngott, S., Beuers, U., Reichel, C., et al. (2004). Sequence analysis of bile salt export pump (ABCB11) and multidrug resistance p-glycoprotein 3 (ABCB4, MDR3) in patients with intrahepatic cholestasis of pregnancy. Pharmacogenetics 14, 91–102.10.1097/00008571-200402000-00003Search in Google Scholar PubMed

Pohl, A., Devaux, P.F., and Herrmann, A. (2005). Function of prokaryotic and eukaryotic ABC proteins in lipid transport. Biochim. Biophys. Acta 1733, 29–52.10.1016/j.bbalip.2004.12.007Search in Google Scholar PubMed

Poupon, R., Barbu, V., Chamouard, P., Wendum, D., Rosmorduc, O., and Housset, C. (2010). Combined features of low phospholipid-associated cholelithiasis and progressive familial intrahepatic cholestasis 3. Liver Int. 30, 327–331.10.1111/j.1478-3231.2009.02148.xSearch in Google Scholar PubMed

Poupon, R., Rosmorduc, O., Boelle, P.Y., Chretien, Y., Corpechot, C., Chazouilleres, O., Housset, C., and Barbu, V. (2013). Genotype-phenotype relationships in the low-phospholipid-associated cholelithiasis syndrome: a study of 156 consecutive patients. Hepatology 58, 1105–1110.10.1002/hep.26424Search in Google Scholar

Puglielli, L., Amigo, L., Arrese, M., Núñez, L., Rigotti, A., Garrido, J., González, S., Mingrone, G., Greco, A.V., Accatino, L., et al. (1994). protective role of biliary cholesterol and phospholipid lamellae against bile acid-induced cell-damage. Gastroenterology 107, 244–254.10.1016/0016-5085(94)90083-3Search in Google Scholar

Raymond, M., Rose, E., Housman, D.E., and Gros, P. (1990). Physical mapping, amplification, and overexpression of the mouse mdr gene family in multidrug-resistant cells. Mol. Cell Biol. 10, 1642–1651.Search in Google Scholar

Reese, M.G., Eeckman, F.H., Kulp, D., and Haussler, D. (1997). Improved splice site detection in Genie. J. Comput. Biol. 4, 311–323.10.1145/267521.267766Search in Google Scholar

Reichert, M.C., and Lammert, F. (2018). ABCB4 gene aberrations in human liver disease: an evolving spectrum. Semin. Liver Dis. 38, 299–307.10.1055/s-0038-1667299Search in Google Scholar

Rodrigues, A.D., Lai, Y., Cvijic, M.E., Elkin, L.L., Zvyaga, T., and Soars, M.G. (2014). Drug-induced perturbations of the bile acid pool, cholestasis, and hepatotoxicity: mechanistic considerations beyond the direct inhibition of the bile salt export pump. Drug Metab. Dispos. 42, 566–574.10.1124/dmd.113.054205Search in Google Scholar

Roulier, M.A., Palenik, B., and Morel, F.M.M. (1990). A method for the measurement of choline and hydrogen peroxide in seawater. Marine Chem. 30, 409–421.10.1016/0304-4203(90)90084-PSearch in Google Scholar

Ruetz, S. and Gros, P. (1994). Phosphatidylcholine translocase – a physiological-role for the Mdr2 gene. Cell 77, 1071–1081.10.1016/0092-8674(94)90446-4Search in Google Scholar

Ruetz, S. and Gros, P. (1995). Enhancement of Mdr2-mediated phosphatidylcholine translocation by the bile salt taurocholate. Implications for hepatic bile formation. J. Biol. Chem. 270, 25388–25395.10.1074/jbc.270.43.25388Search in Google Scholar

Schmitt, L. and Tampe, R. (2002). Structure and mechanism of ABC transporters. Curr. Opin. Struct. Biol. 12, 754–760.10.1016/S0959-440X(02)00399-8Search in Google Scholar

Schmitt, L., Benabdelhak, H., Blight, M.A., Holland, I.B., and Stubbs, M.T. (2003). Crystal structure of the nucleotide-binding domain of the ABC-transporter haemolysin B: identification of a variable region within ABC helical domains. J. Mol. Biol. 330, 333–342.10.1016/S0022-2836(03)00592-8Search in Google Scholar

Schuster, D., Laggner, C., and Langer, T. (2005). Why drugs fail – a study on side effects in new chemical entities. Curr. Pharm. Des. 11, 3545–3559.10.1002/9783527621460.ch1Search in Google Scholar

Shoda, J., Inada, Y., Tsuji, A., Kusama, H., Ueda, T., Ikegami, T., Suzuki, H., Sugiyama, Y., Cohen, D.E., and Tanaka, N. (2004). Bezafibrate stimulates canalicular localization of NBD-labeled PC in HepG2 cells by PPARα-mediated redistribution of ABCB4. J. Lipid Res. 45, 1813–1825.10.1194/jlr.M400132-JLR200Search in Google Scholar

Small, D.M. (2003). Role of ABC transporters in secretion of cholesterol from liver into bile. Proc. Natl. Acad. Sci. USA 100, 4–6.10.1073/pnas.0237205100Search in Google Scholar

Smit, J.J.M., Schinkel, A.H., Oude Elferink, R.P., Groen, A.K., Wagenaar, E., van Deemter, L., Mol, C.A., Ottenhoff, R., van der Lugt, N.M., van Roon, M.A., et al. (1993). Homozygous disruption of the murine MDR2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75, 451–462.10.1016/0092-8674(93)90380-9Search in Google Scholar

Smith, D.A. and Schmid, E.F. (2006). Drug withdrawals and the lessons within. Curr. Opin. Drug Discov. Devel. 9, 38–46.Search in Google Scholar

Smith, A.J., Timmermans-Hereijgers, J.L., Roelofsen, B., Wirtz, K.W., van Blitterswijk, W.J., Smit, J.J., Schinkel, A.H., and Borst, P. (1994). The human MDR3 P-glycoprotein promotes translocation of phosphatidylcholine through the plasma membrane of fibroblasts from transgenic mice. FEBS Lett. 354, 263–266.10.1016/0014-5793(94)01135-4Search in Google Scholar

Smith, A.J., de Vree, J.M., Ottenhoff, R., Oude Elferink, R.P., Schinkel, A.H., and Borst, P. (1998). Hepatocyte-specific expression of the human MDR3 P-glycoprotein gene restores the biliary phosphatidylcholine excretion absent in Mdr2-/- mice. Hepatology 28, 530–536.10.1002/hep.510280234Search in Google Scholar

Smith, A.J., van Helvoort, A., van Meer, G., Szabo, K., Welker, E., Szakacs, G., Varadi, A., Sarkadi, B., and Borst, P. (2000). 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. 275, 23530–23539.10.1074/jbc.M909002199Search in Google Scholar

Smith, P.C., Karpowich, N., Millen, L., Moody, J.E., Rosen, J., Thomas, P.J., and Hunt, J.F. (2002). ATP binding to the motor domain from an ABC transporter drives formation of a nucleotide sandwich dimer. Mol. Cell 10, 139–149.10.1016/S1097-2765(02)00576-2Search in Google Scholar

Stieger, B. (2010). Role of the bile salt export pump, BSEP, in acquired forms of cholestasis. Drug. Metab. Rev. 42, 437–445.10.3109/03602530903492004Search in Google Scholar

Stieger, B., Fattinger, K., Madon, J., Kullak-Ublick, G.A., and Meier, P.J. (2000). Drug- and estrogen-induced cholestasis through inhibition of the hepatocellular bile salt export pump (Bsep) of rat liver. Gastroenterology 118, 422–430.10.1016/S0016-5085(00)70224-1Search in Google Scholar

Swiatecka-Urban, A., Duhaime, M., Coutermarsh, B., Karlson, K.H., Collawn, J., Milewski, M., Cutting, G.R., Guggino, W.B., Langford, G., and Stanton, B.A. (2002). PDZ domain interaction controls the endocytic recycling of the cystic fibrosis transmembrane conductance regulator. J. Biol. Chem. 277, 40099–40105.10.1074/jbc.M206964200Search in Google Scholar

Takahashi, S., Fukami, T., Masuo, Y., Brocker, C.N., Xie, C., Krausz, K.W., Wolf, C.R., Henderson, C.J., and Gonzalez, F.J. (2016). Cyp2c70 is responsible for the species difference in bile acid metabolism between mice and humans. J. Lipid Res. 57, 2130–2137.10.1194/jlr.M071183Search in Google Scholar

Trauner, M., Fickert, P., and Wagner, M. (2007). MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. Semin. Liver Dis. 27, 77–98.10.1055/s-2006-960172Search in Google Scholar

Trauner, M., Fickert, P., Halilbasic, E., and Moustafa, T. (2008). Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases. Wien. Med. Wochenschr. 158, 542–548.10.1007/s10354-008-0592-1Search in Google Scholar

Trauner, M., Halilbasic, E., Claudel, T., Steinacher, D., Fuchs, C., Moustafa, T., Pollheimer, M., Krones, E., Kienbacher, C., Traussnigg, S., et al. (2015). Potential of nor-ursodeoxycholic acid in cholestatic and metabolic disorders. Dig. Dis. 33, 433–439.10.1159/000371904Search in Google Scholar

Urbatsch, I.L., Wilke-Mounts, S., Gimi, K., and Senior, A.E. (2001). Purification and characterization of N-glycosylation mutant mouse and human P-glycoproteins expressed in Pichia pastoris cells. Arch. Biochem. Biophys. 388, 171–177.10.1006/abbi.2001.2299Search in Google Scholar

Vahedi, S., Chufan, E.E., and Ambudkar, S.V. (2017). Global alteration of the drug-binding pocket of human P-glycoprotein (ABCB1) by substitution of fifteen conserved residues reveals a negative correlation between substrate size and transport efficiency. Biochem. Pharmacol. 143, 53–64.10.1016/j.bcp.2017.07.014Search in Google Scholar

Van der Bliek, A.M., Baas, F., Ten Houte de Lange, T., Kooiman, P.M., Van der Velde-Koerts, T., and Borst, P. (1987). The human mdr3 gene encodes a novel P-glycoprotein homologue and gives rise to alternatively spliced mRNAs in liver. EMBO J. 6, 3325–3331.10.1002/j.1460-2075.1987.tb02653.xSearch in Google Scholar

van der Bliek, A.M., Kooiman, P.M., Schneider, C., and Borst, P. (1988). Sequence of mdr3 cDNA encoding a human P-glycoprotein. Gene 71, 401–411.10.1016/0378-1119(88)90057-1Search in Google Scholar

van der Woerd, W.L., Houwen, R.H., and van de Graaf, S.F. (2017). Current and future therapies for inherited cholestatic liver diseases. World J. Gastroenterol. 23, 763–775.10.3748/wjg.v23.i5.763Search in Google Scholar PubMed PubMed Central

van Dijk, R., Kremer, A.E., Smit, W., van den Elzen, B., van Gulik, T., Gouma, D., Lameris, J.S., Bikker, H., Enemuo, V., Stokkers, P.C., et al. (2015). Characterization and treatment of persistent hepatocellular secretory failure. Liver Int. 35, 1478–1488.10.1111/liv.12603Search in Google Scholar

van Helvoort, A., Smith, A.J., Sprong, H., Fritzsche, I., Schinkel, A.H., Borst, P., and van Meer, G. (1996). MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. Cell 87, 507–517.10.1016/S0092-8674(00)81370-7Search in Google Scholar

Vij, M., Valamparampil, J., Shanmugum, N., Reddy, S.M., Rajindrajith, S., and Rela, M. (2018). Paucity of interlobular bile ducts in multidrug-resistant P-glycoprotein 3 (MDR3) deficiency. Int. J. Surg. Pathol. 1066896918799941.10.1177/1066896918799941Search in Google Scholar

Wendum, D., Barbu, V., Rosmorduc, O., Arrive, L., Flejou, J.F., and Poupon, R. (2012). Aspects of liver pathology in adult patients with MDR3/ABCB4 gene mutations. Virchow’s Arch 460, 291–298.10.1007/s00428-012-1202-6Search in Google Scholar

Wikstrom Shemer, E.A., Stephansson, O., Thuresson, M., Thorsell, M., Ludvigsson, J.F., and Marschall, H.U. (2015). Intrahepatic cholestasis of pregnancy and cancer, immune-mediated and cardiovascular diseases: a population-based cohort study. J. Hepatol. 63, 456–461.10.1016/j.jhep.2015.03.010Search in Google Scholar

Williamson, C. and Geenes, V. (2014). Intrahepatic cholestasis of pregnancy. Obstet. Gynecol. 124, 120–133.10.1097/AOG.0000000000000346Search in Google Scholar

Wustner, D., Herrmann, A., and Muller, P. (2000). Head group-independent interaction of phospholipids with bile salts: a fluorescence and EPR study. J. Lipid Res. 41, 395–404.10.1016/S0022-2275(20)34478-3Search in Google Scholar

Yao, Z.M. and Vance, D.E. (1988). The active synthesis of phosphatidylcholine is required for very low-density lipoprotein secretion from rat hepatocytes. J. Biol. Chem. 263, 2998–3004.10.1016/S0021-9258(18)69166-5Search in Google Scholar

Yousef, I.M. and Fisher, M.M. (1976). In vitro effect of free bile acids on the bile canaliular membrane phospholipids in the rat. Can. J. Biochem. 54, 1040–1046.10.1139/o76-152Search in Google Scholar PubMed

Zaitseva, J., Jenewein, S., Oswald, C., Jumpertz, T., Holland, I.B., and Schmitt, L. (2005a). A molecular understanding of the catalytic cycle of the nucleotide-binding domain of the ABC transporter HlyB. Biochem. Soc. Transact. 33, 990–995.10.1042/BST0330990Search in Google Scholar

Zaitseva, J., Jenewein, S., Wiedenmann, A., Benabdelhak, H., Holland, I.B., and Schmitt, L. (2005b). Functional characterization and ATP-induced dimerization of the isolated ABC-domain of the haemolysin B transporter. Biochemistry 44, 9680–9690.10.1021/bi0506122Search in Google Scholar PubMed

Ziol, M., Barbu, V., Rosmorduc, O., Frassati-Biaggi, A., Barget, N., Hermelin, B., Scheffer, G.L., Bennouna, S., Trinchet, J.C., Beaugrand, M., et al. (2008). ABCB4 heterozygous gene mutations associated with fibrosing cholestatic liver disease in adults. Gastroenterology 135, 131–141.10.1053/j.gastro.2008.03.044Search in Google Scholar PubMed

Received: 2018-11-28
Accepted: 2019-01-28
Published Online: 2019-02-07
Published in Print: 2019-10-25

© 2019 Walter de Gruyter GmbH, Berlin/Boston

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