P-Glycoprotein in Clinical Cardiology

Ever since Juliano and Ling first described P-glycoprotein (P-gp) in 1975,1 it has become an important focus of research. P-gp is a member of the ATP-binding cassette (ABC) superfamily of proteins that is highly conserved in distantly related species (from simple eukaryotes to vertebrates).2 These similarities across species suggest that P-gp plays an important role in physiological processes in normal cells. One established function is its active transport of drugs out of the cell against a concentration gradient using ATP as an energy source, which is unusual because unlike most energy-dependent pumps, it has very little substrate specificity. Humans have 2 known P-gp encoding genes, MDR1 (class I) and MDR2 (class III), both localized in chromosome 7.3 The first has been associated with the phenomenon of multiple drug resistance (MDR),4 and the second serves to transport phospholipids into the bile.5 Cloning and sequencing of the MDR gene led to the identification of the composition and structure of P-gp,6 which consists of 2 membrane-bound domains (each with 6 transmembrane segments) and 2 nucleotide-binding domains that bind and hydrolyze ATP.4 The initial and major emphasis of P-gp research was to explain the occurrence of multidrug resistance in tumors that were initially exposed to a single drug and with time developed resistance to a wide range of other unrelated drugs. Concurrent with the investigation of tumor drug resistance, there have been studies linking this MDR protein with phase I and phase II drug biotransformations,7 and others have examined the expression and function of P-gp in chloroquine-resistant Plasmodium falciparum , the causative organism of malaria.8 A new focus of interest has been the study of the role of P-gp …