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ABCB4  -  ATP-binding cassette, sub-family B...

Homo sapiens

Synonyms: ABC21, ATP-binding cassette sub-family B member 4, GBD1, ICP3, MDR2, ...
 
 
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Disease relevance of ABCB4

 

High impact information on ABCB4

  • The homologous MDR3 Pgp is required for phosphatidylcholine secretion into bile [6].
  • After stable transfection of epithelial LLC-PK1 cells, MDR1 and MDR3 Pgp were localized in the apical membrane [6].
  • The mouse mdr1a (also called mdr3) P-GP is abundant in the blood-brain barrier, and its absence in mdr1a (-/-) mice leads to highly increased levels of the drugs ivermectin, vinblastine, digoxin, and cyclosporin A in the brain [7].
  • We have previously shown that absence of the mouse mdr1a (also called mdr3) P-glycoprotein in mdr1a (-/-) "knockout" mice has a profound effect on the tissue distribution and elimination of vinblastine and ivermectin, and hence on the toxicity of these compounds [8].
  • MDR1 mRNA was detected in 25 of 26 cases and MDR3 mRNA in all 26 [9].
 

Chemical compound and disease context of ABCB4

 

Biological context of ABCB4

  • All coding exons, 5 of 6 noncoding exons, 50 to 300 base pairs of the flanking intronic regions, and 2.5 to 2.8 kilobase pairs of the promoter regions of ABCB4 and ABCB11 were sequenced in 159 and 196 DNA samples of Caucasian, African-American, Japanese, and Korean origin [15].
  • Haplotype variability was greater in ABCB11 than in ABCB4 [15].
  • Treatment of these lines with either chemically synthesized siRNAs or transfection with specific vectors that express targeted siRNAs demonstrated decreased mRNA and protein levels of ABCB1 or ABCB4 [3].
  • Our cDNAs provide evidence for alternative splicing of mdr3 pre-mRNAs [16].
  • Conclusion: This study demonstrates that splicing mutations in the MDR3 gene can cause ICP with normal gamma-GT and may be associated with stillbirths and gallstone disease [1].
 

Anatomical context of ABCB4

 

Associations of ABCB4 with chemical compounds

  • Fibrates, including bezafibrate (BF), upregulate the expression of ATP binding cassette protein B4 (ABCB4) through gene transcription in mice [2].
  • One is an ABCB4 mutation which causes a deficiency in biliary PC secretion and the other is a CYP7A1 mutation, the rate-limiting enzyme in the synthesis of bile salts from cholesterol in the liver [19].
  • In vitro drug uptake studies by on-line flow cytometry showed that in leukemia cells expressing either mdr1 or mdr3, the steady-state accumulation of daunorubicin could be significantly increased by addition of cyclosporine and, to a lesser extent, by verapamil [4].
  • Consistent with these data, MDR3 mRNA was significantly induced by both chenodeoxycholate and GW4064 in primary human hepatocytes in time- and dose-dependent fashions [20].
  • The addition of CyA led to significant increases in intracellular Rh123 levels in mdr1 P-gp-negative and mdr3 P-gp-positive leukemic cells [21].
 

Physical interactions of ABCB4

  • We conclude that MDR3 P-glycoprotein can bind and transport a subset of MDR1 P-glycoprotein substrates [22].
 

Regulatory relationships of ABCB4

 

Other interactions of ABCB4

 

Analytical, diagnostic and therapeutic context of ABCB4

  • Expression of MDR1 and MDR3 (also known as PGY3) messenger RNA (mRNA) was quantitatively evaluated by polymerase chain reaction (PCR) in 26 cases [9].
  • Therefore, 149 healthy Caucasian control individuals (control group) were compared to 76 PBC and 46 PSC patients with respect to genetic variations in BSEP and MDR3 [29].
  • Associations with markers of poor prognosis or prior chemotherapy did not reach statistical significance, but MDR-3 P-gp positive patients had significantly shorter survivals than MDR-3 P-gp negative patients [30].
  • We investigated the cross-reactivity of the monoclonal antibodies C219, C494, JSB-1, HYB-241, and MRK16, recognizing human MDR1 P-glycoprotein, with human MDR3 P-glycoprotein using immunocytochemistry and immunoblotting [23].
  • Increased levels of mdr1 mRNAs were evident in 2-AAF-treated rat hepatocytes by Northern blot analysis using rat mdr gene-specific probes, while transcripts of the mdr2 and mdr3 genes were decreased and unaffected respectively [31].

References

  1. Linkage between a new splicing site mutation in the MDR3 alias ABCB4 gene and intrahepatic cholestasis of pregnancy. Schneider, G., Paus, T.C., Kullak-Ublick, G.A., Meier, P.J., Wienker, T.F., Lang, T., van de Vondel, P., Sauerbruch, T., Reichel, C. Hepatology (2007) [Pubmed]
  2. Bezafibrate stimulates canalicular localization of NBD-labeled PC in HepG2 cells by PPARalpha-mediated redistribution of ABCB4. Shoda, J., Inada, Y., Tsuji, A., Kusama, H., Ueda, T., Ikegami, T., Suzuki, H., Sugiyama, Y., Cohen, D.E., Tanaka, N. J. Lipid Res. (2004) [Pubmed]
  3. Inhibition of ABCB1 (MDR1) and ABCB4 (MDR3) expression by small interfering RNA and reversal of paclitaxel resistance in human ovarian cancer cells. Duan, Z., Brakora, K.A., Seiden, M.V. Mol. Cancer Ther. (2004) [Pubmed]
  4. Expression of mdr1 and mdr3 multidrug-resistance genes in human acute and chronic leukemias and association with stimulation of drug accumulation by cyclosporine. Herweijer, H., Sonneveld, P., Baas, F., Nooter, K. J. Natl. Cancer Inst. (1990) [Pubmed]
  5. Intrahepatic cholestasis of pregnancy: the severe form is associated with common variants of the hepatobiliary phospholipid transporter ABCB4 gene. Wasmuth, H.E., Glantz, A., Keppeler, H., Simon, E., Bartz, C., Rath, W., Mattsson, L.A., Marschall, H.U., Lammert, F. Gut (2007) [Pubmed]
  6. MDR1 P-glycoprotein is a lipid translocase of broad specificity, while MDR3 P-glycoprotein specifically translocates phosphatidylcholine. van Helvoort, A., Smith, A.J., Sprong, H., Fritzsche, I., Schinkel, A.H., Borst, P., van Meer, G. Cell (1996) [Pubmed]
  7. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. Schinkel, A.H., Wagenaar, E., Mol, C.A., van Deemter, L. J. Clin. Invest. (1996) [Pubmed]
  8. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. Schinkel, A.H., Wagenaar, E., van Deemter, L., Mol, C.A., Borst, P. J. Clin. Invest. (1995) [Pubmed]
  9. Activity of P-glycoprotein in B-cell chronic lymphocytic leukemia determined by a flow cytometric assay. Ludescher, C., Hilbe, W., Eisterer, W., Preuss, E., Huber, C., Gotwald, M., Hofmann, J., Thaler, J. J. Natl. Cancer Inst. (1993) [Pubmed]
  10. ABCB4 gene mutation-associated cholelithiasis in adults. Rosmorduc, O., Hermelin, B., Boelle, P.Y., Parc, R., Taboury, J., Poupon, R. Gastroenterology (2003) [Pubmed]
  11. MDR3 gene defect in adults with symptomatic intrahepatic and gallbladder cholesterol cholelithiasis. Rosmorduc, O., Hermelin, B., Poupon, R. Gastroenterology (2001) [Pubmed]
  12. Analysis of the in vivo functions of Mrp3. Belinsky, M.G., Dawson, P.A., Shchaveleva, I., Bain, L.J., Wang, R., Ling, V., Chen, Z.S., Grinberg, A., Westphal, H., Klein-Szanto, A., Lerro, A., Kruh, G.D. Mol. Pharmacol. (2005) [Pubmed]
  13. Spontaneous multidrug transport in human glioma cells is regulated by transforming growth factors type beta. Schluesener, H.J., Meyermann, R. Acta Neuropathol. (1991) [Pubmed]
  14. Effects of type and level of training on variation in physician knowledge in the use and acquisition of blood cultures: a cross sectional survey. Parada, J.P., Schwartz, D.N., Schiff, G.D., Weiss, K.B. BMC Infect. Dis. (2005) [Pubmed]
  15. Genetic variability, haplotype structures, and ethnic diversity of hepatic transporters MDR3 (ABCB4) and bile salt export pump (ABCB11). Lang, T., Haberl, M., Jung, D., Drescher, A., Schlagenhaufer, R., Keil, A., Mornhinweg, E., Stieger, B., Kullak-Ublick, G.A., Kerb, R. Drug Metab. Dispos. (2006) [Pubmed]
  16. The human mdr3 gene encodes a novel P-glycoprotein homologue and gives rise to alternatively spliced mRNAs in liver. Van der Bliek, A.M., Baas, F., Ten Houte de Lange, T., Kooiman, P.M., Van der Velde-Koerts, T., Borst, P. EMBO J. (1987) [Pubmed]
  17. Modulation of multidrug resistance gene expression by dexamethasone in cultured hepatoma cells. Zhao, J.Y., Ikeguchi, M., Eckersberg, T., Kuo, M.T. Endocrinology (1993) [Pubmed]
  18. ABC drug transporter expression and functional activity in trophoblast-like cell lines and differentiating primary trophoblast. Evseenko, D.A., Paxton, J.W., Keelan, J.A. Am. J. Physiol. Regul. Integr. Comp. Physiol. (2006) [Pubmed]
  19. Relevance of hereditary defects in lipid transport proteins for the pathogenesis of cholesterol gallstone disease. vanBerge-Henegouwen, G.P., Venneman, N.G., Portincasa, P., Kosters, A., van Erpecum, K.J., Groen, A.K. Scand. J. Gastroenterol. Suppl. (2004) [Pubmed]
  20. Farnesoid X receptor activates transcription of the phospholipid pump MDR3. Huang, L., Zhao, A., Lew, J.L., Zhang, T., Hrywna, Y., Thompson, J.R., de Pedro, N., Royo, I., Blevins, R.A., Peláez, F., Wright, S.D., Cui, J. J. Biol. Chem. (2003) [Pubmed]
  21. Expression of the MDR1 and MDR3 gene products in acute and chronic leukemias. Arai, Y., Masuda, M., Sugawara, I., Arai, T., Motoji, T., Tsuruo, T., Oshimi, K., Mizoguchi, H. Leuk. Res. (1997) [Pubmed]
  22. MDR3 P-glycoprotein, a phosphatidylcholine translocase, transports several cytotoxic drugs and directly interacts with drugs as judged by interference with nucleotide trapping. Smith, A.J., van Helvoort, A., van Meer, G., Szabo, K., Welker, E., Szakacs, G., Varadi, A., Sarkadi, B., Borst, P. J. Biol. Chem. (2000) [Pubmed]
  23. Characterization of the human MDR3 P-glycoprotein and its recognition by P-glycoprotein-specific monoclonal antibodies. Schinkel, A.H., Roelofs, E.M., Borst, P. Cancer Res. (1991) [Pubmed]
  24. Expression and localization of hepatobiliary transport proteins in progressive familial intrahepatic cholestasis. Keitel, V., Burdelski, M., Warskulat, U., Kühlkamp, T., Keppler, D., Häussinger, D., Kubitz, R. Hepatology (2005) [Pubmed]
  25. Characterization of the 5'-flanking region of the human multidrug resistance protein 2 (MRP2) gene and its regulation in comparison withthe multidrug resistance protein 3 (MRP3) gene. Stöckel, B., König, J., Nies, A.T., Cui, Y., Brom, M., Keppler, D. Eur. J. Biochem. (2000) [Pubmed]
  26. Frequent expression of P-glycoprotein/MDR1 by nasal T-cell lymphoma cells. Yamaguchi, M., Kita, K., Miwa, H., Nishii, K., Oka, K., Ohno, T., Shirakawa, S., Fukumoto, M. Cancer (1995) [Pubmed]
  27. Bile salt export pump gene mutations in two Japanese patients with progressive familial intrahepatic cholestasis. Goto, K., Sugiyama, K., Sugiura, T., Ando, T., Mizutani, F., Terabe, K., Ban, K., Togari, H. J. Pediatr. Gastroenterol. Nutr. (2003) [Pubmed]
  28. Hepatic expression of ABC transporters G5 and G8 does not correlate with biliary cholesterol secretion in liver transplant patients. Geuken, E., Visser, D.S., Leuvenink, H.G., de Jong, K.P., Peeters, P.M., Slooff, M.J., Kuipers, F., Porte, R.J. Hepatology (2005) [Pubmed]
  29. BSEP and MDR3 haplotype structure in healthy Caucasians, primary biliary cirrhosis and primary sclerosing cholangitis. Pauli-Magnus, C., Kerb, R., Fattinger, K., Lang, T., Anwald, B., Kullak-Ublick, G.A., Beuers, U., Meier, P.J. Hepatology (2004) [Pubmed]
  30. MDR-1, but not MDR-3 gene expression, is associated with unmutated IgVH genes and poor prognosis chromosomal aberrations in chronic lymphocytic leukemia. Matthews, C., Catherwood, M.A., Larkin, A.M., Clynes, M., Morris, T., Alexander, H.D. Leuk. Lymphoma (2006) [Pubmed]
  31. Differential regulation of mdr genes in response to 2-acetylaminofluorene treatment in cultured rat and human hepatocytes. Lecureur, V., Guillouzo, A., Fardel, O. Carcinogenesis (1996) [Pubmed]
 
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