P-gp

• P-糖タンパク質

関

P-glycoprotein、P-glycoprotein 1

WordNet

1. the 16th letter of the Roman alphabet (同)p
2. a unit of force equal to the force exerted by gravity; used to indicate the force to which a body is subjected when it is accelerated (同)gee, g-force
3. a river in western Thailand; a major tributary of the Chao Phraya (同)Ping River

PrepTutorEJDIC

1. parking
2. phosphorusの化学記号
3. general practitioner一般開業医
4. palladiumの化学記号

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2017/05/23 18:43:59」(JST)

wiki ja

[Wiki ja表示]

P糖タンパク質（Pとうタンパクしつ、英: P-glycoprotein, P-gp, Pgp）は、分子量約18万のリン酸化タンパク質であり、細胞膜上に存在して細胞毒性を有する化合物などの細胞外排出を行う。P-gpはABC輸送体のMDR/TAPサブファミリーに属する分子であり、腸や肺、腎臓の近位尿細管、血液脳関門の毛細血管内皮細胞等に発現している。また、P-gpによる薬物の排出は薬剤耐性の形成に寄与している。P-gpはABCB1（ATP-binding Cassette Sub-family B Member 1）、あるいはMDR1（Multiple drug resistance 1）とも呼ばれる。細胞表面抗原の分類に用いられるCD分類ではP-gpはCD243と番号が振られている。なお、名称頭文字の"P"はその薬剤透過性を変化させる働きから"Permeability（透過性）"に基づいてつけられた。

概要

1976年に、多剤耐性関与たんぱく質としてがん細胞から分離された。その後、消化管上皮細胞の管腔側膜に局在することが確認され、血液脳関門、血液精巣関門、血液胎盤関門にも存在したことから、生体異物への暴露への防御機能を担う重要なたんぱく質との認識がなされるようになった。ヒトP糖タンパク質の遺伝子MDR1/ABCB1は、1986年に単離され、様々な構造の抗癌剤を細胞外へ排出することが明らかになった。その後薬物により誘導されるストレスたんぱく質であることが、抗がん剤やリファンピシンやアスピリンなどに誘導されることから、明らかになった。。

機能

P-gpは細胞膜上にあり、抗がん剤の細胞外排出などに寄与する。

P-gpはMDR1/ABCB1遺伝子産物であり、アデノシン三リン酸（ATP）のエネルギー依存的に疎水性化合物の細胞外排出を行う輸送体タンパク質である。P-gpをコードする遺伝子は7q21に位置し、28個のエキソンから構成される。腫瘍細胞は薬物に曝される事によりP-gpの発現が亢進し、薬剤耐性となる。また、悪性腫瘍細胞でなくともP-gpを発現している細胞もあり、薬物の排出に寄与している。

構造

P-gpは12回膜貫通型の糖タンパク質であり、1280個のアミノ酸から構成される。アミノ基側末端及びカルボキシル基側末端は共に細胞内に存在しており、12個ある膜貫通ドメインのうち6つ目と7つ目の間及びカルボキシル基末端にATP結合ドメインを保有している。

基質

P糖タンパク質により排出される物質には以下のようなものがある。

• 各種抗ガン剤
• コルヒチンやタクロリムスなどの薬剤
• 脂質
• ペプチド
• ステロイド
• ビリルビン
• 強心配糖体（ジゴキシン）
• 抗不整脈薬（キニジン、ベラパミル）
• 免疫抑制剤
• 抗HIV薬

阻害剤

P-gpの阻害剤であるゾスキダルなどは、薬剤耐性を克服し抗がん剤の効果を高める薬剤として治験が行われている。

出典

• 今堀 和友、山川 民夫 編集 『生化学辞典 第4版』 東京化学同人 2007年 ISBN 978-4-8079-0670-3
• Tannock IF,Hill RP,Bristow RG and Harrington L.『がんのベーシックサイエンス 日本語版 第3版』メディカル･サイエンス･インターナショナル 2006年 ISBN 4-89592-460-2
• 田中 千賀子、加藤 隆一 編集 『NEW薬理学 第4版』 南江堂 2002年 ISBN 978-4-524-22083-0

wiki en

[Wiki en表示]

ABCB1
Identifiers
Aliases	ABCB1, ABC20, CD243, CLCS, GP170, MDR1, P-GP, PGY1, ATP binding cassette subfamily B member 1
External IDs	MGI: 97570 HomoloGene: 55496 GeneCards: ABCB1
Gene ontology Molecular function • ATPase activity, coupled to transmembrane movement of substances • nucleotide binding • transporter activity • ATPase activity • protein binding • hydrolase activity • ATP binding • xenobiotic-transporting ATPase activity • phosphatidylethanolamine-translocating ATPase activity • phosphatidylcholine-translocating ATPase activity • ceramide-translocating ATPase activity Cellular component • integral component of membrane • membrane • plasma membrane • cell surface • extracellular exosome • apical plasma membrane Biological process • stem cell proliferation • xenobiotic transport • G2/M transition of mitotic cell cycle • transmembrane transport • transport • response to drug • phospholipid translocation • drug transmembrane transport • ceramide translocation Sources:Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
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_035206.2 NP_035206
Location (UCSC)	Chr 7: 87.5 – 87.71 Mb	Chr 5: 8.66 – 8.75 Mb
PubMed search
Wikidata
View/Edit Human View/Edit Mouse

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: - 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. 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. 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.

P-gp 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 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.

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

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. In 2009, the first structure of a mammalian P-glycoprotein was solved (3G5U). 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) 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. 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.

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. P-gp is also found in brain capillary endothelial cells.

Exogenous inhibitors

Some common pharmacological inhibitors of P-glycoprotein include: amiodarone, clarithromycin, ciclosporin, colchicine, diltiazem, erythromycin, felodipine, lansoprazole, omeprazole and other proton-pump inhibitors, nifedipine, paroxetine, sertraline, quinidine, tamoxifen and verapamil.

Detecting the activity of the transporter

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

P-gp is also used to differentiate transitional B-cells from naive B-cells. Dyes such as Rhodamine 123 and MitoTracker Dyes from Invitrogen can be used to make this differentiation.

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.

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

References

Further reading

• Ling V (1997). "Multidrug resistance: molecular mechanisms and clinical relevance". Cancer Chemotherapy and Pharmacology. 40 Suppl (7): S3–8. doi:10.1007/s002800051053. PMID 9272126. 
• Kerb R, Hoffmeyer S, Brinkmann U (Feb 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 (Dec 2001). "[Mechanisms of drug resistance and reversal of the resistance]". Human 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 Foundation Symposium. 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 Foundation Symposium. Novartis Foundation Symposia. 243: 54–65; discussion 65–8, 180–5. doi:10.1002/0470846356.ch5. ISBN 978-0-470-84635-3. PMID 11990782. 
• Hegedus T, Orfi L, Seprodi A, Váradi A, Sarkadi B, Kéri G (Jul 2002). "Interaction of tyrosine kinase inhibitors with the human multidrug transporter proteins, MDR1 and MRP1". Biochimica et Biophysica Acta. 1587 (2-3): 318–25. doi:10.1016/s0925-4439(02)00095-9. PMID 12084474. 
• Pallis M, Turzanski J, Higashi Y, Russell N (Jun 2002). "P-glycoprotein in acute myeloid leukaemia: therapeutic implications of its association with both a multidrug-resistant and an apoptosis-resistant phenotype". Leukemia & Lymphoma. 43 (6): 1221–8. doi:10.1080/10428190290026277. PMID 12152989. 
• Schaich M, Illmer T (Jul 2002). "Mdr1 gene expression and mutations in Ras proto-oncogenes in acute myeloid leukemia". Leukemia & Lymphoma. 43 (7): 1345–54. doi:10.1080/10428190290033279. PMID 12389613. 
• Fromm MF (Nov 2002). "The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans". Advanced Drug Delivery Reviews. 54 (10): 1295–310. doi:10.1016/S0169-409X(02)00064-9. PMID 12406646. 
• Ambudkar SV, Kimchi-Sarfaty C, Sauna ZE, Gottesman MM (Oct 2003). "P-glycoprotein: from genomics to mechanism". Oncogene. 22 (47): 7468–85. doi:10.1038/sj.onc.1206948. PMID 14576852. 
• Jamroziak K, Robak T (Apr 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, Oosumi K, Nagakura M, Tarui S (Jul 2004). "Pharmacogenomics of drug transporters: a new approach to functional analysis of the genetic polymorphisms of ABCB1 (P-glycoprotein/MDR1)". Biological & Pharmaceutical Bulletin. 27 (7): 939–48. doi:10.1248/bpb.27.939. PMID 15256718. 
• Lee W, Lockhart AC, Kim RB, Rothenberg ML (Feb 2005). "Cancer pharmacogenomics: powerful tools in cancer chemotherapy and drug development". The Oncologist. 10 (2): 104–11. doi:10.1634/theoncologist.10-2-104. PMID 15709212. 
• Gambrelle J, Labialle S, Dayan G, Gayet L, Barakat S, Michaud M, Grange JD, Baggetto LG (Jun 2005). "[Multidrug resistance in uveal melanoma]". Journal Français d'Ophtalmologie. 28 (6): 652–9. doi:10.1016/s0181-5512(05)81112-x. PMID 16141933. 
• Al-Shawi MK, Omote H (Dec 2005). "The remarkable transport mechanism of P-glycoprotein: a multidrug transporter". Journal of Bioenergetics and Biomembranes. 37 (6): 489–96. doi:10.1007/s10863-005-9497-5. PMC 1459968 . PMID 16691488. 
• 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. 
• Orlowski S, Martin S, Escargueil A (May 2006). "P-glycoprotein and 'lipid rafts': some ambiguous mutual relationships (floating on them, building them or meeting them by chance?)". Cellular and Molecular Life Sciences. 63 (9): 1038–59. doi:10.1007/s00018-005-5554-9. PMID 16721513. 
• Annese V, Valvano MR, Palmieri O, Latiano A, Bossa F, Andriulli A (Jun 2006). "Multidrug resistance 1 gene in inflammatory bowel disease: a meta-analysis". World Journal of Gastroenterology. 12 (23): 3636–44. doi:10.3748/wjg.v12.i23.3636. PMID 16773678. 
• Sekine I, Minna JD, Nishio K, Tamura T, Saijo N (Jan 2006). "A literature review of molecular markers predictive of clinical response to cytotoxic chemotherapy in patients with lung cancer". Journal of Thoracic Oncology. 1 (1): 31–7. doi:10.1097/01243894-200601000-00008. PMID 17409824. 
• 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 Metabolism and Drug Interactions. 25 (1-4): 3–16. doi:10.1515/DMDI.2010.006. PMID 21417789. 
• Shityakov S, Förster C (2013). "Multidrug resistance protein P-gp interaction with nanoparticles (fullerenes and carbon nanotube) to assess their drug delivery potential: a theoretical molecular docking study". International Journal of Computational Biology and Drug Design. 6 (4): 343–57. doi:10.1504/IJCBDD.2013.056801. PMID 24088267. 
• Shityakov S, Förster C (2014). "In silico structure-based screening of versatile P-glycoprotein inhibitors using polynomial empirical scoring functions". Advances and Applications in Bioinformatics and Chemistry. 7 (7): 1–9. doi:10.2147/AABC.S56046. PMC 3969253 . PMID 24711707. 
• 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. 

External links

• P-Glycoprotein at the US 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. 
• P-glycoprotein substrate prediction
• NextBio.com
• PharmGKB.org
• The role of MDR1-MDCK in permeability studies The performance of MDR1-MDCK permeability studies for P-glycoprotein substrate identification.
• ABCB1 human gene location in the UCSC Genome Browser.
• ABCB1 human gene details in the UCSC Genome Browser.

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

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Related Pictures

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★リンクテーブル★

リンク元	「P-糖タンパク質」「P-glycoprotein 1」
関連記事	「P」「GP」「gp」「p」「Pd」

「P-糖タンパク質」

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英

P-glycoprotein、P-gp

関

P糖タンパク質、P-糖タンパク質1

「P-glycoprotein 1」

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• P-糖タンパク質1

関

P-gp

「P」

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• プロリン proline
• P波 P wave
• リン phosphorus

　 　 　

「GP」

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• 糖タンパク質

関

glycoprotein

　

「gp」

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同

gene product

同

gene product

「p」

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• ピコ

10の-12乗

関

pico

「Pd」

　　[★] パラジウム palladium