P-glycoprotein: Difference between revisions
m →Mechanism of action: typo. |
|||
Line 77: | Line 77: | ||
== Tissue distribution == |
== Tissue distribution == |
||
P-glycoprotein is expressed primarily in certain cell types in the liver, pancreas, kidney, colon, and jejunum.<ref name="pmid2444983">{{cite journal | author = Thiebaut F, Tsuruo T, Hamada H, [[Michael M. Gottesman|Gottesman MM]], Pastan I, Willingham MC | title = Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 84 | issue = 21 | pages = 7735–8 | year = 1987 | month = November | pmid = 2444983 | pmc = 299375 | doi = 10.1073/pnas.84.21.7735 }}</ref> |
P-glycoprotein is expressed primarily in certain cell types in the [[liver]], [[pancreas]], [[kidney]], [[colon]], and [[jejunum]].<ref name="pmid2444983">{{cite journal | author = Thiebaut F, Tsuruo T, Hamada H, [[Michael M. Gottesman|Gottesman MM]], Pastan I, Willingham MC | title = Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 84 | issue = 21 | pages = 7735–8 | year = 1987 | month = November | pmid = 2444983 | pmc = 299375 | doi = 10.1073/pnas.84.21.7735 }}</ref> |
||
==Detecting the activity of the transporter== |
==Detecting the activity of the transporter== |
Revision as of 13:32, 18 October 2012
ABCB1 at EBI Gene Expression Atlas
| ||
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: ![]() | ||
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 a glycoprotein that in humans is encoded by the ABCB1 gene.[1] 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.[2]
Pgp is extensively distributed and expressed in the intestinal epithelium, hepatocytes, renal proximal tubular cells, adrenal gland and capillary endothelial cells comprising the blood-brain and blood-testis barrier.
Function
The membrane-associated protein encoded by this gene is a member of 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. The protein encoded by this gene 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.[3]
ABCB1 is an ATP-dependent efflux pump with broad substrate specificity. It likely evolved as a defense mechanism against harmful substances.
ABCB1 transports various substrates across the cell membrane including:
- Drugs such as colchicine, tacrolimus and quinidine
- Chemotherapeutic agents such as etoposide, doxorubicin, and vinblastine
- Lipids
- Steroids
- Xenobiotics
- Peptides
- Bilirubin
- Cardiac glycosides like digoxin
- Immunosuppressive agents
- Glucocorticoids like dexamethasone
- HIV-type 1 antiretroviral therapy agents like protease inhibitors and nonnucleoside reverse transcriptase inhibitors.
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, 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 entry into the central nervous system
- The migration of dendritic cells
- Protection of hematopoietic stem cells from toxins.[2]
Structure
Pgp 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.[4] In 2009, the first structure of a mammalian P-glycoprotein was solved (3G5U).[5] 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)Ward A, Reyes CL, Yu J, Roth CB, Chang G (2007). "Flexibility in the ABC transporter MsbA: Alternating access with a twist". Proc. Natl. Acad. Sci. U.S.A. 104 (48): 19005–10. doi:10.1073/pnas.0709388104. PMC 2141898. PMID 18024585. {{cite journal}}
: Unknown parameter |month=
ignored (help)CS1 maint: multiple names: authors list (link) 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.
Mechanism of action
Binding of a substrate and ATP molecule occur simultaneously. 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.
Tissue distribution
P-glycoprotein is expressed primarily in certain cell types in the liver, pancreas, kidney, colon, and jejunum.[6]
Detecting the activity of the transporter
The activity of the transporter can be determined by both membrane ATPase and cellular calcein assays.
The ABCB1 Transporter 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.Wirths S, Lanzavecchia A (2005). "ABCB1 transporter discriminates human resting naive B cells from cycling transitional and memory B cells". Eur. J. Immunol. 35 (12): 3433–41. doi:10.1002/eji.200535364. PMID 16259010. {{cite journal}}
: Unknown parameter |month=
ignored (help)
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.[2][7]
Radioactive verapamil can be used for measuring P-glycoprotein function with positron emission tomography.[8]
See also
References
- ^ Ueda K, Clark DP, Chen CJ, Roninson IB, Gottesman MM, Pastan I (1987). "The human multidrug resistance (mdr1) gene. cDNA cloning and transcription initiation". J. Biol. Chem. 262 (2): 505–8. PMID 3027054.
{{cite journal}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ a b c Dean, Michael (2002-11-01). "The Human ATP-Binding Cassette (ABC) Transporter Superfamily". National Library of Medicine (US), NCBI. Retrieved 2008-03-02.
{{cite web}}
: Cite has empty unknown parameter:|coauthors=
(help) - ^ "Entrez Gene: ABCB1".
- ^ Franck Viguié (1998-03-01). "ABCB1". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Retrieved 2008-03-02.
{{cite web}}
: Cite has empty unknown parameter:|coauthors=
(help) - ^ Stephen Aller (2009-03-27). "Structure of P-glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding". Science. 323 (5922). Science: 1718–1722. doi:10.1126/science.1168750. PMC 2720052. PMID 19325113. Retrieved 2009-04-12.
{{cite journal}}
: Unknown parameter|coauthors=
ignored (|author=
suggested) (help) - ^ Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, Willingham MC (1987). "Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues". Proc. Natl. Acad. Sci. U.S.A. 84 (21): 7735–8. doi:10.1073/pnas.84.21.7735. PMC 299375. PMID 2444983.
{{cite journal}}
: Unknown parameter|month=
ignored (help)CS1 maint: multiple names: authors list (link) - ^ Juliano RL, Ling V (1976). "A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants". Biochim. Biophys. Acta. 455 (1): 152–62. doi:10.1016/0005-2736(76)90160-7. PMID 990323.
- ^ Luurtsema G, Windhorst AD, Mooijer MPJ, Herscheid A, Lammertsma AA, Franssen EJF (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.
{{cite journal}}
: CS1 maint: multiple names: authors list (link)
Further reading
- Ling V (1997). "Multidrug resistance: molecular mechanisms and clinical relevance". Cancer Chemother. Pharmacol. 40 Suppl (7): S3–8. doi:10.1007/s002800051053. 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.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - 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. Novartis Foundation Symposia. 243: 207–10, discussion 210–2, 231–5. doi:10.1002/0470846356.ch15. ISBN 978-0-470-84635-3. PMID 11990778.
- Váradi A, Szakács G, Bakos E, Sarkadi B (2002). "P glycoprotein and the mechanism of multidrug resistance". Novartis Found. Symp. Novartis Foundation Symposia. 243: 54–65, discussion 65–8, 180–5. doi:10.1002/0470846356.ch5. ISBN 978-0-470-84635-3. PMID 11990782.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - 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.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - 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. doi:10.1080/10428190290026277. PMID 12152989.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - Schaich M, Illmer T (2003). "Mdr1 gene expression and mutations in Ras proto-oncogenes in acute myeloid leukemia". Leuk. Lymphoma. 43 (7): 1345–54. doi:10.1080/10428190290033279. 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. doi:10.1016/S0169-409X(02)00064-9. 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.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - 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. doi:10.1248/bpb.27.939. PMID 15256718.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - 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.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - Gambrelle J, Labialle S, Dayan G; et al. (2005). "[Multidrug resistance in uveal melanoma.]". Journal français d'ophtalmologie. 28 (6): 652–9. PMID 16141933.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - 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. PMC 1459968. 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.
{{cite journal}}
: CS1 maint: multiple names: authors list (link) - 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.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - 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.
{{cite journal}}
: Explicit use of et al. in:|author=
(help)CS1 maint: multiple names: authors list (link) - Kumar YS, Adukondalu D, Sathish D, Vishnu YV, Ramesh G, Latha AB, Reddy PC, Sarangapani M, Rao YM (2010). "P-Glycoprotein- and cytochrome P-450-mediated herbal drug interactions". Drug Metabol Drug Interact. 25 (1–4): 3–16. doi:10.1515/DMDI.2010.006. PMID 21417789.
{{cite journal}}
: CS1 maint: multiple names: authors list (link)
External links
- P-Glycoprotein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Jessica R Oesterheld (2002-05-01). "P-glycoprotein". Mental Health Connections, Inc. Archived from the original on 2008-02-07. Retrieved 2008-03-02.
{{cite web}}
: Cite has empty unknown parameter:|coauthors=
(help) - P-glycoprotein substrate prediction
- NextBio.com
- PharmGKB.org
This article incorporates text from the United States National Library of Medicine, which is in the public domain.