Preferential efflux by P-glycoprotein, but not MRP1, of compounds containing a free electron donor amine.
Multidrug resistance (MDR) in model systems is known to be conferred by two different integral proteins, the 170-kDa P-glycoprotein (P-gp) and the 190-kDa multidrug resistance-associated protein (MRP1), both of which pump drugs out of MDR cells. The presence of a nitrogen atom, charged at physiological pH, has frequently been considered to be a hallmark of P-gp substrates and inhibitors. The present study was aimed at investigating the role of nitrogen in the ability of the pump to recognise substrate. We measured the kinetics of active efflux of seven new anthracycline derivatives in P-gp-expressing K562/ADR cells and in MRP1-expressing GLC4/ADR cells. Six of these compounds represent analogues of daunorubicin in which the amino sugar nitrogen is bound to an amino- or a nitro-substituted benzyl moiety, the seventh is a doxorubicin derivative in which benzyl group is bound with 4'-oxygen. We found that the compounds with a nitro group on the benzyl ring were poor substrates for P-gp despite the presence of a secondary amine that can be protonated. In contrast, compounds that have a free amino group were very good substrates even though this amine is not protonated in the pH range studied (pK approximately 3). These results show that the nitrogen atom does not interact with P-gp in a charged form but rather as an electron donating group.
Salerno
Milena
M
Laboratoire de Physicochimie Biomoléculaire et Cellulaire, UMR 7033, Université Paris Nord, 74 Rue Marcel Cachin, 93017 Bobigny, France.
Przewloka
Teresa
T
Fokt
Izabela
I
Priebe
Waldemar
W
Garnier-Suillerot
Arlette
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000588:Amines / Q000737:chemistry / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000494:pharmacology; D001692:Biological Transport; D002455:Cell Division / Q000187:drug effects; D003630:Daunorubicin / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D007700:Kinetics; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000588:Amines; D000903:Antibiotics, Antineoplastic; D003630:Daunorubicin; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1