Expression and function of P-glycoprotein in a mouse kidney cell line.
P-glycoprotein (PGP), a transporter conferring multidrug resistance to cancer cells, is expressed in the kidney. C219 monoclonal antibody binding revealed PGP in proximal tubules and mesangium of mouse kidneys. A cell line (TKPTS) expressing PGP was developed from proximal tubules of the 8Tg(SV40E)Bri7 mouse. Northern blot analysis demonstrated a 5.0-kb message identified as mdr1 by ribonuclease protection assay. Cyclosporin A (CSA) at 0.15 and 10 microM increased cellular accumulation of verapamil (VRP) by 32 and 121%, respectively (P < 0.001). VRP at 5 microM increased steady-state cellular accumulation of CSA by 46% (P = 0.02). Basal-to-apical transport of the PGP substrate vinblastine was inhibited by VRP. Rhodamine-123 (R-123) influx was rapid and independent of PGP. R-123 efflux was inhibited by VRP and CSA. Inhibition of PGP transport by VRP, CSA, and PSC-833 decreased the 50% effective dose of adriamycin. The concomitant administration of VRP and CSA was not deleterious and coincided with preferential accumulation of VRP over CSA. Inhibition of PGP-mediated transport is demonstrated as a mechanism of renal cell toxicity.
Ernest
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S
Department of Internal Medicine, University of Texas Medical Branch, Galveston 77555, USA.
Bello-Reuss
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E
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D016764:Cell Polarity; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology; D004848:Epithelium / Q000502:physiology; D006706:Homeostasis; D007158:Immunologic Techniques; D007668:Kidney / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000378:metabolism; D020112:Rhodamine 123; D012235:Rhodamines / Q000493:pharmacokinetics; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D012333:RNA, Messenger; D012235:Rhodamines; D020112:Rhodamine 123; D016572:Cyclosporine; D014700:Verapamil