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 language | English |
|---|---|
| Pages (from-to) | 6077-6080 |
| Number of pages | 4 |
| Journal | Journal of Biological Chemistry |
| Volume | 268 |
| Issue number | 9 |
| Publication status | Published - 1993 Mar 25 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
Cite this
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 journal › Article
}
TY - JOUR
T1 - Human P-glycoprotein transports cyclosporin A and FK506
AU - Saeki, Tohru
AU - Ueda, Kazumitsu
AU - Tanigawara, Yusuke
AU - Hori, Ryohei
AU - Komano, Tohru
PY - 1993/3/25
Y1 - 1993/3/25
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=0027418815&partnerID=8YFLogxK
M3 - Article
C2 - 7681059
AN - SCOPUS:0027418815
VL - 268
SP - 6077
EP - 6080
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
SN - 0021-9258
IS - 9
ER -