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P-glycoprotein




ATP-binding cassette, sub-family B (MDR/TAP), member 1
Identifiers
Symbol(s) ABCB1; ABC20; CD243; CLCS; GP170; MDR1; MGC163296; P-gp; PGY1
External IDs OMIM: 171050 MGI: 97570 Homologene: 55496
RNA expression pattern

More reference expression data

Orthologs
Human Mouse
Entrez 5243 18671
Ensembl ENSG00000085563 ENSMUSG00000040584
Uniprot P08183 Q9QX25
Refseq NM_000927 (mRNA)
NP_000918 (protein)
NM_011076 (mRNA)
NP_035206 (protein)
Location Chr 7: 86.97 - 87.18 Mb Chr 5: 8.67 - 8.75 Mb
Pubmed search [1] [2]

P-glycoprotein (abbreviated as P-gp or Pgp) is a well characterized human ABC-transporter of the MDR/TAP subfamily. It is extensively distributed and expressed in normal cells such as those lining the intestine, liver cells, renal proximal tubular cells, and capillary endothelial cells comprising the blood-brain barrier. P-gp is also called ABCB1, ATP-binding cassette sub-family B member 1, MDR1, and PGY1.

Additional recommended knowledge

Contents

Function

ABCB1 is an ATP-dependent efflux pump with broad substrate specificity. It likely evolved as a defence mechanism against harmful substances.

ABCB1 transports various substrates across the cell membrane including:


Its ability to transport the above substrates accounts for the many roles of ABCB1 including:

  • Regulating the distribution and bioavailability of drugs
    • Increased intestinal expression of P-glycoprotein can reduce the absorption of drugs that are substrates for P-glycoprotein. Thus, there is a reduced bioavailability, therapeutic plasma concentrations are not attained. On the other hand, supratherapeutic plasma concentrations and drug toxicity may result because of decreased P-glycoprotein expression
    • Active cellular transport of antineoplastics resulting in multidrug resistance to these drugs
  • The removal of toxic metabolites and xenobiotics from cells into urine, bile and the intestinal lumen
  • The transport of compounds out of the brain across the blood-brain barrier
  • Digoxin uptake
  • Prevention of ivermectin entry into the central nervous system
  • The migration of dendritic cells
  • Protection of hematopoietic stem cells from toxins.[3]

Structure

Pgp is a 170 kDa transmembrane glycoprotein which includes 10-15 kDa of N-terminal glycosylation. The N-term half of the molecule contains 6 transmembrane domains, followed by a large cytoplasmic domain with an ATP binding site, and then a second section with 6 transmembrane domains and an ATP binding site which shows over 65% of amino acid similarity with the first half of the polypeptide.[4]


History

ABCB1 was first cloned and characterized using its ability to confer a multidrug resistance phenotype to cancer cells that had developed resistance to chemotherapy drugs.[5][6]

References

  1. ^  NCBI
  2. ^  Dean, Michael. The Human ATP-Binding Cassette (ABC) Transporter Superfamily. Bethesda (MD):National Library of Medicine (US), NCBI; 2002 November.
  3. ^  Juliano R.L., Ling V.A. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta. 455:152-162; 1976 Entrez PubMed 990323
  4. ^  Viguié F . ABCB1. Atlas Genet Cytogenet Oncol Haematol. March 1998 [7]

Further reading

  • Ling V (1997). "Multidrug resistance: molecular mechanisms and clinical relevance.". Cancer Chemother. Pharmacol. 40 Suppl: S3-8. PMID 9272126.
  • Kerb R, Hoffmeyer S, Brinkmann U (2001). "ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2.". Pharmacogenomics 2 (1): 51-64. doi:10.1517/14622416.2.1.51. PMID 11258197.
  • Akiyama S (2002). "[Mechanisms of drug resistance and reversal of the resistance]". Hum. Cell 14 (4): 257-60. PMID 11925925.
  • Brinkmann U (2002). "Functional polymorphisms of the human multidrug resistance (MDR1) gene: correlation with P glycoprotein expression and activity in vivo.". Novartis Found. Symp. 243: 207-10; discussion 210-2, 231-5. PMID 11990778.
  • Váradi A, Szakács G, Bakos E, Sarkadi B (2002). "P glycoprotein and the mechanism of multidrug resistance.". Novartis Found. Symp. 243: 54-65; discussion 65-8, 180-5. PMID 11990782.
  • Hegedus T, Orfi L, Seprodi A, et al. (2002). "Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1.". Biochim. Biophys. Acta 1587 (2-3): 318-25. PMID 12084474.
  • Pallis M, Turzanski J, Higashi Y, Russell N (2003). "P-glycoprotein in acute myeloid leukaemia: therapeutic implications of its association with both a multidrug-resistant and an apoptosis-resistant phenotype.". Leuk. Lymphoma 43 (6): 1221-8. PMID 12152989.
  • Schaich M, Illmer T (2003). "Mdr1 gene expression and mutations in Ras proto-oncogenes in acute myeloid leukemia.". Leuk. Lymphoma 43 (7): 1345-54. PMID 12389613.
  • Fromm MF (2003). "The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans.". Adv. Drug Deliv. Rev. 54 (10): 1295-310. PMID 12406646.
  • Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM (2003). "P-glycoprotein: from genomics to mechanism.". Oncogene 22 (47): 7468-85. doi:10.1038/sj.onc.1206948. PMID 14576852.
  • Jamroziak K, Robak T (2004). "Pharmacogenomics of MDR1/ABCB1 gene: the influence on risk and clinical outcome of haematological malignancies.". Hematology 9 (2): 91-105. doi:10.1080/10245330310001638974. PMID 15203864.
  • Ishikawa T, Onishi Y, Hirano H, et al. (2005). "Pharmacogenomics of drug transporters: a new approach to functional analysis of the genetic polymorphisms of ABCB1 (P-glycoprotein/MDR1).". Biol. Pharm. Bull. 27 (7): 939-48. PMID 15256718.
  • Lee W, Lockhart AC, Kim RB, Rothenberg ML (2005). "Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development.". Oncologist 10 (2): 104-11. doi:10.1634/theoncologist.10-2-104. PMID 15709212.
  • Gambrelle J, Labialle S, Dayan G, et al. (2005). "[Multidrug resistance in uveal melanoma.]". Journal français d'ophtalmologie 28 (6): 652-9. PMID 16141933.
  • Al-Shawi MK, Omote H (2006). "The remarkable transport mechanism of P-glycoprotein: a multidrug transporter.". J. Bioenerg. Biomembr. 37 (6): 489-96. doi:10.1007/s10863-005-9497-5. PMID 16691488.
  • Orlowski S, Martin S, Escargueil A (2006). "P-glycoprotein and 'lipid rafts': some ambiguous mutual relationships (floating on them, building them or meeting them by chance?).". Cell. Mol. Life Sci. 63 (9): 1038-59. doi:10.1007/s00018-005-5554-9. PMID 16721513.
  • Annese V, Valvano MR, Palmieri O, et al. (2006). "Multidrug resistance 1 gene in inflammatory bowel disease: a meta-analysis.". World J. Gastroenterol. 12 (23): 3636-44. PMID 16773678.
  • Sekine I, Minna JD, Nishio K, et al. (2007). "A literature review of molecular markers predictive of clinical response to cytotoxic chemotherapy in patients with lung cancer.". Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 1 (1): 31-7. PMID 17409824.

See also

  • MDR1 defect
 
This article is licensed under the GNU Free Documentation License. It uses material from the Wikipedia article "P-glycoprotein". A list of authors is available in Wikipedia.
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