P-glycoprotein and multidrug resistance.
Although the phenomenon of simultaneous resistance to multiple cytotoxic drugs (multidrug resistance) in cancer cells has been discussed for more than two decades, and the human and mouse genes encoding an energy-dependent transporter (the multidrug transporter or P-glycoprotein) responsible for multidrug resistance were cloned 10 years ago, there is still considerable controversy about the mechanism of action of this efflux pump and its true biological function. This review summarizes the current research on the mechanism of action of the multidrug transporter, including the hydrophobic cleaner and altered partitioning models, the possible function of P-glycoprotein as a chloride and/or ATP channel, the role of phosphorylation in its function and fact and speculation about its physiological role.
Gottesman
M M
MM
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA. gottesman@od1em1.od.nih.gov
Pastan
I
I
Ambudkar
S V
SV
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000502:physiology*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D018118:Chloride Channels / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007700:Kinetics; D051379:Mice; D010766:Phosphorylation; D017354:Point Mutation
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018118:Chloride Channels; D000251:Adenosine Triphosphatases