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 capillaryendothelial cells comprising the blood-brain barrier. P-gp is also called ABCB1, ATP-binding cassette sub-family B member 1, MDR1, and PGY1.
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, therapeutic plasma concentrations are not attained. On the other hand, supratherapeutic plasma concentrations and drug toxicity may result because of decreased P-glycoprotein expression
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]
^ Dean, Michael. The Human ATP-Binding Cassette (ABC) Transporter Superfamily. Bethesda (MD):National Library of Medicine (US), NCBI; 2002 November.
^ 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
^ 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.". Pharmacogenomics2 (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. Cell14 (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. Acta1587 (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. Lymphoma43 (6): 1221-8. PMID 12152989.
Schaich M, Illmer T (2003). "Mdr1 gene expression and mutations in Ras proto-oncogenes in acute myeloid leukemia.". Leuk. Lymphoma43 (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.". Oncogene22 (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.". Hematology9 (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.". Oncologist10 (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'ophtalmologie28 (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 Cancer1 (1): 31-7. PMID 17409824.
Amino acid (CD98) - Fatty acid (CD36) - Ion channels - Ion pumps - Mitochondrial membrane transport protein - Neurotransmitter transport proteins - Nuclear (Karyopherin)