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Structural, mechanistic and clinical aspects of MRP1
D R Hipfner1, R G Deeley, S P Cole
1Cancer Research Laboratories, Queen's University, Kingston, Ont., Canada.
Abstract:
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.
Insights
The multidrug resistance-associated protein 1 (MRP1) is a key transporter in cancer cells, conferring resistance to chemotherapy. Understanding MRP1
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- The ATP-binding cassette (ABC) multidrug resistance protein MRP1 was identified in a drug-selected lung cancer cell line.
- MRP1 belongs to a conserved branch of the ABC superfamily found across diverse species.
- Members of this MRP1 branch share structural features suggesting functional similarities.
Purpose of the Study:
- To review the discovery and evolutionary relationships of MRP1 within the ABC superfamily.
- To summarize the current understanding of MRP1's structure and transport functions.
- To elucidate MRP1's role in in vitro and clinical multidrug resistance.
Main Methods:
- Cloning of the MRP1 cDNA from resistant cell lines.
- Comparative analysis of structural features within the ABC superfamily.
- Review of existing literature on MRP1 transport mechanisms and clinical relevance.
Main Results:
- MRP1 actively transports diverse organic anions, including xenobiotics and their metabolites.
- MRP1 is implicated in cellular processes involving glutathione, particularly in drug resistance.
- Structural similarities among MRP1 homologs suggest conserved transport mechanisms.
Conclusions:
- MRP1 is a crucial transporter involved in multidrug resistance, particularly against natural product chemotherapeutics.
- Its function as an organic anion transporter is linked to biotransformation pathways.
- Further research into MRP1's structure and function is vital for understanding and overcoming clinical drug resistance.