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P-glycoprotein
 
 
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P-glycoprotein (plasma glycoprotein, abbreviated as P-gp or Pgp) is a well-characterized ABC-transporter 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. It delivers cytosolic peptides into the endoplasmic reticulum , where they bind to nascent MHC class I molecules....
 subfamily. P-gp is also called ABCB1, ATP-binding cassette sub-family B member 1, MDR1, and PGY1. P-glycoprotein has also recently been designated CD243 (cluster of differentiation
Cluster of differentiation

The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on leukocytes. CD molecules can act in numerous ways, often acting as receptor or ligand important to the cell....
 243). In humans, P-glycoprotein is encoded by the ABCB1 gene.

Pgp is extensively distributed and expressed in the intestinal epithelium
Intestinal epithelium

The intestinal epithelium is the epithelium that covers the small intestine and large intestine. It is simple columnar and Cilia.They primarily take part in the digestive system....
, hepatocyte
Hepatocyte

Hepatocytes make up 70-80% of the cytoplasmic mass of the liver.These cells are involved in protein synthesis, protein storage and transformation of carbohydrates, synthesis of cholesterol, bile salts and phospholipids, and detoxification, modification and excretion of exogenous and endogenous substances....
s, renal proximal tubular cells, and capillary
Capillary

Capillaries are the smallest of a body's blood vessels, measuring 5-10 micrometre in diameter, which connect arterioles and venules, and enable the interchange of water, oxygen, carbon dioxide, and many other nutrient and waste chemical substances between blood and surrounding tissue s....
 endothelial
Endothelium

The endothelium is the thin layer of cell that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall....
 cells comprising the blood-brain barrier
Blood-brain barrier

The blood-brain barrier is a metabolic or cellular structure in the central nervous system that restricts the passage of various chemical substances and microscopic objects between the bloodstream and the neural tissue itself, while still allowing the passage of substances essential to metabolism function ....
.

membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters.






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P-glycoprotein (plasma glycoprotein, abbreviated as P-gp or Pgp) is a well-characterized ABC-transporter 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. It delivers cytosolic peptides into the endoplasmic reticulum , where they bind to nascent MHC class I molecules....
 subfamily. P-gp is also called ABCB1, ATP-binding cassette sub-family B member 1, MDR1, and PGY1. P-glycoprotein has also recently been designated CD243 (cluster of differentiation
Cluster of differentiation

The cluster of differentiation is a protocol used for the identification and investigation of cell surface molecules present on leukocytes. CD molecules can act in numerous ways, often acting as receptor or ligand important to the cell....
 243). In humans, P-glycoprotein is encoded by the ABCB1 gene.

Pgp is extensively distributed and expressed in the intestinal epithelium
Intestinal epithelium

The intestinal epithelium is the epithelium that covers the small intestine and large intestine. It is simple columnar and Cilia.They primarily take part in the digestive system....
, hepatocyte
Hepatocyte

Hepatocytes make up 70-80% of the cytoplasmic mass of the liver.These cells are involved in protein synthesis, protein storage and transformation of carbohydrates, synthesis of cholesterol, bile salts and phospholipids, and detoxification, modification and excretion of exogenous and endogenous substances....
s, renal proximal tubular cells, and capillary
Capillary

Capillaries are the smallest of a body's blood vessels, measuring 5-10 micrometre in diameter, which connect arterioles and venules, and enable the interchange of water, oxygen, carbon dioxide, and many other nutrient and waste chemical substances between blood and surrounding tissue s....
 endothelial
Endothelium

The endothelium is the thin layer of cell that line the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall....
 cells comprising the blood-brain barrier
Blood-brain barrier

The blood-brain barrier is a metabolic or cellular structure in the central nervous system that restricts the passage of various chemical substances and microscopic objects between the bloodstream and the neural tissue itself, while still allowing the passage of substances essential to metabolism function ....
.

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 resistance
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....
. 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 metabolic or cellular structure in the central nervous system that restricts the passage of various chemical substances and microscopic objects between the bloodstream and the neural tissue itself, while still allowing the passage of substances essential to metabolism function ....
.

ABCB1 is an ATP
Adenosine triphosphate

This article is about the chemical used by cells as an energy carrier. For other uses, see ATP .Adenosine-5'-triphosphate is a multifunctional nucleotide, and plays an important role in cell biology as a coenzyme that is the "molecule unit of currency" of intracellular energy transfer....
-dependent efflux pump with broad substrate
Substrate (biochemistry)

In biochemistry, a substrate is a molecule upon which an enzyme acts. Enzymes catalysis chemical reactions involving the substrate. The substrate binds with the enzyme active site, and an enzyme-substrate complex is formed....
 specificity. It likely evolved as a defense mechanism against harmful substances.

ABCB1 transports various substrates across the cell membrane including:
  • Drugs such as colchicine
    Colchicine

    Colchicine is a toxic natural product and secondary metabolite, originally extracted from plants of the genus Colchicum . Originally used to treat rheumatic complaints and especially gout, it was also prescribed for its cathartic and emetic effects....
    , tacrolimus
    Tacrolimus

    Tacrolimus is an immunosuppression medication whose main use is after allogenic organ transplant to reduce the activity of the patient's immune system and so the risk of organ Transplant rejection....
     and quinidine
    Quinidine

    Quinidine is a pharmaceutical Medication 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....
  • Chemotherapeutic agents such as etoposide
    Etoposide

    Etoposide phosphate is an inhibitor of the enzyme topoisomerase II. It is used as a form of chemotherapy for malignancies such as Ewing's sarcoma, lung cancer, testicular cancer, lymphoma, non-lymphocytic leukemia, and glioblastoma multiforme....
    , doxorubicin
    Doxorubicin

    Doxorubicin is a pharmaceutical used in cancer chemotherapy. It is an anthracycline antibiotic, closely related to the natural product daunorubicin, and like all anthracyclines it intercalation DNA....
    , and vinblastine
    Vinblastine

    Vinblastine is an mitotic inhibitor medication 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....
  • Lipids
  • Steroids
  • 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....
    s
  • Peptides
  • Bilirubin
    Bilirubin

    Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is formed from hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile, and its levels are elevated in certain diseases....
  • Cardiac glycoside
    Cardiac glycoside

    Cardiac glycosides are medication 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....
    s like digoxin
    Digoxin

    Digoxin , also known as Digitalis, is a purified cardiac glycoside extracted from the foxglove plant, Digitalis lanata. Its corresponding aglycone is digoxigenin....
  • Immunosuppressive agents
  • Glucocorticoid
    Glucocorticoid

    Glucocorticoids are a class of steroid hormones which bind to the glucocorticoid receptor , which is present in almost every animal cell.GCs are part of the feedback mechanism in the immune system which turns immune activity down....
    s like dexamethasone
    Dexamethasone

    Dexamethasone is a potent synthetic member of the glucocorticoid class of steroid hormones. It acts as an anti-inflammatory and immunosuppressive drug....
  • 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 expression
      Gene expression

      Gene expression is the process by which inheritable information from a gene, such as the DNA sequence, is made into a functional gene product, such as protein or RNA....
    • Active cellular transport
      Active transport

      Active transport is the mediated process of moving particles across a biological membrane against a Concentration_gradient#In_biology . If the process uses chemical energy, such as from adenosine triphosphate , it is termed primary active transport....
       of antineoplastic
      Antineoplastic

      Antineoplastics are drugs that inhibit and combat the development of neoplasms.In the Anatomical Therapeutic Chemical Classification System, they are classified under ATC code L01#L01D Cytotoxic antibiotics and related substances....
      s resulting in multidrug resistance
      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....
       to these drugs
  • The removal of toxic metabolites and xenobiotics from cells into urine
    Urine

    Urine is a liquid waste product of the body secreted by the kidneys by a process of filtration from blood called urination and excreted through the urethra....
    , bile, and the intestinal lumen
  • The transport of compounds out of the brain
    Brain

    The brain is the center of the nervous system in all vertebrate, and most invertebrate, animals. Some primitive animals such as cnidarian and echinoderm have a decentralized nervous system without a brain, while sponges lack any nervous system at all....
     across the blood-brain barrier
    Blood-brain barrier

    The blood-brain barrier is a metabolic or cellular structure in the central nervous system that restricts the passage of various chemical substances and microscopic objects between the bloodstream and the neural tissue itself, while still allowing the passage of substances essential to metabolism function ....
  • Digoxin uptake
  • Prevention of ivermectin
    Ivermectin

    Ivermectin is a broad-spectrum antiparasitic medication.It is sold under brand names Stromectol in the United States, Mectizan in Canada by Merck & Co....
     entry into the central nervous system
    Central nervous system

    The central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of multicellular organisms....
  • The migration of dendritic cells
  • Protection of hematopoietic stem cells from toxins.


Structure

Pgp is a 170 kDa transmembrane glycoprotein
Glycoprotein

Not to be confused with peptidoglycan or proteoglycan.Glycoproteins are proteins that contain oligosaccharide chains covalently attached to their Peptide side-chains....
, 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.

Function

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.

Detecting the activity of the transporter

The activity of the transporter can be determined by both membrane ATPase
ATPase assay

The ATPase assay is a membrane assay that indirectly measures the activity of ATP binding cassette transporters. ATP Binding Cassette or efflux transporters mediate the transport of substrates across cell membranes against a concentration gradient....
 and cellular calcein
Calcein

Calcein, also known as fluorexon, fluorescein complex, is a fluorescent dye with an excitation and emission wavelengths of 495/515nm, respectively....
 assays.

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.

In 2001 a procedure for the synthesis of 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....
 was descriped. This compound can be used for measuring P-glycoprotein function with positron emission tomography
Positron emission tomography

Positron emission tomography is a nuclear medicine medical imaging technique which produces a three-dimensional image or picture of functional processes in the body....
.

Further reading


See also

  • MDR1 defect
  • Silken Windhound
    Silken Windhound

    The Silken Windhound is a rare American breed of dog, a member of the sighthound family.Description Appearance...
  • Longhaired Whippet
    Longhaired Whippet

    The Longhaired Whippet is a medium-sized sighthound. They are not a variety of the Whippet, but rather a hybrid between the whippet, borzoi and shetland sheepdog....


External links