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P-glycoprotein: from genomics to mechanism
Suresh V Ambudkar1, Chava Kimchi-Sarfaty, Zuben E Sauna
1Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute/NIH, 37 Convent Drive, Building 37, Room 1A-09, Bethesda, MD 20892-4254, USA. ambudkar@helix.nih.gov
Oncogene
|October 25, 2003
Summary
Multidrug resistance (MDR) in cancer involves efflux pumps like P-glycoprotein (P-gp), encoded by the MDR1 gene. Understanding P-gp
Area of Science:
- Biochemistry
- Genetics
- Pharmacology
Background:
- Multidrug resistance (MDR) is a major challenge in cancer therapy, often caused by ATP-dependent efflux pumps.
- P-glycoprotein (P-gp), encoded by the human MDR1 gene, is a key efflux pump identified in MDR.
- P-gp belongs to the ATP-binding cassette (ABC) transporter superfamily.
Purpose of the Study:
- To elucidate the structure, function, and biological significance of P-glycoprotein (P-gp) in multidrug resistance (MDR).
- To explore the role of P-gp in drug pharmacokinetics and its implications for cancer treatment.
Main Methods:
- Sequence analysis and comparison with other ATP-binding cassette (ABC) proteins to infer P-gp structure.
- Investigating P-gp's physiological roles in barrier tissues and xenobiotic excretion.
- Analyzing the impact of MDR1 gene polymorphisms on drug pharmacokinetics.
Main Results:
- P-gp is predicted to have a structure with two transmembrane and two nucleotide-binding domains.
- P-gp functions as a barrier and excretes xenobiotics in various tissues.
- MDR1 gene polymorphisms can influence the pharmacokinetics of numerous drugs, including anticancer agents.
Conclusions:
- Understanding P-gp's biology, genetics, and biochemistry is crucial for improving cancer treatment outcomes.
- Knowledge of P-gp mechanisms can explain the variable pharmacokinetics of commonly used drugs.