Functional polymorphisms of the human multidrug resistance (MDR1) gene: correlation with P glycoprotein expression and activity in vivo.

Abstract

The human MDR1 gene encodes an integral membrane protein, P glycoprotein (Pgp), whose function is the energy dependent export of substances from the inside of cells, and from membranes, to the outside. Its physiological role is the protection of cells from toxic substances or metabolites. Many drugs that have been developed for the treatment of human diseases are substrates of Pgp. Because of that, the degree of expression and the functionality of the MDR1 gene product can directly affect the therapeutic effectiveness of such agents. This is of particular importance in cancer therapy where high expression and activity of MDR1 causes cancer cells to become refractory to the treatment with many agents, all of which are Pgp substrates. MDR1 is also expressed on different non-malignant cells in various organs, e.g. in the intestine and at the blood brain barrier. Modulation of MDR1 expression in these normal cell types can also influence the activity and bioavailability of drugs. In the intestine, modulation of MDR1 may control the degree of drug uptake following drug ingestion. At the blood-brain barrier, Pgp may influence the uptake of substrates into the brain: high Pgp levels may limit the uptake of sufficient amounts of desired drugs into the brain, and reduced Pgp activity could lead to abnormally increased accumulation in the brain and undesired side effects of drugs.