Interaction of organic chemicals with P-glycoprotein in the adrenal gland, kidney, and a multidrug-resistant KB cell.
P-glycoprotein (P-gp) is thought to mediate the transport of anti-cancer drugs and to be responsible for the multidrug-resistant (MDR) phenotype in tumor cells. However, the function of P-gp in normal tissues is still not well understood. We present evidence indicating that the active efflux of several structurally unrelated organic compounds is mediated by P-gp in multidrug-resistant KB (KB-C2) cells and that these compounds interact with P-gp in the kidney and adrenal gland. The photoactive radioactive calcium channel blocker [3H]azidopine labels a protein of approximately 140 kDa in crude membrane fractions from human kidney and adrenal gland and a 130-kDa protein from bovine adrenal gland. These photolabeled proteins are immunoprecipitated with an anti-P-gp antibody. Photolabeling is inhibited by vinblastine, reserpine, and several other organic chemicals. These data indicate that the kidney and adrenal gland express P-gp (or a protein closely related to P-gp) that can interact with several organic compounds and that the P-gp expressed in these tissues has a drug-binding site similar to that of P-gp in KB-C2 cells. Our findings thus strongly support the hypothesis that P-gp can transport a wide variety of organic chemicals as well as anti-cancer drugs and that one of the physiological functions of P-gp is the excretion of certain classes of organic compounds.
Ichikawa
M
M
Cancer Research Institute, Faculty of Medicine, Kagoshima University, Japan.
Yoshimura
A
A
Sumizawa
T
T
Shudo
N
N
Kuwazuru
Y
Y
Furukawa
T
T
Akiyama
S
S
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000311:Adrenal Glands / Q000378:metabolism*; D000345:Affinity Labels; D000970:Antineoplastic Agents / Q000494:pharmacology; D001386:Azides; D001692:Biological Transport; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D004396:Coloring Agents / Q000493:pharmacokinetics*; D004095:Dihydropyridines; D004140:Dinitrophenols / Q000494:pharmacology; D004351:Drug Resistance; D006801:Humans; D007668:Kidney / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; D000970:Antineoplastic Agents; D001386:Azides; D002352:Carrier Proteins; D004396:Coloring Agents; D004095:Dihydropyridines; D004140:Dinitrophenols; D008562:Membrane Glycoproteins; C041130:azidopine