Søren Kragh Moestrup

Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin

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Cobalamin (Cbl, vitamin B(12)) deficiency in humans is a cause of hematologic and neurologic 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 showed a role in cellular Cbl 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 physiologic 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 malabsorption because of 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.
Original languageEnglish
JournalGekkan Blood
Volume115
Issue8
Pages (from-to)1632-9
Number of pages8
ISSN0915-0803
DOIs
Publication statusPublished - 2010

    Research areas

  • Adenosine Triphosphate, Animals, Biological Transport, CHO Cells, Cricetinae, Cricetulus, HeLa Cells, Humans, Intestinal Absorption, Intestinal Mucosa, Mice, Mice, Knockout, Multidrug Resistance-Associated Proteins, Rats, Vitamin B 12, Vitamin B 12 Deficiency

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