Regular Article

British Journal of Cancer (1999) 81, 783–789. doi:10.1038/sj.bjc.6690764 www.bjcancer.com
Published online 15 October 1999

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

J C Taylor1, D R Ferry2, C F Higgins3 and R Callaghan1

  1. 1Nuffield Department of Clinical Biochemistry & Cellular Science, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK
  2. 2Department of Clinical Oncology, Queen Elizabeth Hospital, Edgbaston, Birmingham, UK
  3. 3MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, London, UK

Received 5 January 1999; Revised 27 May 1999; Accepted 3 June 1999.

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Abstract

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 plusminus 0.2 muM for P-gp1a and 3.5 plusminus 0.5 muM 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.

Keywords:

P-glycoprotein, MDR, drug binding, steroid hormones

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