P-glycoprotein

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

P-gp is extensively distributed and expressed in the

P-gp was discovered in 1971 by Victor Ling.

Gene

A 2015 review of polymorphisms in ABCB1 found that "the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance."^[7]

Protein

P-gp is a 170 kDa transmembrane glycoprotein, which includes 10-15 kDa of N-terminal glycosylation. The N-terminal half of the protein contains 6 transmembrane helixes, followed by a large cytoplasmic domain with an ATP-binding site, and then a second section with 6 transmembrane helixes and an ATP-binding domain 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.

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]

Species, tissue, and subcellular distribution

P-gp is expressed primarily in certain cell types in the liver, pancreas, kidney, colon, and

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.

The protein belongs to the superfamily of

• Drugs such as colchicine, desloratadine,^[15] tacrolimus and quinidine.
• Chemotherapeutic agents such as topoisomerase inhibitors (i.e.
  tyrosine kinase inhibitors (i.e. gefitinib, sunitinib
  ).
• Lipids
• Steroids
• Xenobiotics
• Peptides
• Bilirubin
• Cardiac glycosides like digoxin
• Immunosuppressive agents
• Glucocorticoids like dexamethasone
• HIV-type 1 antiretroviral therapy agents like
  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
  • 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]

After 2008, microRNAs (miRNAs) were identified as new players in regulating the expression of P-gp in both transcriptional and post-transcriptional levels. Some miRNAs decrease the expression of P-gp. For example, miR-200c down-regulates the expression of P-gp through the JNK signaling pathway^[23] or ZEB1 and ZEB2;^[25] miR-145 down-regulates the 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.^[26] Some other miRNAs increase the expression of P-gp. For example, miR-27a up-regulates P-gp expression by suppressing the Raf kinase inhibitor protein (RKIP);^[27] alternatively, miR-27a can also directly bind to the promoter of the P-gp gene, which works in a similar way with the mechanism of action of transcriptional factors.^[28]

The expression of P-gp is also regulated by post-translational events, such as

Some common pharmacological inhibitors of P-glycoprotein include: amiodarone, clarithromycin, ciclosporin, colchicine, diltiazem, erythromycin, felodipine, ketoconazole,^[32] lansoprazole, omeprazole and other proton-pump inhibitors, nifedipine, paroxetine, reserpine,^[33] saquinavir,^[32] sertraline, quinidine, tamoxifen, verapamil,^[34] and duloxetine.^[35] Elacridar and CP 100356 are other common^{[citation needed]} P-gp inhibitors. Zosuquidar and tariquidar were also developed with this in mind.^{[clarification needed]} Lastly, valspodar and reversan are other examples of such agents. ABCB1 is linked to the daily dose of warfarin required to maintain the INR to a target of 2.5. Patients with the GT or TT genotypes of the 2677G>T SNP require around 20% more warfarin daily.^[36]

Common pharmacological inducers of P-glycoprotein include

Substrates of P-glycoprotein are susceptible to changes in pharmacokinetics due to drug interactions with P-gp inhibitors or inducers. Some of these substrates include colchicine, ciclosporin, dabigatran,^[33] digoxin, diltiazem,^[38] fexofenadine, indinavir, morphine, and sirolimus.^[32]

Diseases (non-cancer)

Decreased P-gp expression has been found in Alzheimer's disease brains.^[39]

Altered P-gp function has also been linked to

P-gp efflux activity is capable of lowering intracellular concentrations of otherwise beneficial compounds, such as chemotherapeutics and other medications, to sub-therapeutic levels. Consequently, P-gp overexpression is one of the main mechanisms behind decreased intracellular drug accumulation and development of multidrug resistance in human multidrug-resistant (MDR) cancers.[43]^[44]

History

P-gp was first characterized in 1976. P-gp was shown to be responsible for conferring multidrug resistance upon mutant cultured cancer cells that had developed resistance to cytotoxic drugs.^[5][45]

The structure of mouse P-gp, which has 87% sequence identity to human P-gp, was resolved by x-ray crystallography in 2009.^[9] The first structure of human P-gp was solved in 2018, with the protein in its ATP-bound, outward-facing conformation. ^[46]

Research

Radioactive verapamil can be used for measuring P-gp function with positron emission tomography.^[47]

P-gp is also used to differentiate

It has been suggested that MDR1 inhibitors might treat various diseases, especially cancers, but none have done well in clinical trials.^[49]

Single nucleotide polymorphism rs1045642

Homozygous subjects, identified with the TT genotype, are usually more able to extrude xenobiotics from the cell. A Homozygous genotype for the allele ABCB1/MDR1 is capable of a higher absorption from the blood vessels and a lower extrusion into the lumen.

Further reading

• 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.
  S2CID 10573193
  .
• Kim Y, Chen J (February 2018). "Molecular structure of human P-glycoprotein in the ATP-bound, outward-facing conformation". Science. 359 (6378): 915–919.
  PMID 29371429
  .

External links

Wikimedia Commons has media related to P-glycoprotein.

• P-Glycoprotein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• 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.