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Abcb1a  -  ATP-binding cassette, sub-family B...

Mus musculus

Synonyms: ATP-binding cassette sub-family B member 1A, Abcb4, Evi32, MDR1A, MDR3, ...
 
 
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Disease relevance of Abcb1a

  • Studies with inside-out plasma membrane vesicles from multidrug-resistant (MDR 3) murine erythroleukemia (MEL/VCR-6) cells have provided evidence for down-modulation of P-glycoprotein (P-gp) function by Ca(2+)-calmodulin (CLM) [1].
  • The role of P-gp in affecting efficacy and toxicity of environmental toxicants such as pesticides and heavy metals has not been adequately investigated [2].
  • Increased expression of P-gp is implicated in decreased HIV drug availability at certain intracellular sites [2].
  • For this purpose, drug-sensitive murine melanoma cells (B16V) and their multidrug-resistant variant cells, (B16VDXR; selected for resistance to DOX) which over-produce P-gp, were employed [3].
  • The effects of length and composition of this connecting region on Pgp cell surface expression and the ability of the two halves to interact were explored using both stable transfections of Pgp mutants in mammalian cell lines and a vaccinia virus transient expression system [4].
 

Psychiatry related information on Abcb1a

  • P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model [5].
  • Furthermore, the mechanism by which d-MPH-induced locomotor activity was attenuated in P-gp KO mice remains to be elucidated [6].
  • No difference neither in the dose response relationship, nor in the time course of response latency times were observed between P-gp knockout and wildtype mice [7].
  • Thus, multidrug-resistant Sa 180 tumors express different defense mechanisms whereas L 1210 tumors express only one defense mechanism (P-glycoprotein) [8].
 

High impact information on Abcb1a

  • The human MDR1 P-glycoprotein (Pgp) extrudes a variety of drugs across the plasma membrane [9].
  • By comparison of mdr1a (+/+) and (-/-) mice, we found that the mdr1a P-glycoprotein is the major P-glycoprotein in the blood-brain barrier and that its absence results in elevated drug levels in many tissues (especially in brain) and in decreased drug elimination [10].
  • Lentiviral vector retargeting to P-glycoprotein on metastatic melanoma through intravenous injection [11].
  • We report here that expression of P-glycoprotein generates volume-regulated, ATP-dependent, chloride-selective channels, with properties similar to channels characterized previously in epithelial cells [12].
  • Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies [13].
 

Chemical compound and disease context of Abcb1a

 

Biological context of Abcb1a

  • We have mutated residues Y397, Y618, Y1040, and Y1263 to tryptophan and analyzed the effect of these substitutions on transport properties, ATP binding, and ATP hydrolysis by Abcb1a (mouse Mdr3) [19].
  • METHODS: We compared the tissue distribution of methadone (R)- and (S)-enantiomers and EDDP in the Abcb1a-/- gene knockout mice and the Abcb1a+/+ wild-type mice 1 h following intraperitoneal administration of 15 microg Rac-methadone/g mouse [20].
  • We hypothesized that there are changes in placental Abcb1a and Abcb1b gene expression and ABCB1 protein levels during pregnancy [21].
  • In conclusion, there are dramatic decreases in Abcb1a and Abcb1b mRNA and in ABCB1 at the maternal-fetal interface over the second half of gestation, suggesting that the fetus may become increasingly susceptible to the influences of xenobiotics and natural steroids in the maternal circulation [21].
  • RESULTS: Two forms of rat Abcb1a were cloned from Sprague-Dawley cDNA that differ by six amino acids and a base pair deletion [22].
 

Anatomical context of Abcb1a

  • Brain penetration of methadone (R)- and (S)-enantiomers is greatly increased by P-glycoprotein deficiency in the blood-brain barrier of Abcb1a gene knockout mice [20].
  • METHODS: We cloned rat Abcb1a and generated a stable LLC-PK1 cell line [22].
  • Intravenous administration of the P-gp substrate drugs [(3)H]digoxin, [(14)C]saquinavir, or paclitaxel to pregnant dams revealed that 2.4-, 7-, or 16-fold more drug, respectively, entered the Mdr1a(-/-)/1b(-/-) fetuses than entered wild-type fetuses [23].
  • MDR cell lines possess multiple phenotypic changes, suggesting that P-gp function could be complemented by some additional mechanisms associated with cytotoxic selection [24].
  • Biochemical characterization of IOVs from control and P-gp-expressing cells isolated by this procedure show that they are greatly enriched for plasma membrane markers, are tightly sealed, and are competent for D-glucose transport [25].
 

Associations of Abcb1a with chemical compounds

  • However, the brain concentrations of (R)- and (S)-methadone in the Abcb1a-/- mice were markedly higher (15- and 23-fold, respectively, P<0.0001) than those of the Abcb1a+/+ wild-type mice [20].
  • Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A [26].
  • The inhibitory effect of UIC2 in vitro was as strong as that of verapamil (a widely used Pgp inhibitor) at its highest clinically achievable concentrations [27].
  • Cells transfected with and expressing MDR1 showed a marked 7- to 10-fold preferential resistance to colchicine and Adriamycin compared with cells expressing equivalent amounts of MDR3 [28].
  • Conversely, cells transfected with and expressing MDR3 showed a two- to threefold preferential resistance to actinomycin D over their cellular counterpart expressing MDR1 [28].
 

Regulatory relationships of Abcb1a

  • Moreover, Mrp1 was rather expressed than P-gp in parenchyma astrocytes and in glia limitans lining the meninges [29].
  • Serum unesterified cholesterol and phospholipids were increased by griseofulvin because of formation of lipoprotein-X in control and Mdr1a/b(-/-) mice only [30].
  • METHODS: Transgenic MDR3-expressing hepatocytes as well as normal mdr2(+/+) hepatocytes were transplanted in mdr2(-/-) mice, and liver repopulation was assessed by immunohistochemistry and measurement of biliary lipid secretion [31].
  • 3. The present study demonstrates that TGF-beta lowers the endothelial permeability and enhances the functional activity of P-gp, suggesting that cellular constituents producing TGF-beta in the brain may keep the BBB functioning [32].
 

Other interactions of Abcb1a

  • We report the cloning and functional analysis of a complete clone for the third member of the mouse mdr gene family, mdr3 [28].
  • Histologically, massive PP deposits were found in livers of control and Mdr1a/b(-/-) mice but not in those of Mdr2(-/-) mice [30].
  • Subsequently, Mdr1a/b/Mrp2 knockout mice were generated [33].
  • Indeed, choroidal and ependymal cells expressed Mrp1 rather than P-gp [29].
  • We were unable to detect significant coinduction of MDR1, MDR2, or MDR3 mRNA with CYP1A1 mRNA or with Cyp1a-1 or Nmo-1 transcription under any conditions [34].
 

Analytical, diagnostic and therapeutic context of Abcb1a

  • Using in situ hybridization, we demonstrated that Abcb1b mRNA is the predominant placental isoform and that there are profound gestational changes in the expression of both Abcb1a and Abcb1b mRNA [21].
  • IMPLICATIONS: Enhanced drug accumulation in nonmalignant tissues after Pgp blockade should be carefully considered in future clinical trials of Pgp modulation [35].
  • Furthermore, placental P-gp activity could be completely inhibited by oral administration of the P-gp blockers PSC833 or GG918 to heterozygous mothers [23].
  • Cellular expression of Pgp results in multidrug resistance (MDR) in vitro and is believed to be a clinically relevant mechanism for tumor resistance to chemotherapy [27].
  • In the present study, the effects of this vaccination were compared in MPC11 cells and their isogenic sublines selected for mdr1/P-glycoprotein (Pgp)-mediated multidrug resistance (MDR) [36].

References

  1. Functional modulation of multidrug resistance-related P-glycoprotein by Ca(2+)-calmodulin. Schlemmer, S.R., Yang, C.H., Sirotnak, F.M. J. Biol. Chem. (1995) [Pubmed]
  2. A role for P-glycoprotein in environmental toxicology. Abu-Qare, A.W., Elmasry, E., Abou-Donia, M.B. Journal of toxicology and environmental health. Part B, Critical reviews. (2003) [Pubmed]
  3. Dipyridamole modulates multidrug resistance and intracellular as well as nuclear levels of doxorubicin in B16 melanoma cells. Damle, B.D., Sridhar, R., Desai, P.B. Int. J. Cancer (1994) [Pubmed]
  4. Structural flexibility of the linker region of human P-glycoprotein permits ATP hydrolysis and drug transport. Hrycyna, C.A., Airan, L.E., Germann, U.A., Ambudkar, S.V., Pastan, I., Gottesman, M.M. Biochemistry (1998) [Pubmed]
  5. P-glycoprotein deficiency at the blood-brain barrier increases amyloid-beta deposition in an Alzheimer disease mouse model. Cirrito, J.R., Deane, R., Fagan, A.M., Spinner, M.L., Parsadanian, M., Finn, M.B., Jiang, H., Prior, J.L., Sagare, A., Bales, K.R., Paul, S.M., Zlokovic, B.V., Piwnica-Worms, D., Holtzman, D.M. J. Clin. Invest. (2005) [Pubmed]
  6. The role of the polymorphic efflux transporter P-glycoprotein on the brain accumulation of d-methylphenidate and d-amphetamine. Zhu, H.J., Wang, J.S., DeVane, C.L., Williard, R.L., Donovan, J.L., Middaugh, L.D., Gibson, B.B., Patrick, K.S., Markowitz, J.S. Drug Metab. Dispos. (2006) [Pubmed]
  7. Antinociceptive effects of morphine-6-glucuronide in homozygous MDR1a P-glycoprotein knockout and in wildtype mice in the hotplate test. Lötsch, J., Tegeder, I., Angst, M.S., Geisslinger, G. Life Sci. (2000) [Pubmed]
  8. Resistance mechanisms in murine tumors with acquired multidrug resistance. Volm, M., Efferth, T., Mattern, J., Pommerenke, E.W. Arzneimittel-Forschung. (1992) [Pubmed]
  9. 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]
  10. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Schinkel, A.H., Smit, J.J., van Tellingen, O., Beijnen, J.H., Wagenaar, E., van Deemter, L., Mol, C.A., van der Valk, M.A., Robanus-Maandag, E.C., te Riele, H.P. Cell (1994) [Pubmed]
  11. Lentiviral vector retargeting to P-glycoprotein on metastatic melanoma through intravenous injection. Morizono, K., Xie, Y., Ringpis, G.E., Johnson, M., Nassanian, H., Lee, B., Wu, L., Chen, I.S. Nat. Med. (2005) [Pubmed]
  12. Volume-regulated chloride channels associated with the human multidrug-resistance P-glycoprotein. Valverde, M.A., Díaz, M., Sepúlveda, F.V., Gill, D.R., Hyde, S.C., Higgins, C.F. Nature (1992) [Pubmed]
  13. Detection of P-glycoprotein in multidrug-resistant cell lines by monoclonal antibodies. Kartner, N., Evernden-Porelle, D., Bradley, G., Ling, V. Nature (1985) [Pubmed]
  14. Effect of P-glycoprotein on the pharmacokinetics and tissue distribution of enaminone anticonvulsants: analysis by population and physiological approaches. Cox, D.S., Scott, K.R., Gao, H., Eddington, N.D. J. Pharmacol. Exp. Ther. (2002) [Pubmed]
  15. Kinetics of daunorubicin transport in Ehrlich ascites tumor cells with different expression of P-glycoprotein. Nielsen, D., Maare, C., Skovsgaard, T. Biochem. Pharmacol. (1994) [Pubmed]
  16. P-glycoprotein (MDR 1 gene product) in cells of the immune system: its possible physiologic role and alteration in aging and human immunodeficiency virus-1 (HIV-1) infection. Gupta, S., Gollapudi, S. J. Clin. Immunol. (1993) [Pubmed]
  17. Modulation and prevention of multidrug resistance by inhibitors of P-glycoprotein. Sikic, B.I., Fisher, G.A., Lum, B.L., Halsey, J., Beketic-Oreskovic, L., Chen, G. Cancer Chemother. Pharmacol. (1997) [Pubmed]
  18. Disruption of mdr1a p-glycoprotein gene results in dysfunction of blood-inner ear barrier in mice. Zhang, Z.J., Saito, T., Kimura, Y., Sugimoto, C., Ohtsubo, T., Saito, H. Brain Res. (2000) [Pubmed]
  19. Mutational analysis of conserved aromatic residues in the A-loop of the ABC transporter ABCB1A (mouse Mdr3). Carrier, I., Urbatsch, I.L., Senior, A.E., Gros, P. FEBS Lett. (2007) [Pubmed]
  20. Brain penetration of methadone (R)- and (S)-enantiomers is greatly increased by P-glycoprotein deficiency in the blood-brain barrier of Abcb1a gene knockout mice. Wang, J.S., Ruan, Y., Taylor, R.M., Donovan, J.L., Markowitz, J.S., DeVane, C.L. Psychopharmacology (Berl.) (2004) [Pubmed]
  21. Multidrug resistance phosphoglycoprotein (ABCB1) in the mouse placenta: fetal protection. Kalabis, G.M., Kostaki, A., Andrews, M.H., Petropoulos, S., Gibb, W., Matthews, S.G. Biol. Reprod. (2005) [Pubmed]
  22. Development and characterization of LLC-PK1 cells containing Sprague-Dawley rat Abcb1a (Mdr1a): comparison of rat P-glycoprotein transport to human and mouse. Booth-Genthe, C.L., Louie, S.W., Carlini, E.J., Li, B., Leake, B.F., Eisenhandler, R., Hochman, J.H., Mei, Q., Kim, R.B., Rushmore, T.H., Yamazaki, M. Journal of pharmacological and toxicological methods. (2006) [Pubmed]
  23. Absence or pharmacological blocking of placental P-glycoprotein profoundly increases fetal drug exposure. Smit, J.W., Huisman, M.T., van Tellingen, O., Wiltshire, H.R., Schinkel, A.H. J. Clin. Invest. (1999) [Pubmed]
  24. Multidrug resistance after retroviral transfer of the human MDR1 gene correlates with P-glycoprotein density in the plasma membrane and is not affected by cytotoxic selection. Choi, K., Frommel, T.O., Stern, R.K., Perez, C.F., Kriegler, M., Tsuruo, T., Roninson, I.B. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  25. Functional expression of P-glycoprotein encoded by the mouse mdr3 gene in yeast cells. Ruetz, S., Raymond, M., Gros, P. Proc. Natl. Acad. Sci. U.S.A. (1993) [Pubmed]
  26. 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]
  27. Efficient inhibition of P-glycoprotein-mediated multidrug resistance with a monoclonal antibody. Mechetner, E.B., Roninson, I.B. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  28. Two members of the mouse mdr gene family confer multidrug resistance with overlapping but distinct drug specificities. Devault, A., Gros, P. Mol. Cell. Biol. (1990) [Pubmed]
  29. Expression of P-glycoprotein (ABCB1) and Mrp1 (ABCC1) in adult rat brain: focus on astrocytes. Mercier, C., Masseguin, C., Roux, F., Gabrion, J., Scherrmann, J.M. Brain Res. (2004) [Pubmed]
  30. Mdr P-glycoproteins are not essential for biliary excretion of the hydrophobic heme precursor protoporphyrin in a griseofulvin-induced mouse model of erythropoietic protoporphyria. Plösch, T., Bloks, V.W., Baller, J.F., Havinga, R., Verkade, H.J., Jansen, P.L., Kuipers, F. Hepatology (2002) [Pubmed]
  31. Correction of liver disease by hepatocyte transplantation in a mouse model of progressive familial intrahepatic cholestasis. De Vree, J.M., Ottenhoff, R., Bosma, P.J., Smith, A.J., Aten, J., Oude Elferink, R.P. Gastroenterology (2000) [Pubmed]
  32. Transforming growth factor-beta1 upregulates the tight junction and P-glycoprotein of brain microvascular endothelial cells. Dohgu, S., Yamauchi, A., Takata, F., Naito, M., Tsuruo, T., Higuchi, S., Sawada, Y., Kataoka, Y. Cell. Mol. Neurobiol. (2004) [Pubmed]
  33. Carcinogen and anticancer drug transport by Mrp2 in vivo: studies using Mrp2 (Abcc2) knockout mice. Vlaming, M.L., Mohrmann, K., Wagenaar, E., de Waart, D.R., Elferink, R.P., Lagas, J.S., van Tellingen, O., Vainchtein, L.D., Rosing, H., Beijnen, J.H., Schellens, J.H., Schinkel, A.H. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  34. Murine mdr-1, mdr-2, and mdr-3 gene expression: no coinduction with the Cyp1a-1 and Nmo-1 genes in liver by 2,3,7,8-tetrachlorodibenzo-p-dioxin. Teeter, L.D., Petersen, D.D., Nebert, D.W., Kuo, M.T. DNA Cell Biol. (1991) [Pubmed]
  35. Altered pharmacokinetics of vinblastine in Mdr1a P-glycoprotein-deficient Mice. van Asperen, J., Schinkel, A.H., Beijnen, J.H., Nooijen, W.J., Borst, P., van Tellingen, O. J. Natl. Cancer Inst. (1996) [Pubmed]
  36. Cytokine-based tumor cell vaccine is equally effective against parental and isogenic multidrug-resistant myeloma cells: the role of cytotoxic T lymphocytes. Shtil, A.A., Turner, J.G., Durfee, J., Dalton, W.S., Yu, H. Blood (1999) [Pubmed]
 
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