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

Function, Expression, and History

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 MDR1A gene was originally connected to ABCB1 in the BBB after a study with knockout mice. When the mice were infested with mites, a harmless treatment of the pesticide ivermectin was sprayed on the (+/+) and (-/-) mice. When the researchers returned the next day, all of the knockout mice were dead while the wild type mice were unaffected. This result lead to the conclusion that the MDR1a knockout mice had a lack of efflux of the ivermectin, a neurotoxin, out of the BBB.^[4] The ABCB1 gene is located on Chromosome 7 (region 7q21.12), and codes a protein with 1280 amino acids. ^[5] 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, many 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]

Large-scale sequencing programs including the 1000 Genome Project and the Exome Sequencing Project have recorded approximately 8600 SNP variants, consisting of 390 coding sequence variants. These variations could also cause the inter-individual variance by differences in folding that influence the substrate specifictiy and flexibility of the protein. Furthermore, the stability of messenger RNA (mRNA) could be reduced influencing the insertion of the protein into the membrane. The polymorphisms likely effect the pharmacokinetics and drug responses, posing clinical challenges for therapeutic treatments.^[5]

Structure

ABCB1 is located in the cellular membrane, adopting an inward-facing "V-shaped" structure, with two pairs of transmembrane domains. 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] However, recent research suggests that multiple portals exist, allowing the entrance of substrates from the cytoplasm and the membrane.^[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, but further research is needed to determine the interactions and the safe administration dosage.^[4]