ABC Transporter Proteins and Cellular Drug Resistance

Abstract

Mammalian cells possess a natural battery of defense mechanisms against xenobiotic assault. A class of proteins actively transports an extensive array of structurally unrelated large lipophilic compounds from the cell, providing what is often known as multiple drug resistance (MDR) (1). MDR is characterized by active efflux or pumping of xenobiotics and pharmaceuticals via transmembrane proteins acting as hydrophobic “vacuum cleaners” (2,3). The MDR1 gene encodes a 170 kD integral plasma membrane phosphorylated glycoprotein, P-glycoprotein (P-gp), which is the best known and most extensively studied among these transporters, and which thus far has the largest substrate list. The gross structural features of P-gp are shared by a large family of membrane transporters known as adenosine 5’-triphosphate (ATP)-binding cassette (ABC) transporters, which evidently act as ATP-driven pumps that remove xenobiotics from the interior of cells. Expression of P-gp in normal human tissues—particularly within the cellular membranes of the gastrointestinal tract, liver, blood–brain barrier (BBB), adrenal glands, and kidneys—suggests that the protein plays a role in cellular protection as well as in secretion (1–4). Although the primary function of this protein is unknown, its ability to confer resistance to a wide variety of structurally and chemically unrelated compounds remains impressive. Indeed, the substrate list for this transporter reveals that P-gp shares a similar tolerance or acceptance for chemicals as cytochrome P450 3A4 (CYP3A4), the predominant intestinal and hepatic cytochrome P450 oxygenase enzyme, and may even prove to be more extensive in its substrate recognition and as an avenue of drug elimination (5).

yea, at that very moment Consideration, like an angel, came And whipp’d the offending Adam out of him, Leaving his body as a paradise, To envelop and contain celestial spirits...

King Henry V