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

Biochem Biophys Res Commun. 1992 Oct 15;188(1):440-5. doi: 10.1016/0006-291x(92)92404-l.


[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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Allosteric Site
  • Antineoplastic Agents / pharmacology*
  • Binding Sites
  • Calcium Channel Blockers / pharmacology
  • Cell Membrane / metabolism
  • Dihydropyridines / metabolism*
  • Drug Resistance
  • Humans
  • Kinetics
  • Lung Neoplasms
  • Membrane Glycoproteins / metabolism*
  • Tumor Cells, Cultured
  • Vinblastine / metabolism*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Calcium Channel Blockers
  • Dihydropyridines
  • Membrane Glycoproteins
  • Vinblastine
  • 1,4-dihydropyridine