P-glycoprotein

P-glycoprotein (abbreviated as P-gp or Pgp) is a well characterized human ABC-transporter of the MDR/TAP subfamily. 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.

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Function

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

ABCB1 transports various substrates across the cell membrane including:

• Drugs such as colchicine and tacrolimus
• Chemotherapeutic agents such as etoposide, adriamycin, 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, 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.^[3]

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 which shows over 65% of amino acid similarity with the first half of the polypeptide.^[4]

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.^[5][6]

References

Further reading

See also

• MDR1 defect