P-glycoprotein

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P-glycoprotein (abbreviated as P-gp or Pgp) is a well-characterized human ABC-transporter of the MDR/TAP subfamily.^[1] It is extensively distributed and expressed in normal cells such as those lining the intestine, liver cells, renal proximal tubular cells, and capillary endothelial cells comprising the blood-brain barrier. 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 243).

[edit] Function

ABCB1 is an ATP-dependent efflux pump with broad substrate specificity. It likely evolved as a defense mechanism against harmful substances.

ABCB1 transports various substrates across the cell membrane including:

• Drugs such as colchicine and tacrolimus
• 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 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
  • 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 entry into the central nervous system
• The migration of dendritic cells
• Protection of hematopoietic stem cells from toxins.^[1]

[edit] Structure

Pgp is a 170 kDa transmembrane glycoprotein, 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.^[2]

[edit] 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.

[edit] 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.^[1][3]

[edit] References

[edit] Further reading

[edit] See also

• MDR1 defect

[edit] External links

• Jessica R Oesterheld (2002-05-01). P-glycoprotein. Mental Health Connections, Inc. Retrieved on 2008-03-02.
• MeSH P-Glycoprotein