P-glycoprotein

P-glycoprotein 1 (permeability glycoprotein,

ABCB1
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. Identifiers
Aliases ABCB1, ABC20, CD243, CLCS, GP170, MDR1, P-GP,
P-gp is extensively distributed and expressed in
PGY1, ATP binding cassette subfamily B member 1, P-
the intestinal epithelium where it pumps
glycoprotein, P-gp, Pgp
xenobiotics (such as toxins or drugs) back into
the intestinal lumen, in liver cells where it pumps External MGI: 97570 HomoloGene: 55496 GeneCards: ABCB1
them into bile ducts, in the cells of the proximal IDs
tubule of the kidney where it pumps them into Gene location (Mouse)
urinary filtrate (in the proximal tubule), 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- Chr. Chromosome 5 (mouse)[1]
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 Band 5 A1|5 3.43 cM Start 8,660,077 bp[1]
back into the gut lumen by P-gp
End 8,748,575 bp[1]
pharmacokinetically reduces the efficacy of some
pharmaceutical drugs (which are said to be P-gp RNA expression pattern
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 byVictor Ling.

 Contents
Gene
Protein
Species, tissue, and subcellular
distribution
Function
Regulation of expression and function
of P-gp in cancer cells
Clinical significance More reference expression data
Drug interactions
Diseases Gene ontology
History Molecular • ATPase activity, coupled to transmembrane
Research function movement of substances
Single nucleotide polymorphism • nucleotide binding
rs1045642 • transporter activity
References • ATPase activity
Further reading • protein binding
External links • hydrolase activity
• ATP binding
• xenobiotic-transporting ATPase activity
Gene • phosphatidylethanolamine-translocating
ATPase activity
A 2015 review of polymorphisms in ABCB1
• phosphatidylcholine-translocating ATPase
found that "the effect of ABCB1 variation on P-
activity
glycoprotein expression (messenger RNA and
• ceramide-translocating ATPase activity
protein expression) and/or activity in various
tissues (e.g. the liver, gut and heart) appears to be Cellular • integral component of membrane
small. Although polymorphisms and haplotypes component • membrane
of ABCB1 have been associated with alterations • plasma membrane
in drug disposition and drug response, including • cell surface
adverse events with various ABCB1 substrates in • extracellular exosome
different ethnic populations, the results have been • apical plasma membrane
majorly conflicting, with limited clinical Biological • stem cell proliferation
relevance."[6] process • xenobiotic transport
• G2/M transition of mitotic cell cycle
Protein • transmembrane transport
P-gp is a 170 kDa transmembrane glycoprotein,
• response to drug
which includes 10-15 kDa of N-terminal • phospholipid translocation
glycosylation. The N-terminal half of the • drug transmembrane transport
molecule contains 6 transmembrane domains, • ceramide translocation
followed by a large cytoplasmic domain with an • regulation of response to osmotic stress
ATP-binding site, and then a second section with • positive regulation of anion channel activity
6 transmembrane domains and an ATP-binding • regulation of chloride transport
site that shows over 65% of amino acid similarity • transport
with the first half of the polypeptide.[7] In 2009, Sources:Amigo / QuickGO
the first structure of a mammalian P-glycoprotein
Orthologs
was solved (3G5U).[8] The structure was derived
from the mouse MDR3 gene product Species Human Mouse
heterologously expressed in Pichia pastoris Entrez 5243 18671
yeast. The structure of mouse P-gp is similar to
structures of the bacterial ABC transporter MsbA Ensembl
(3B5W and 3B5X)[9] that adopt an inward facing n/a ENSMUSG00000040584

conformation that is believed to be important for

binding substrate along the inner leaflet of the
UniProt
P08183 P21447
membrane. Additional structures (3G60 and
3G61) of P-gp were also solved revealing the RefSeq
binding site(s) of two different cyclic peptide NM_000927 NM_011076
(mRNA)
substrate/inhibitors. The promiscuous binding
pocket of P-gp is lined with aromatic amino acid RefSeq
NP_000918 NP_035206
side chains. Through Molecular Dynamic (MD) (protein)
NP_001335873
simulations, this sequence was proved to have a
NP_001335874
direct impact in the transporter's structural
NP_001335875
stability (in the nucleotide-binding domains) and
defining a lower boundary for the internal drug-
Location n/a Chr : 8.66 – 8.75 Mb
binding pocket.[10]
(UCSC)
PubMed [2] [3]
Species, tissue, and search
subcellular distribution Wikidata

P-gp is expressed primarily in certain cell types View/Edit Human View/Edit Mouse

in the liver, pancreas, kidney, colon, and

jejunum.[11] P-gp is also found in brain capillary endothelial cells.[12] ABCB1 at EBI Gene Expression
Atlas

Function ABCB1 is differentially expressed in 97

experiments [93 up/106 dn]: 26 organism
parts: kidney [2 up/0 dn], bone marrow [0
Substrate enters P-gp either from an opening within the inner leaflet of the up/2 dn], ...; 29 disease states: normal
[10 up/3 dn], glioblastoma [0 up/2 dn], ...;
membrane or from an opening at the cytoplasmic side of the protein. ATP binds at 30 cell types, 22 cell lines, 11 compound
the cytoplasmic side of the protein. Following binding of each, ATP hydrolysis treatments and 16 other conditions.
shifts the substrate into a position to be excreted from the cell. Release of the Factor Value Factor Up/Down
phosphate (from the original ATP molecule) occurs concurrently with substrate Legend: - number of studies the
excretion. ADP is released, and a new molecule of ATP binds to the secondary
gene is up/down in
ATP-binding site. Hydrolysis and release of ADP and a phosphate molecule resets
Normal Disease 10/3
the protein, so that the process can start again.
state
The protein belongs to the superfamily of ATP-binding cassette (ABC) None Compound 3/0
transporters. ABC proteins transport various molecules across extra- and intra- treatment
cellular membranes. ABC genes are divided into seven distinct subfamilies
Stromal cell Cell type 1/2
(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 Kidney Cell type 2/0
multidrug resistance. P-gp is an ATP-dependent drug efflux pump for xenobiotic MDA-MB-231 Cell line 0/2
compounds with broad substrate specificity. It is responsible for decreased drug Glioblastoma Disease 0/2
accumulation in multidrug-resistant cells and often mediates the development of state
resistance to anticancer drugs. This protein also functions as a transporter in the
Epithelial Cell type 0/2
blood–brain barrier.[13]
cell
P-gp transports various substrates across the cell membrane including: HeLa Cell line 0/2

Drugs such as colchicine, tacrolimus and quinidine

Primary Disease 2/0
staging
 Chemotherapeutic agents such as topoisomerase inhibitors (i.e. Bone Organism 0/2
etoposide, doxorubicin), microtubule-targeted drugs (i.e.vinblastine),
and tyrosine kinase inhibitors(i.e. gefitinib, sunitinib). marrow part
Lipids ABCB1 expression data in ATLAS
Steroids
Xenobiotics
Peptides
Bilirubin
Cardiac glycosides like digoxin
Immunosuppressive agents
Glucocorticoids like dexamethasone
HIV-type 1 antiretroviral therapy agents likeprotease 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 transportof antineoplastics resulting in multidrug resistance to these drugs
The removal of toxic metabolites and xenobiotics from cells intourine, bile, and the intestinal lumen
The transport of compounds out of thebrain 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 hematopoieticstem 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.[14]

Regulation of expression and function of P-gp in cancer cells

At transcriptional level, the expression of P-gp has been intensively studied, and numerous transcriptional factors and pathways are
known to play roles. A variety of transcriptional factors, such as p53,[15] YB-1,[16] and NF-𝜅B[17] are involved in the direct
regulation of P-gp by binding to the promoter regions of P-gp gene. Many cell singling pathways are also involved in transcriptional
regulation of P-gp. For example, PI3K/Akt pathway[16] and Wnt/ β-catenin pathway[18] were reported to positively regulate the
expression of P-gp. Mitogen-activated protein kinase (MAPK) signaling pathways includes three pathways: the classical
MAPK/ERK pathway, p38 MAPK pathway, and c-Jun N-terminal kinase (JNK) pathway, all of which were reported to have
implications in the regulation of the expression of P-gp. Studies suggested that MAPK/ERK pathway is involved in the positive
regulation of P-gp;[19] p38 MAPK pathway negatively regulates the expression of P-gp gene;[20] JNK pathway were reported to be
[21][22]
involved in both positive regulation and negative regulation of P-gp.

After year 2008, microRNAs (miRNAs) are identified as new players in regulating the expression of P-gp in both transcriptional and
post-transcriptional levels. Some members of miRNAs decrease the expression of P-gp. For example, miR-200c down-regulates the
expression of P-gp through JNK signaling pathway[21] or ZEB1 and ZEB2;[23] miR-145 down-regulates mRNA of P-gp by directly
binding to the 3'-UTR of the gene of P-gp and thus suppresses the translation of P-gp.[24] Some other members of miRNAs increase
the expression of P-gp. For example, miR-27a up-regulates P-gp expression by suppressing Raf kinase inhibitor protein (RKIP);[25]
alternatively, miR-27a can also directly bind to the promoter of P-gp gene, which works in a similar way with the mechanism of
action of transcriptional factors.[26]

The expression of P-gp is also regulated by post-translational events, such as post-transcriptional modification, degradation, and
intracellular trafficking of P-gp. Pim-1 protects P-gp from ubiquitination and the following degradation in proteasome.[27] Small
GTPases Rab5 down-regulates the endocytotic trafficking of P-gp and thus increases the functional P-gp level on cell membrane;[28]
while Small GTPases Rab4 work in an opposite way: Rab4 down-regulates the exocytotic trafficking of P-gp from intracellular
[29]
compartments to cell membrane, and therefore decreases the functional P-gp level on cell membrane.

Clinical significance

Drug interactions
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.[30]

Diseases
Decreased P-gp expression has been found inAlzheimer’s disease brains.[31]

Altered P-gp function has also been linked to inflammatory bowel diseases (IBD),[32] however, due to its ambivalent effects in
intestinal inflammation many questions remain so far unanswered.[33] While decreased efflux activity may promote disease
susceptibility and drug toxicity, increased efflux activity may confer resistance to therapeutic drugs in IBD.[33] Mice deficient in
, which appears to resemble humanulcerative colitis.[34]
MDR1A develop chronic intestinal inflammation spontaneously

History
P-gp was first characterized in 1976. It was shown to be responsible for conferring multidrug resistance upon mutant cultured cancer
[5][35]
cells that had developed resistance to cytotoxic drugs.

The structure of P-gp was resolved byx-ray crystallography in 2009.[8]

Research
Radioactive verapamil can be used for measuring P-gp function withpositron emission tomography.[36]

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.[37]

Single nucleotide polymorphism rs1045642

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Further reading
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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.
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implications of its association with both a multidrug-resistant and an apoptosis-resistant phenotype".
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Schaich M, Illmer T (Jul 2002). "Mdr1 gene expression and mutations in Ras proto-oncogenes in acute myeloid
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PMID 15203864.
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External links
P-Glycoprotein at the US National Library of MedicineMedical Subject Headings(MeSH)
Jessica R Oesterheld (2002-05-01)."P-glycoprotein". Mental Health Connections, Inc. Archived fromthe original on
2008-02-07. Retrieved 2008-03-02.
P-glycoprotein substrate prediction
NextBio.com
PharmGKB.org
The role of MDR1-MDCK in permeability studiesThe performance of MDR1-MDCK permeability studies for P-
glycoprotein substrate identification.
ABCB1 human gene location in theUCSC Genome Browser.
ABCB1 human gene details in theUCSC Genome Browser.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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