Abstract

P-GLYCOPROTEIN: A UNIQUE TARGET FOR PROBLEMS ASSOCIATED WITH BIOAVAILABILITY OF DRUGS

Vyas Jigar and Hasan Jahid*

ABSTRACT

Multidrug resistance (MDR) is regarded as one of the bottlenecks of successful clinical treatment for various chemotherapeutic agents. Different key regulators are alleged to be liable for MDR and making the treatment regimens ineffective. P-gp, a unique ATP-dependent membrane transport protein, is one of those key regulators which are present in the lining of the colon, endothelial cells of the blood brain barrier (BBB), bile duct, adrenal gland, kidney tubules, small intestine, pancreatic ducts and in many other tissues like heart, lungs, spleen, skeletal muscles, etc. Due to its varied tissue distribution, P-gp is a novel protective barrier to stop the intake of xenobiotics into the human body. Over-expression of P-gp leads to decreased intracellular accretion of many chemotherapeutic agents thus helping in the development of MDR. Ultimately, the effectiveness of these drugs is decreased. P-gp inhibitors act by altering intracellular ATP levels which are the source of energy and/or by affecting membrane contours to increase permeability. An X-ray crystal structure shows that drugs interact with P-glycoprotein within the trans-membrane regions by fitting into a large flexible binding pocket, which can accommodate two substrate molecules simultaneously. The nucleotide-binding domains of P- glycoprotein appear to hydrolyse ATP in an alternating manner, however, it is still not clear whether transport is driven by ATP hydrolysis or ATP binding.

Keywords: ABCB1; ABCB4; ABCB11; multidrug resistance; chemotherapy; drug distribution; blood brain barrier; modulators; X-ray crystal structure; substrate binding pocket; drug transport; hydrophobic vacuum cleaner; flippase; ATP hydrolysis; vanadate.