The equilibrium and kinetic drug binding properties of the mouse P-gp1a and P-gp1b P-glycoproteins are similar

Citation
Jc. Taylor et al., The equilibrium and kinetic drug binding properties of the mouse P-gp1a and P-gp1b P-glycoproteins are similar, BR J CANC, 81(5), 1999, pp. 783-789
Citations number
33
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Oncology,"Onconogenesis & Cancer Research
Journal title
BRITISH JOURNAL OF CANCER
ISSN journal
0007-0920 → ACNP
Volume
81
Issue
5
Year of publication
1999
Pages
783 - 789
Database
ISI
SICI code
0007-0920(199911)81:5<783:TEAKDB>2.0.ZU;2-6
Abstract
The gene encoding the multidrug resistance P-glycoprotein (P-gp) is duplica ted in rodent species and the functional basis for this remains unresolved. Despite a high sequence similarity, the mouse P-gp1a and P-gp1b isoforms s how distinct patterns of tissue distribution which suggest a specific role of the P-gp1b isoform in steroid transport. In the present study possible b iochemical differences between the isoforms were directly investigated at t he level of drug interaction. There was no detectable difference in the aff inity or binding capacity of the two isoforms towards [H-3]vinblastine at e quilibrium. Similarly, the rate at which [H-3]vinblastine associates with P -gp was indistinguishable between the two isoforms. Some modest differences were observed in the relative abilities of the multidrug-resistant (MDR) r eversing agents CP100-356, nicardipine and verapamil to displace equilibriu m [H-3]vinblastine binding to P-gp1a and P-gp1b. The steroid hormone proges terone displayed a low affinity (K-i = 1.2 +/- 0.2 mu M for P-gp1a and 3.5 +/- 0.5 mu M for P-gp1b), suggesting an unlikely role as a physiological su bstrate. Thus the mouse isoforms do not appear to exhibit functional differ ences at the level of initial substrate interaction with protein. (C) 1999 Cancer Research Campaign.