PMID- 11248673
OWN - NLM
STAT- MEDLINE
DCOM- 20010503
LR  - 20181130
IS  - 0014-2956 (Print)
IS  - 0014-2956 (Linking)
VI  - 268
IP  - 6
DP  - 2001 Mar
TI  - P-glycoprotein preferentially effluxes anthracyclines containing free basic 
      versus charged amine.
PG  - 1561-7
AB  - The multidrug resistant (MDR) tumor phenotype, characterized by a decreased 
      cellular drug accumulation is achieved by ATP-dependent extrusions of drugs from 
      cells by P-glycoprotein (P-gp) and/or by multidrug resistance protein (MRP1). 
      Despite the huge amount of research that has been performed on the mechanisms of 
      P-gp-mediated efflux of drug, it is not yet known what the molecular parameters 
      are required for a molecule to be recognized and pumped out by P-gp. 
      Anthracyclines are weak bases and, depending on the pH, can exist either in the 
      neutral or in the positively charged form. The aim of the work reported here was 
      to determine which molecular form is actively pumped out by P-gp (the neutral 
      form, the protonated form, or both), and if both, the relative efficiencies of 
      pumping. We used spectrofluorometric methods to determine the efflux of 
      anthracyclines in K562/Adr cells, at different intracellular and extracellular pH 
      levels. Using 3'-deamino, 3'-hydroxyl doxorubicin (OH-DOX), which is permanently 
      neutral, we first verified that our methodologies were accurate and that the 
      P-gp-mediated efflux of OH-DOX would not depend on the pH being in the range 
      6.6--8.4. The P-gp-mediated efflux of daunorubicin (DNR) and 3'-hydroxy-4-amino 
      (WP608) was determined at different pH values. These two drugs were chosen 
      because: (a) the lipophilicity of the neutral forms of these two molecules is so 
      similar that any difference in the P-gp-mediated efflux cannot be assigned to 
      lipohilicity variation, and (b) their pKa values are different (8.4 and 7.7 for 
      DNR and WP608, respectively), which makes it easy to obtain a large variation in 
      the proportions of the neutral and positively charged forms. Our data show that 
      both forms are recognized by P-gp but the neutral form is pumped about three 
      times more efficiently than the charged form. This is corroborated by results 
      showing the active efflux (checked at pH(i) 7.3 only) of five other anthracycline 
      containing a basic center. We interpret these data to mean that: (a) the positive 
      charge of anthracycline is not a necessary requirement for P-gp recognition, but 
      that (b) the presence of a protonable basic nitrogen facilitates the processing 
      of these compounds by MDR efflux system.
FAU - Frezard, F
AU  - Frezard F
AD  - Laboratoire de Physicochimie Biomoleculaire et Cellulaire (ESA 7033), Universite 
      Paris Nord, Bobigny, France.
FAU - Pereira-Maia, E
AU  - Pereira-Maia E
FAU - Quidu, P
AU  - Quidu P
FAU - Priebe, W
AU  - Priebe W
FAU - Garnier-Suillerot, A
AU  - Garnier-Suillerot A
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Eur J Biochem
JT  - European journal of biochemistry
JID - 0107600
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Amines)
RN  - 0 (Antibiotics, Antineoplastic)
RN  - ZS7284E0ZP (Daunorubicin)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/*metabolism
MH  - Amines/*metabolism
MH  - Antibiotics, Antineoplastic/*metabolism
MH  - Biological Transport
MH  - Daunorubicin/*metabolism
MH  - Drug Resistance, Multiple
MH  - Humans
MH  - Hydrogen-Ion Concentration
MH  - K562 Cells
MH  - Kinetics
EDAT- 2001/03/15 10:00
MHDA- 2001/05/05 10:01
CRDT- 2001/03/15 10:00
PHST- 2001/03/15 10:00 [pubmed]
PHST- 2001/05/05 10:01 [medline]
PHST- 2001/03/15 10:00 [entrez]
AID - ejb1989 [pii]
PST - ppublish
SO  - Eur J Biochem. 2001 Mar;268(6):1561-7.