Journal Article

Interaction of Digitalis-Like Compounds with P-Glycoprotein

Elnaz Gozalpour, Hanneke G. M. Wittgen, Jeroen J. M. W. van den Heuvel, Rick Greupink, Frans G. M. Russel and Jan B. Koenderink

in Toxicological Sciences

Volume 131, issue 2, pages 502-511
Published in print February 2013 | ISSN: 1096-6080
Published online October 2012 | e-ISSN: 1096-0929 | DOI:
Interaction of Digitalis-Like Compounds with P-Glycoprotein

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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-gp drug-binding amino acids—Leu65, Ile306, Phe336, Ile340, Phe343, Phe728, Phe942, Thr945, Leu975, and Val982—were generated and expressed in HEK293 cells with a mammalian baculovirus system. The uptake of [3H]-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 two- to fourfold compared with 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 Phe336 and Phe942 is absent. Our results showed that a δ-lactone ring and a sugar moiety at 3β of the steroid body are favorable 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.

Keywords: digitalis-like compounds; P-glycoprotein; vesicle assay; mutagenesis; baculovirus.

Journal Article.  6087 words.  Illustrated.

Subjects: Medical Toxicology ; Toxicology (Non-medical)

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