Human P-glycoprotein transports cyclosporin A and FK506

Tohru Saeki, Kazumitsu Ueda, Yusuke Tanigawara, Ryohei Hori, Tohru Komano

Research output: Contribution to journalArticle

605 Citations (Scopus)

Abstract

Cyclosporin A, a cyclic undecapeptide, and FK506 are efficient immunosuppressive agents. They also attract attention as effective P-glycoprotein modulators that inhibit P-glycoprotein from binding to anticancer drugs and overcome multidrug resistance. Cyclosporin A itself interacts with a common binding site of P-glycoprotein to which Vinca alkaloids and verapamil bind. We were interested to determine whether cyclosporin A and FK506 are substrates for P-glycoprotein to transport, and we studied their transcellular transport. In LLC-PK1 cells, derived from porcine kidney proximal tubule and forming a highly polarized epithelium, cyclosporin A was transported in a saturable manner. LLC-GA5-COL300, a transformant cell line derived by transfecting LLC-PK1 with human MDR1 cDNA isolated from normal adrenal gland, expresses P-glycoprotein specifically on the apical surface and shows a typical multidrug-resistant phenotype. LLC-GA5-COL300 cells showed increased transport of cyclosporin A from the basal to the apical side. Kinetic analysis showed that this transport was a typical saturable transport with the calculated apparent Michaelis constant (Kmapp) and the maximum flux (Vmax) as 8.4 μM and 2.4 nmol/mg protein/h, respectively. LLC-GA5-COL300 also snowed increased transport of FK506 from the basal to the apical side. These results indicate that P-glycoprotein transports the immunosuppressive agents cyclosporin A and FK506.

Original languageEnglish
Pages (from-to)6077-6080
Number of pages4
JournalJournal of Biological Chemistry
Volume268
Issue number9
Publication statusPublished - 1993 Mar 25
Externally publishedYes

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P-Glycoprotein
Tacrolimus
Cyclosporine
Immunosuppressive Agents
LLC-PK1 Cells
Vinca Alkaloids
Transcytosis
Proximal Kidney Tubule
Multiple Drug Resistance
Adrenal Glands
Verapamil
Modulators
Swine
Epithelium
Complementary DNA
Binding Sites
Cells
Fluxes
Phenotype
Cell Line

ASJC Scopus subject areas

  • Biochemistry

Cite this

Saeki, T., Ueda, K., Tanigawara, Y., Hori, R., & Komano, T. (1993). Human P-glycoprotein transports cyclosporin A and FK506. Journal of Biological Chemistry, 268(9), 6077-6080.

Human P-glycoprotein transports cyclosporin A and FK506. / Saeki, Tohru; Ueda, Kazumitsu; Tanigawara, Yusuke; Hori, Ryohei; Komano, Tohru.

In: Journal of Biological Chemistry, Vol. 268, No. 9, 25.03.1993, p. 6077-6080.

Research output: Contribution to journalArticle

Saeki, T, Ueda, K, Tanigawara, Y, Hori, R & Komano, T 1993, 'Human P-glycoprotein transports cyclosporin A and FK506', Journal of Biological Chemistry, vol. 268, no. 9, pp. 6077-6080.
Saeki T, Ueda K, Tanigawara Y, Hori R, Komano T. Human P-glycoprotein transports cyclosporin A and FK506. Journal of Biological Chemistry. 1993 Mar 25;268(9):6077-6080.
Saeki, Tohru ; Ueda, Kazumitsu ; Tanigawara, Yusuke ; Hori, Ryohei ; Komano, Tohru. / Human P-glycoprotein transports cyclosporin A and FK506. In: Journal of Biological Chemistry. 1993 ; Vol. 268, No. 9. pp. 6077-6080.
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