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P-glycoprotein preferentially effluxes anthracyclines containing free basic versus charged amine.
F Frézard1, E Pereira-Maia, P Quidu
1Laboratoire de Physicochimie Biomoléculaire et Cellulaire (ESA 7033), Université Paris Nord, Bobigny, France.
European Journal of Biochemistry
|March 15, 2001
Summary
Multidrug resistance (MDR) involves P-glycoprotein (P-gp) pumping drugs out of cells. This study found that while P-gp recognizes both neutral and charged anthracyclines, it pumps the neutral form more efficiently, aiding MDR drug efflux.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) in tumors is often mediated by P-glycoprotein (P-gp) and multidrug resistance protein 1 (MRP1), which reduce intracellular drug accumulation.
- Understanding the molecular parameters for P-gp drug recognition is crucial for overcoming MDR, but remains incompletely understood.
Purpose of the Study:
- To determine which molecular form of anthracyclines, neutral or protonated, is actively pumped by P-gp.
- To compare the relative efficiencies of P-gp-mediated efflux for neutral versus protonated anthracyclines.
Main Methods:
- Spectrofluorometric analysis of anthracycline efflux in K562/Adr cells at varying intracellular and extracellular pH levels.
- Utilized 3'-deamino, 3'-hydroxyl doxorubicin (OH-DOX) as a control for permanently neutral drug efflux.
- Investigated daunorubicin (DNR) and WP608 efflux due to similar lipophilicity of neutral forms and distinct pKa values.
Main Results:
- P-glycoprotein (P-gp) recognizes and actively effluxes both neutral and protonated forms of anthracyclines.
- The neutral form of anthracyclines is pumped approximately three times more efficiently by P-gp than the protonated (charged) form.
- Efflux of other tested anthracyclines with a basic center was also confirmed.
Conclusions:
- A positive charge is not essential for P-gp recognition of anthracyclines.
- The presence of a protonable basic nitrogen atom in anthracyclines facilitates their recognition and processing by the MDR efflux system, particularly the neutral form.