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Blood First Edition Paper, prepublished online November 6, 2009; DOI 10.1182/blood-2009-07-232587. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Beedholm-Ebsen, R. Articles by Moestrup, S. K. PubMed PubMed Citation Articles by Beedholm-Ebsen, R. Articles by Moestrup, S. K. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted July 22, 2009; accepted October 1, 2009. Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin R. Beedholm-Ebsen1, K. van de Wetering2, T. Hardlei3, E. Nexo3, P. Borst2 and S. K. Moestrup1,4 1 Department of Medical Biochemistry, University of Aarhus, Aarhus; 2 Division of Molecular Biology, The Netherlands Cancer Institute, Amsterdam, Netherlands; 3 Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus * Corresponding author; email: skm{at}biokemi.au.dk Abstract Cobalamin (Cbl, vitamin B12) deficiency in humans is a common cause of hematological and neurological disorders. We show here that the cellular export of Cbl, in contrast to the carrier- and receptor-dependent cellular import of Cbl, occurs by transmembrane transport of 'free' Cbl. Screening of candidate transporters by cellular gene silencing revealed a role in cellular cobalamin efflux of the ATP-binding cassette (ABC)-drug transporter, ABCC1, alias Multidrug Resistance Protein 1 (MRP1), which is present in the basolateral membrane of intestinal epithelium and in other cells. The ability of MRP1 to mediate ATP-dependent Cbl transport was confirmed by vesicular transport experiments, and a physiological role of MRP1 in mammalian Cbl homeostasis is indicated by the phenotype of knockout mice with targeted disruption of MRP1. These animals have a reduced concentration of Cbl in plasma and in the storage organs liver and kidney. In contrast, Cbl accumulates in the terminal part of the intestine of these mice suggesting a functional malabsorbtion due to a lower epithelial basolateral Cbl efflux. The identification of this Cbl export mechanism now allows the delineation of a coherent pathway for Cbl trafficking from food to the body cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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