title: Identification of multidrug resistance protein 1 (MRP1/ABCC1) as a molecular gate for cellular export of cobalamin.
abstract: 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.
authors.affiliation: Department of Medical Biochemistry, University of Aarhus, Aarhus, Denmark.
authors.forename: Rasmus
authors.initials: R
authors.lastname: Beedholm-Ebsen
authors.forename: Koen
authors.initials: K
authors.lastname: van de Wetering
authors.forename: Tore
authors.initials: T
authors.lastname: Hardlei
authors.forename: Ebba
authors.initials: E
authors.lastname: Nexø
authors.forename: Piet
authors.initials: P
authors.lastname: Borst
authors.forename: Søren K
authors.initials: SK
authors.lastname: Moestrup
mesh_terms: D000255:Adenosine Triphosphate / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D006367:HeLa Cells; D006801:Humans; D007408:Intestinal Absorption / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D014805:Vitamin B 12 / Q000235:genetics / Q000378:metabolism*; D014806:Vitamin B 12 Deficiency / Q000235:genetics / Q000378:metabolism
chemical_list: D000255:Adenosine Triphosphate; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014805:Vitamin B 12; C421109:multidrug resistance-associated protein 1