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The gene encoding the multidrug resistance P-glycoprotein (P-gp) is duplicated in rodent species and the functional basis for this remains unresolved. Despite a high sequence similarity, the mouse P-gp1a and P-gp1b isoforms show distinct patterns of tissue distribution which suggest a specific role of the P-gp1b isoform in steroid transport. In the present study possible biochemical differences between the isoforms were directly investigated at the level of drug interaction. There was no detectable difference in the affinity or binding capacity of the two isoforms towards [3H]vinblastine at equilibrium. Similarly, the rate at which [3H]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) reversing agents CP100-356, nicardipine and verapamil to displace equilibrium [3H]vinblastine binding to P-gp1a and P-gp1b. The steroid hormone progesterone displayed a low affinity (Ki = 1.2 +/- 0.2 microM for P-gp1a and 3.5 +/- 0.5 microM for P-gp1b), suggesting an unlikely role as a physiological substrate. Thus the mouse isoforms do not appear to exhibit functional differences at the level of initial substrate interaction with protein.

Original publication

DOI

10.1038/sj.bjc.6690764

Type

Journal article

Journal

Br J Cancer

Publication Date

11/1999

Volume

81

Pages

783 - 789

Keywords

ATP Binding Cassette Transporter, Subfamily B, ATP-Binding Cassette Transporters, Animals, Binding, Competitive, CHO Cells, Cell Membrane, Cricetinae, Drug Resistance, Multiple, Isoquinolines, Kinetics, Mice, Nicardipine, Progesterone, Protein Binding, Protein Isoforms, Quinazolines, Verapamil, Vinblastine