Structural, mechanistic and clinical aspects of MRP1.
The cDNA encoding ATP-binding cassette (ABC) multidrug resistance protein MRP1 was originally cloned from a drug-selected lung cancer cell line resistant to multiple natural product chemotherapeutic agents. MRP1 is the founder of a branch of the ABC superfamily whose members (from species as diverse as plants and yeast to mammals) share several distinguishing structural features that may contribute to functional and mechanistic similarities among this subgroup of transport proteins. In addition to its role in resistance to natural product drugs, MRP1 (and related proteins) functions as a primary active transporter of structurally diverse organic anions, many of which are formed by the biotransformation of various endo- and xenobiotics by Phase II conjugating enzymes, such as the glutathione S-transferases. MRP1 is involved in a number of glutathione-related cellular processes. Glutathione also appears to play a key role in MRP1-mediated drug resistance. This article reviews the discovery of MRP1 and its relationships with other ABC superfamily members, and summarizes current knowledge of the structure, transport functions and relevance of this protein to in vitro and clinical multidrug resistance.
Hipfner
D R
DR
Cancer Research Laboratories, Queen's University, Kingston, Ont., Canada.
Deeley
R G
RG
Cole
S P
SP
D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D027321:Anion Transport Proteins; D000911:Antibodies, Monoclonal / Q000737:chemistry; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000737:chemistry; D003600:Cytosol / Q000737:chemistry; D018432:Drug Resistance, Multiple / Q000235:genetics; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D018384:Oxidative Stress; D010641:Phenotype; D016415:Sequence Alignment
D018528:ATP-Binding Cassette Transporters; D000251:Adenosine Triphosphatases; D027321:Anion Transport Proteins; D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D005978:Glutathione; D027425:ATP-Binding Cassette, Sub-Family C Proteins