Sandbox PgpWWC

P-glycoprotein (P-gp, ABCB1) is an ATP binding casette (ABC) transporter that hydrolyses ATP for conformational changes after a variety of substrates are transported. It is one of the membrane proteins responsible for the multi drug resistance (MDR) in cancer treatment, as well as various other drug therapies.^[1][2] ABCB1 can be found in tumor cells, as well as in the liver, kidney, adrenal gland, intestine, blood-brain barrier (BBB), placenta, blood-testis barrier, and blood-ovarian barriers. An effective MDR transport protein, the high amount of active ABCB1 substrates stems from the polyspecificity for hydrophobic and aromatic compounds.^[3]

Hydrophobic, Polar

Gottesman, M. M., Pastan, I., & Ambudkar, S. V. (1996). P-glycoprotein and multidrug resistance. Current opinion in genetics & development, 6(5), 610-617.

Functions and Expression

As mentioned previously, ABCB1 is located in the liver, kidney, adrenal gland, intestine, BBB, placenta, blood-testis barrier, and blood-ovarian barriers. Furthermore, ABCB1 is overexpressed in tumor cells. The presence of ABCB1 in these locations prevents the entry of toxins into the cells, but also prevents the accumulation of therapeutic drugs. Toxins are effluxed into bile, urine, and the intestinal lumen, in order for excretion from the body.^[3]

The ABCB1 gene is located on Chromosome 7 (region 7q21.12). ^[4] ABCB1 genetic polymorphisms from the MDR1 gene influence the function of the protein, substrate specificity, and drug-drug interactions. Most variation is caused by single nucleotide polymorphisms (SNPs) that do not often result in a change in the amino acid sequence. Conflicting studies have been published on the extent of the effects of SNPs on ABCB1 expression and activity with various substrates. However, any studies have connected a pre-disposition for certain diseases or cancers with SNPs of ABCB1. Inter-individual variance has also been identified for different ethnicities. Some studies suggest that differences in diet may account for differences in function and activity, although variability in haplotype in populations likely affects the expression as well. Inter individual variance also affects the localization of ABCB1 throughout the body, and recent studies have explored inducers that stimulate the expression in certain endothelial cells.^[3]

History

Structure

ABCB1 is located in the cellular membrane, adopting an inward-facing "V-shaped" structure. Since the hydrophobic substrates are hydrophobic and can partition into the lipid bilayer, research suggests that substrate enters ABCB1 through two portals within the lipid bilayer.^[1] When a substrate binds to the binding site, a conformational change causes the protein to open to the outside of the cell, releasing the substrate. ATP is then hydrolyzed to re-induce the inward-facing conformation in preparation for the binding of another substrate compound from the bilayer.^[5] This efflux of substrate out of the cell prevents the accumulation of potentially toxic xenobiotics; however, this effective expulsion of a wide variety of substrates causes the multi-drug resistance.

The polyspecificity of ABCB1 is often attributed to a large internal cavity of ~6,000 Å that can transport up to two compounds simultaneously ranging from sizes of 330-4,000 Da. Three binding sites have been proposed, including the H (Hoescht), R (rhodamine), and P (prazosin and progesterone) sites. Since multiple substrates can be transported simultaneously, the binding of substrate to one site can stimulate the transport in the other sites. For example, the substrate binding on the P site stimulates transport at the R and H sites. However, these regions signify areas of residues that interact with substrates, while binding sites and the corresponding residue interactions are specific for different substrates transported. This specific affinity suggests primary and secondary sites that overlap.^[1]

Clinical Relevance

For the BBB, this protein prevents the entry of many psychotherapeutic drugs. For chemotherapeutic treatments, the inter individual variance can prevent the accumulation of the drugs, who interactions could increase the toxicity. ABCB1 is an important component of understanding the adverse drug reactions for individuals.^[3] The interactions of multiple therapeutic drugs and herbal medicines in ABCB1 can stimulate or prevent the accumulation of compounds in cells. In order to explore the implications of interactions, further research is needed to determine the binding sites and interactions of various compounds to identify possible harmful interactions in therapeutic treatments. ^[6] Thus, administering pharmacotherapeutics with ABCB1 blockers could increase the accumulation of the drugs by preventing the efflux.^[7]