Molecular analysis of the multidrug transporter, P-glycoprotein

Inherent or acquired resistance of tumor cells to cytotoxic drugs represent s a major limitation to the successful chemotherapeutic treatment of cancer . During the past three decades dramatic progress has been made in the unde rstanding of the molecular basis of this phenomenon. Analyses of drug-selec ted tumor cells which exhibit simultaneous resistance to structurally unrel ated anti-cancer drugs have led to the discovery of the human MDR1 gene pro duct, P-glycoprotein, as one of the mechanisms responsible for multidrug re sistance. Overexpression of this 170 kDa N-glycosylated plasma membrane pro tein in mammalian cells has been associated with ATP-dependent reduced drug accumulation? suggesting that P-glycoprotein may act as an energy-dependen t drug efflux pump. P-glycoprotein consists of two highly homologous halves each of which contains a transmembrane domain and an ATP binding fold. Thi s overall architecture is characteristic for members of the ATP-binding cas sette or ABC super-family of transporters. Cell biological, molecular genet ic and biochemical approaches have been used for structure-function studies of P-glycoprotein and analysis of its mechanism of action. This review sum marizes the current status of knowledge on the domain organization, topolog y and higher order structure of P-glycoprotein, the location of drug- and A TP binding sites within P-glycoprotein, its ATPase and drug transport activ ities, its possible functions as an ion channel, ATP channel and lipid tran sporter, its potential role in cholesterol biosynthesis, and the effects of phosphorylation on P-glycoprotein activity.