Sandbox PgpWWC: Difference between revisions

ABCB1 is located in the cellular membrane, adopting an inward-facing "V-shaped" structure, with two pairs of transmembrane domains. Since the hydrophobic substrates can partition into the lipid bilayer, research suggests substrate enter ABCB1 through two portals within the lipid bilayer.<ref name="Aller" /> However, recent research suggests that multiple portals exist, allowing the entrance of substrates from the cytoplasm and the membrane.<ref name="Wolking"> 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 from the cytoplasm is then hydrolyzed for active transport of the drugs against a concentration gradient, and ATP is again hydrolyzed to re-induce the inward-facing conformation in preparation for the binding of another substrate compound from the bilayer.<ref>Chufan, E. E., Sim, H. M., & Ambudkar, S. V. (2014). Chapter Three – Molecular Basis of the Polyspecificity of P-Glycoprotein (ABCB1): Recent Biochemical and Structural Studies. Advances in Cancer Research, 125, 71-96.</ref> 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.<ref name="Aller" />

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.<ref name="Marchetti" /> 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. <ref name="Zhou">PMID: 15072439</ref> 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.<ref name="Schinkel">PMID: 10837715</ref>