P-glycoprotein

Jump to: navigation, search


ATP-binding cassette, sub-family B (MDR/TAP), member 1
Identifiers
Symbols ABCB1 ; ABC20; CD243; CLCS; GP170; MDR1; MGC163296; P-gp; PGY1
External IDs OMIM: 171050 MGI97570 HomoloGene55496
RNA expression pattern
File:PBB GE ABCB1 209994 s at tn.png
File:PBB GE ABCB1 209993 at tn.png
More reference expression data
Orthologs

| | bgcolor="#C3FDB8" | Human | bgcolor="#C3FDB8" | Mouse |-

    | bgcolor="#C3FDB8" | Entrez 
    | bgcolor="#eeeeee" style="border-top:2px solid #dddddd; border-right:2px solid #dddddd"| 5243
    | bgcolor="#eeeeee" style="border-top:2px solid #dddddd; border-right:2px solid #dddddd"| 18671

|-

     | bgcolor="#C3FDB8" | Ensembl
     | bgcolor="#eeeeee" style="border-top:2px solid #dddddd; border-right:2px solid #dddddd"| ENSG00000085563
     | bgcolor="#eeeeee" style="border-top:2px solid #dddddd; border-right:2px solid #dddddd"| ENSMUSG00000040584

|-

    | bgcolor="#C3FDB8" | Uniprot
    | bgcolor="#eeeeee" style="border-top:2px solid #dddddd; border-right:2px solid #dddddd"| P08183
    | bgcolor="#eeeeee" style="border-top:2px solid #dddddd; border-right:2px solid #dddddd"| Q9QX25

|-

    | bgcolor="#C3FDB8" | Refseq
    | bgcolor="#eeeeee" style="border-top:2px solid #dddddd; border-right:2px solid #dddddd" | NM_000927 (mRNA)
NP_000918 (protein)
| bgcolor="#eeeeee" style="border-top:2px solid #dddddd; border-right:2px solid #dddddd" |NM_011076 (mRNA)
NP_035206 (protein)

|-

    | bgcolor="#C3FDB8" | Location
    | bgcolor="#eeeeee" style="border-top:2px solid #dddddd; border-right:2px solid #dddddd"|  Chr 7: 86.97 - 87.18 Mb 
    | bgcolor="#eeeeee" style="border-top:2px solid #dddddd; border-right:2px solid #dddddd"|  Chr 5: 8.67 -  8.75 Mb 

|-

|-

    | bgcolor="#C3FDB8" | Pubmed search 
    | bgcolor="#eeeeee" style="border-top:2px solid #dddddd; border-right:2px solid #dddddd"| [1]
| bgcolor="#eeeeee" style="border-top:2px solid #dddddd; border-right:2px solid #dddddd"| [2]
Species Human Mouse
Entrez n/a n/a
Ensembl n/a n/a
UniProt n/a n/a
RefSeq (mRNA) n/a n/a
RefSeq (protein) n/a n/a
Location (UCSC) n/a n/a
PubMed search n/a n/a

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.

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

External links

de:P-Glykoprotein fa:پروتئین P-gp


Linked-in.jpg