DMD Simcyp

Home Help [Feedback] [For Subscribers] [Archive] [Search] --
QUICK SEARCH:   [advanced]


     

Drug Metabolism and Disposition Fast Forward
First published on May 9, 2007; DOI: 10.1124/dmd.107.015479

This Article
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
dmd.107.015479v1
35/8/1372    most recent
Right arrow Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Author home page(s):
Isabelle J. Letourneau
Andrew J. Slot
Roger G. Deeley
Susan P.C. Cole
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Letourneau, I. J.
Right arrow Articles by Cole, S. P.C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Letourneau, I. J.
Right arrow Articles by Cole, S. P.C.


Received for publication March 1, 2007.
Revised April 26, 2007.
Accepted for publication May 8, 2007.

MUTATIONAL ANALYSIS OF A HIGHLY CONSERVED PROLINE RESIDUE IN MRP1, MRP2 AND MRP3 REVEALS A PARTIALLY CONSERVED FUNCTION

Isabelle J. Letourneau 1, Andrew J. Slot 1, Roger G. Deeley 1, Susan P.C. Cole 1*

1 Queen's University

* Address correspondence to: E-mail: coles{at}post.queensu.ca

Abstract

The ATP-binding cassette multidrug resistance protein 1 MRP1 (ABCC1) mediates the cellular efflux of organic anions including conjugated metabolites, chemotherapeutic agents and toxicants. We previously described a mutation in cytoplasmic loop 7 (CL7) of MRP1, Pro1150Ala, which reduced leukotriene C4 (LTC4) transport but increased estradiol glucuronide (E217{beta}G) and methotrexate (MTX) transport. Vanadate-induced trapping of [{alpha}32P]8N3ADP by the Pro1150Ala mutant in the absence of substrate was also greatly reduced compared to wild-type MRP1 suggesting an uncoupling of ATP hydrolysis and transport activity. To determine if the functional importance of MRP1-Pro1150 is conserved, the analogous Pro1158 and Pro1147 residues in the MRP2 and MRP3 transporters, respectively, were mutated to Ala. Expression levels of the three mutants were unaffected; however, the vesicular transport activity of at least one organic anion substrate was significantly altered. As observed for MRP1-Pro1150Ala, LTC4 transport by MRP2-Pro1158Ala was decreased. However, E217{beta}G and MTX transport was comparable to wild-type MRP2, rather than increased as observed for MRP1-Pro1150Ala. In the case of MRP3-Pro1147Ala, LTC4 transport was increased, while E217{beta}G transport was unaffected. MTX transport by MRP3-Pro1147Ala was also increased, but to a lesser extent than for MRP1-Pro1150Ala. In contrast, all three mutants showed a marked reduction in levels of vanadate-induced trapped [{alpha}32P]8N3ADP. We conclude that MRP1-Pro1150, MRP2-Pro1158 and MRP3-Pro1147 in CL7 differ in their influence on substrate specificity but share a common role in the nucleotide interactions of these transporters.


Key words: ABC transporters, isolated membranes, leukotrienes, organic anion transport, transporters


This article has been cited by other articles:


Home page
 Drug Metab. Dispos.Home page
A. J. Slot, D. D. Wise, R. G. Deeley, T. J. Monks, and S. P. C. Cole
Modulation of Human Multidrug Resistance Protein (MRP) 1 (ABCC1) and MRP2 (ABCC2) Transport Activities by Endogenous and Exogenous Glutathione-Conjugated Catechol Metabolites
Drug Metab. Dispos., March 1, 2008; 36(3): 552 - 560.
[Abstract] [Full Text] [PDF]


Home Help [Feedback] [For Subscribers] [Archive] [Search] --
All ASPET Journals Molecular Pharmacology Pharmacological Reviews
Molecular Interventions Drug Metabolism and Disposition

Copyright © 2007 by the American Society for Pharmacology and Experimental Therapeutics.