P-glycoprotein
Encyclopedia
| 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 a glycoprotein
Glycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
that in humans is encoded by the ABCB1 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. P-gp is a well-characterized ABC-transporter (which transports a wide variety of substrates across extra- and intracellular membranes) of the MDR
Multidrug resistance
Multiple drug resistance or Multidrug resistance is a condition enabling a disease-causing organism to resist distinct drugs or chemicals of a wide variety of structure and function targeted at eradicating the organism...
/TAP
Transporter associated with antigen processing
Transporter associated with antigen processing is a member of the ATP-binding-cassette transporter family. It delivers cytosolic peptides into the endoplasmic reticulum , where they bind to nascent MHC class I molecules....
subfamily.
Pgp is extensively distributed and expressed in the intestinal epithelium
Intestinal epithelium
The intestinal epithelium is the epithelium that covers the small and large intestine. It is simple columnar and nonciliated.They primarily take part in the digestive system. However, they also express TLR 4 receptors, and are thus a part of the immune system, both as a barrier and as a first-line...
, hepatocyte
Hepatocyte
A hepatocyte is a cell of the main tissue of the liver. Hepatocytes make up 70-80% of the liver's cytoplasmic mass.These cells are involved in:* Protein synthesis* Protein storage* Transformation of carbohydrates...
s, renal proximal tubular cells, adrenal gland and capillary
Capillary
Capillaries are the smallest of a body's blood vessels and are parts of the microcirculation. They are only 1 cell thick. These microvessels, measuring 5-10 μm in diameter, connect arterioles and venules, and enable the exchange of water, oxygen, carbon dioxide, and many other nutrient and waste...
endothelial
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
cells comprising the blood-brain
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
and blood-testis barrier
Blood-testis barrier
The blood–testis barrier is a physical barrier between the blood vessels and the seminiferous tubules of the animal testes...
.
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 resistanceMultidrug resistance
Multiple drug resistance or Multidrug resistance is a condition enabling a disease-causing organism to resist distinct drugs or chemicals of a wide variety of structure and function targeted at eradicating the organism...
. The protein encoded by this gene is an ATP-dependent drug efflux pump for xenobiotic
Xenobiotic
A xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual...
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
Blood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
.
ABCB1 is an ATP
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...
-dependent efflux pump
Efflux (microbiology)
Active efflux is a mechanism responsible for extrusion of toxic substances and antibiotics outside the cell; this is considered to be a vital part of xenobiotic metabolism...
with broad substrate
Substrate (biochemistry)
In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalyze chemical reactions involving the substrate. In the case of a single substrate, the substrate binds with the enzyme active site, and an enzyme-substrate complex is formed. The substrate is transformed into one or...
specificity. It likely evolved as a defense mechanism against harmful substances.
ABCB1 transports various substrates across the cell membrane including:
- Drugs such as colchicineColchicineColchicine is a medication used for gout. It is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum...
, tacrolimusTacrolimusTacrolimus is an immunosuppressive drug that is mainly used after allogeneic organ transplant to reduce the activity of the patient's immune system and so lower the risk of organ rejection...
and quinidineQuinidineQuinidine is a pharmaceutical agent that acts as a class I antiarrhythmic agent in the heart. It is a stereoisomer of quinine, originally derived from the bark of the cinchona tree.-Mechanism:... - Chemotherapeutic agents such as etoposideEtoposideEtoposide phosphate is an anti-cancer agent. It is known in the laboratory as a topoisomerase poison. Etoposide is often incorrectly referred to as a topoisomerase inhibitor in order to avoid using the term "poison" in a clinical setting...
, doxorubicinDoxorubicinDoxorubicin INN is a drug used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunomycin, and like all anthracyclines, it works by intercalating DNA....
, and vinblastineVinblastineVinblastine is an antimicrotubule drug used to treat certain kinds of cancer, including Hodgkin's lymphoma, non-small cell lung cancer, breast cancer, head and neck cancer, and testicular cancer. It is also used to treat Langerhan cell histiocytosis.... - Lipids
- Steroids
- XenobioticXenobioticA xenobiotic is a chemical which is found in an organism but which is not normally produced or expected to be present in it. It can also cover substances which are present in much higher concentrations than are usual...
s - Peptides
- BilirubinBilirubinBilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
- Cardiac glycosideCardiac glycosideCardiac glycosides are drugs used in the treatment of congestive heart failure and cardiac arrhythmia. These glycosides are found as secondary metabolites in several plants, but also in some animals, such as the milkweed butterflies. -Function:...
s like digoxinDigoxinDigoxin INN , also known as digitalis, is a purified cardiac glycoside and extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin, and its acetyl derivative is acetyldigoxin... - Immunosuppressive agents
- GlucocorticoidGlucocorticoidGlucocorticoids are a class of steroid hormones that bind to the glucocorticoid receptor , which is present in almost every vertebrate animal cell...
s like dexamethasoneDexamethasoneDexamethasone is a potent synthetic member of the glucocorticoid class of steroid drugs. It acts as an anti-inflammatory and immunosuppressant... - 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 expressionGene expressionGene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
- Active cellular transportActive transportActive transport is the movement of a substance against its concentration gradient . In all cells, this is usually concerned with accumulating high concentrations of molecules that the cell needs, such as ions, glucose, and amino acids. If the process uses chemical energy, such as from adenosine...
of antineoplastics resulting in multidrug resistanceMultidrug resistanceMultiple drug resistance or Multidrug resistance is a condition enabling a disease-causing organism to resist distinct drugs or chemicals of a wide variety of structure and function targeted at eradicating the organism...
to these 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
- The removal of toxic metabolites and xenobiotics from cells into urineUrineUrine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, bile, and the intestinal lumen - The transport of compounds out of the brainBrainThe brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
across the blood-brain barrierBlood-brain barrierThe blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion... - Digoxin uptake
- Prevention of ivermectin entry into the central nervous systemCentral nervous systemThe central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
- The migration of dendritic cells
- Protection of hematopoietic stem cells from toxins.
Structure
Pgp is a 170 kDa transmembrane glycoproteinGlycoprotein
Glycoproteins are proteins that contain oligosaccharide chains covalently attached to polypeptide side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. In proteins that have segments extending...
, 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 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.
Mechanism of action
Binding of a substrate and ATP molecule occur simulatenously. 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.Detecting the activity of the transporter
The activity of the transporter can be determined by both membrane ATPaseATPase assay
The ATPase assay is a membrane assay that indirectly measures the activity of efflux transporters. ATP Binding Cassette or efflux transporters mediate the transport of substrates across cell membranes against a concentration gradient. ATP cleavage is tightly linked to substrate translocation, as...
and cellular calcein
Calcein
Calcein, also known as fluorexon, fluorescein complex, is a fluorescent dye with an excitation and emission wavelengths of 495/515 nm, respectively. Calcein also self-quenches even at concentrations below 100mM. It is used as a complexometric indicator for titration of calcium ions with EDTA,...
assays.
The ABCB1 Transporter is also used to differentiate Transitional B-cells
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
from Naive B-cells. Dyes such as Rhodamine123 and MitoTracker Dyes from Invitrogen can be used to make this differentiation.
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.Radioactive verapamil
Verapamil
Verapamil is an L-type calcium channel blocker of the phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and most recently, cluster headaches. It is also an effective preventive medication for migraine...
can be used for measuring P-glycoprotein function with positron emission tomography
Positron emission tomography
Positron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
.