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Interaction of digitalis-like compounds with P-glycoprotein.

Toxicol Sci. 2012 Oct 26;

Authors: Gozalpour E, Wittgen HG, van den Heuvel JJ, Greupink R, Russel FG, Koenderink JB


Digitalis-like compounds (DLCs) or cardiac glycosides are produced and sequestered by certain plants and animals as a protective mechanism against herbivores or predators. Currently, the DLCs digoxin and digitoxin are used in the treatment of cardiac congestion and some types of cardiac arrhythmia, despite a very narrow therapeutic index. P-glycoprotein (P-gp, ABCB1) is the only known ATP-dependent efflux transporter that handles digoxin as a substrate. Ten alanine mutants of human P-glycoprotein drug-binding amino acids, Leu(65), Ile(306), Phe(336), Ile(3401), Phe(343), Phe(728), Phe(942), Thr(945), Leu(975) and Val(982) were generated and expressed in HEK293 cells with a mammalian baculovirus system. The uptake of [(3)H]-N-methyl-quinidine (NMQ), the P-gp substrate in vesicular transport assays, was determined. The mutations I306A, F343A, F728A, T945A and L975A abolished NMQ transport activity of P-gp. For the other mutants the apparent affinities for six DLCs (cymarin, digitoxin, digoxin, peruvoside, proscillaridin A and strophanthidol) were determined. The affinities of digoxin, proscillaridin A, peruvoside and cymarin for mutants F336A and I340A were decreased 2- to 4-fold compared to wild-type, whereas that of digitoxin and strophanthidol did not change. In addition, the presence of a hydroxyl group at position 12β seems to reduce the apparent affinity when the side chain of Phe(336) and Phe(942) is absent. Our results showed that a δ-lactone ring and a sugar moiety at 3β of the steroid body are favourable for DLC binding to P-gp. Moreover, DLC inhibition is increased by hydroxyl groups at positions 5β and 19, whereas inhibition is decreased by those at positions 1β, 11α, 12β, and 16β. The understanding of the P-gp DLC interaction improves our insight into DLCs toxicity and might enhance the replacement of digoxin with other DLCs that have less adverse drug effects.

PMID: 23104431 [PubMed - as supplied by publisher]