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Biochem Biophys Res Commun. 1992 Oct 15;188(1):440-5.

P-glycoprotein possesses a 1,4-dihydropyridine-selective drug acceptor site which is alloserically coupled to a vinca-alkaloid-selective binding site.

Author information

1
Department of Pharmacology, University of Birmingham, The Medical School, Edgbaston, United Kingdom.

Abstract

[3H]Vinblastine bound with high affinity to surface membranes prepared from H69/LX4 cells which express P-glycoprotein (P-gp) and as a consequence are multidrug resistant (MDR). The KD was 9.8 +/- 1.5 nM and density of sites 31.2 +/- 8.6 pmol/mg of protein. [3H]Vinblastine binding was inhibited by cytotoxics and agents known to reverse MDR. 1,4-Dihydropyridine MDR reversing agents including nicardipine and nifedipine accelerated the dissociation of [3H]vinblastine from P-gp indicating a negative heterotropic allosteric effect. Cyclosporin A, vincristine and actinomycin D did not alter [3H]vinblastine dissociation kinetics. It is concluded that P-gp possesses at least two allosterically coupled drug acceptor sites, receptor site-1 that is selective for vinca alkaloids and cyclosporin A, and receptor site-2 that is selective for 1,4-dihydropyridines.

PMID:
1358068
DOI:
10.1016/0006-291x(92)92404-l
[Indexed for MEDLINE]

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