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P-glycoprotein

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ABCB1
Identifiers
AliasesABCB1, ABC20, CD243, CLCS, GP170, MDR1, P-GP, PGY1, ATP binding cassette subfamily B member 1, P-glycoprotein, P-gp, Pgp
External IDsOMIM: 171050; MGI: 97570; HomoloGene: 55496; GeneCards: ABCB1; OMA:ABCB1 - orthologs
Orthologs
SpeciesHumanMouse
Entrez

5243

18671

Ensembl

ENSG00000085563

ENSMUSG00000040584

UniProt

P08183

P21447

RefSeq (mRNA)

NM_000927

NM_011076

RefSeq (protein)

NP_000918
NP_001335873
NP_001335874
NP_001335875

NP_035206

Location (UCSC)n/aChr 5: 8.71 – 8.8 Mb
PubMed search[2][3]
Wikidata
View/Edit HumanView/Edit Mouse
ABCB1 is differentially expressed in 97 experiments [93 up/106 dn]: 26 organism parts: kidney [2 up/0 dn], bone marrow [0 up/2 dn], ...; 29 disease states: normal [10 up/3 dn], glioblastoma [0 up/2 dn], ...; 30 cell types, 22 cell lines, 11 compound treatments and 16 other conditions.
Factor Value Factor Up/Down
Legend: - number of studies the gene is up/down in
Normal Disease state 10/3
None Compound treatment 3/0
Stromal cell Cell type 1/2
Kidney Cell type 2/0
MDA-MB-231 Cell line 0/2
Glioblastoma Disease state 0/2
Epithelial cell Cell type 0/2
HeLa Cell line 0/2
Primary Disease staging 2/0
Bone marrow Organism part 0/2
ABCB1 expression data in ATLAS

P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein of the cell membrane that pumps many foreign substances out of cells. More formally, it is an ATP-dependent efflux pump with broad substrate specificity. It exists in animals, fungi and bacteria and likely evolved as a defense mechanism against harmful substances.

P-gp is extensively distributed and expressed in the intestinal epithelium where it pumps xenobiotics (such as toxins or drugs) back into the intestinal lumen, in liver cells where it pumps them into bile ducts, in the cells of the proximal tubule of the kidney where it pumps them into urine-conducting ducts, and in the capillary endothelial cells composing the blood–brain barrier and blood-testis barrier, where it pumps them back into the capillaries.

P-gp is a glycoprotein that in humans is encoded by the ABCB1 gene.[4] P-gp is a well-characterized ABC-transporter (which transports a wide variety of substrates across extra- and intracellular membranes) of the MDR/TAP subfamily.[5] The normal excretion of xenobiotics back into the gut lumen by P-gp pharmacokinetically reduces the efficacy of some pharmaceutical drugs (which are said to be P-gp substrates). In addition, some cancer cells also express large amounts of P-gp, further amplifying that effect and rendering these cancers multidrug resistant. Many drugs inhibit P-gp, typically incidentally rather than as their main mechanism of action; some foods do as well. Any such substance can sometimes be called a P-gp inhibitor.

P-gp was discovered in 1971 by Victor Ling.

Function

The protein belongs to the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance. P-gp is an ATP-dependent drug efflux pump for xenobiotic compounds with broad substrate specificity. It is responsible for decreased drug accumulation in multidrug-resistant cells and often mediates the development of resistance to anticancer drugs. This protein also functions as a transporter in the blood–brain barrier.[6]

P-gp transports various substrates across the cell membrane including:

Its ability to transport the above substrates accounts for the many roles of P-gp 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, and 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 and loperamide entry into the central nervous system
  • The migration of dendritic cells
  • Protection of hematopoietic stem cells from toxins.[5]

It is inhibited by many drugs, such as Amiodarone, Azithromycin, Captopril, Clarithromycin, Cyclosporine, Piperine, Quercetin, Quinidine, Quinine, Reserpine, Ritonavir, Tariquidar, and Verapamil[7].

Structure

P-gp is a 170 kDa transmembrane glycoprotein, which includes 10-15 kDa of N-terminal glycosylation. The N-terminal 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 that shows over 65% of amino acid similarity with the first half of the polypeptide.[8] In 2009, the first structure of a mammalian P-glycoprotein was solved (3G5U).[9] The structure was derived from the mouse MDR3 gene product heterologously expressed in Pichia pastoris yeast. The structure of mouse P-gp is similar to structures of the bacterial ABC transporter MsbA (3B5W and 3B5X)[10] that adopt an inward facing conformation that is believed to be important for binding substrate along the inner leaflet of the membrane. Additional structures (3G60 and 3G61) of P-gp were also solved revealing the binding site(s) of two different cyclic peptide substrate/inhibitors. The promiscuous binding pocket of P-gp is lined with aromatic amino acid side chains. However, the murine P-gp structure is incomplete, missing an intermediate linker sequence proved to be essential for substrate recognition and ATP hydrolysis. Through Molecular Dynamic (MD) simulations, this sequence was proved to have a direct impact in the transporter's structural stability (in the nucleotide-binding domains) and defining a lower boundary for the internal drug-binding pocket.[11]

Mechanism of action

Substrate enters P-gp either from an opening within the inner leaflet of the membrane or from an opening at the cytoplasmic side of the protein. ATP binds at the cytoplasmic side of the protein. Following binding of each, ATP hydrolysis shifts the substrate into a position to be excreted from the cell. Release of the phosphate (from the original ATP molecule) occurs concurrently with substrate excretion. ADP is released, and a new molecule of ATP binds to the secondary ATP-binding site. Hydrolysis and release of ADP and a phosphate molecule resets the protein, so that the process can start again...

Tissue distribution

P-gp is expressed primarily in certain cell types in the liver, pancreas, kidney, colon, and jejunum.[12] P-gp is also found in brain capillary endothelial cells.[13]

Detecting the activity of the transporter

Radioactive verapamil can be used for measuring P-gp function with positron emission tomography.[14]

P-gp is also used to differentiate transitional B-cells from naive B-cells. Dyes such as Rhodamine123 and MitoTracker Dyes from Invitrogen can be used to make this differentiation.[15]

History

P-gp was first cloned and characterized in 1976. It was shown to be responsible for conferring multidrug resistance upon mutant cultured cancer cells that had developed resistance to cytotoxic drugs.[5][16]

The structure of P-gp was resolved by x-ray crystallography in 2009.[9]

References

  1. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000040584 – Ensembl, May 2017
  2. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ Ueda K, Clark DP, Chen CJ, Roninson IB, Gottesman MM, Pastan I (Jan 1987). "The human multidrug resistance (mdr1) gene. cDNA cloning and transcription initiation". The Journal of Biological Chemistry. 262 (2): 505–8. PMID 3027054.
  5. ^ a b c Dean, Michael (2002-11-01). "The Human ATP-Binding Cassette (ABC) Transporter Superfamily". National Library of Medicine (US), NCBI. Archived from the original on 2006-02-12. Retrieved 2008-03-02. {{cite web}}: Unknown parameter |deadurl= ignored (|url-status= suggested) (help)
  6. ^ "Entrez Gene: ABCB1".
  7. ^ "Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers".
  8. ^ Franck Viguié (1998-03-01). "ABCB1". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Retrieved 2008-03-02.
  9. ^ a b Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G (Mar 2009). "Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding". Science. 323 (5922). Science: 1718–22. doi:10.1126/science.1168750. PMC 2720052. PMID 19325113.
  10. ^ Ward A, Reyes CL, Yu J, Roth CB, Chang G (Nov 2007). "Flexibility in the ABC transporter MsbA: Alternating access with a twist". Proceedings of the National Academy of Sciences of the United States of America. 104 (48): 19005–10. doi:10.1073/pnas.0709388104. PMC 2141898. PMID 18024585.
  11. ^ Ferreira RJ, Ferreira MJ, Dos Santos DJ (Jun 2012). "Insights on P-Glycoprotein's Efflux Mechanism Obtained by Molecular Dynamics Simulations". Journal of Chemical Theory and Computation. 8 (6): 1853–64. doi:10.1021/ct300083m. PMID 26593820.
  12. ^ Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (Nov 1987). "Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues". Proceedings of the National Academy of Sciences of the United States of America. 84 (21): 7735–8. doi:10.1073/pnas.84.21.7735. PMC 299375. PMID 2444983.
  13. ^ Schinkel AH (Apr 1999). "P-Glycoprotein, a gatekeeper in the blood-brain barrier". Advanced Drug Delivery Reviews. 36 (2–3): 179–194. doi:10.1016/S0169-409X(98)00085-4. PMID 10837715.
  14. ^ Luurtsema G, Windhorst AD, Mooijer MP, Herscheid A, Lammertsma AA, Franssen EJ (2002). "Fully automated high yield synthesis of (R)- and (S)-[C-11]verapamil for measuring P-glycoprotein function with positron emission tomography". Journal of Labelled Compounds & Radiopharmaceuticals. 45 (14): 1199–1207. doi:10.1002/jlcr.632.
  15. ^ Wirths S, Lanzavecchia A (Dec 2005). "ABCB1 transporter discriminates human resting naive B cells from cycling transitional and memory B cells". European Journal of Immunology. 35 (12): 3433–41. doi:10.1002/eji.200535364. PMID 16259010.
  16. ^ Juliano RL, Ling V (Nov 1976). "A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants". Biochimica et Biophysica Acta. 455 (1): 152–62. doi:10.1016/0005-2736(76)90160-7. PMID 990323.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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