Inostamycin, an inhibitor of P-glycoprotein function, interacts specifically with phosphatidylethanolamine.
The mechanism of inostamycin action was further studied. When multidrug-resistant KB-C4 cells were preincubated with inostamycin for 30 min, the accumulation of [3H]vinblastine was increased for as long as 48 h thereafter. Inostamycin inhibited azidopine binding to P-glycoprotein, even after KB plasma membranes had been preincubated with inostamycin and washed. Carbon 14-labeled inostamycin bound to KB plasma membranes irreversibly, but the binding capacity did not parallel the amount of P-glycoprotein in three KB cell lines. Inostamycin was found to interact specifically with purified phosphatidylethanolamine. These results suggest that inostamycin can inhibit P-glycoprotein irreversibly by binding to plasma membranes irreversibly through phosphatidylethanolamine.
Kawada
M
M
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, Yokohama.
Umezawa
K
K
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics; D001386:Azides / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism / Q000494:pharmacology; D005663:Furans / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007624:KB Cells; D010714:Phosphatidylethanolamines / Q000378:metabolism*; D012680:Sensitivity and Specificity; D014316:Tritium; D014747:Vinblastine / Q000493:pharmacokinetics
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000900:Anti-Bacterial Agents; D000972:Antineoplastic Agents, Phytogenic; D001386:Azides; D004095:Dihydropyridines; D005663:Furans; D010714:Phosphatidylethanolamines; D014316:Tritium; C071861:inostamycin; D014747:Vinblastine; C041130:azidopine