title: Separate pathways for cellular uptake of ferric and ferrous iron.
abstract: Separate pathways for transport of nontransferrin ferric and ferrous iron into tissue cultured cells were demonstrated. Neither the ferric nor ferrous pathway was shared with either zinc or copper. Manganese shared the ferrous pathway but had no effect on cellular uptake of ferric iron. We postulate that ferric iron was transported into cells via beta(3)-integrin and mobilferrin (IMP), whereas ferrous iron uptake was facilitated by divalent metal transporter-1 (DMT-1; Nramp-2). These conclusions were documented by competitive inhibition studies, utilization of a beta(3)-integrin antibody that blocked uptake of ferric but not ferrous iron, development of an anti-DMT-1 antibody that blocked ferrous iron and manganese uptake but not ferric iron, transfection of DMT-1 DNA into tissue culture cells that showed enhanced uptake of ferrous iron and manganese but neither ferric iron nor zinc, hepatic metal concentrations in mk mice showing decreased iron and manganese but not zinc or copper, and data showing that the addition of reducing agents to tissue culture media altered iron binding to proteins of the IMP and DMT-1 pathways. Although these experiments show ferric and ferrous iron can enter cells via different pathways, they do not indicate which pathway is dominant in humans.
authors.affiliation: USA Cancer Center, University of South Alabama, Mobile, Alabama 36688, USA. mconrad@usamail.usouthal.edu
authors.forename: M E
authors.initials: ME
authors.lastname: Conrad
authors.forename: J N
authors.initials: JN
authors.lastname: Umbreit
authors.forename: E G
authors.initials: EG
authors.lastname: Moore
authors.forename: L N
authors.initials: LN
authors.lastname: Hainsworth
authors.forename: M
authors.initials: M
authors.lastname: Porubcin
authors.forename: M J
authors.initials: MJ
authors.lastname: Simovich
authors.forename: M T
authors.initials: MT
authors.lastname: Nakada
authors.forename: K
authors.initials: K
authors.lastname: Dolan
authors.forename: M D
authors.initials: MD
authors.lastname: Garrick
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001692:Biological Transport; D002352:Carrier Proteins / Q000378:metabolism*; D027682:Cation Transport Proteins; D002412:Cations / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism; D002460:Cell Line; D002712:Chlorides / Q000493:pharmacokinetics; D005290:Ferric Compounds / Q000493:pharmacokinetics*; D005296:Ferrous Compounds / Q000493:pharmacokinetics*; D006801:Humans; D039661:Integrin beta3; D033862:Iron-Binding Proteins; D020014:K562 Cells; D007668:Kidney; D017895:Manganese Compounds / Q000493:pharmacokinetics; D051379:Mice; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D051381:Rats; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D017967:Zinc Compounds / Q000493:pharmacokinetics; D000099236:Solute Carrier Family 11, Member 2
chemical_list: D015703:Antigens, CD; D002352:Carrier Proteins; D027682:Cation Transport Proteins; D002412:Cations; D002413:Cations, Divalent; D002712:Chlorides; D005290:Ferric Compounds; D005296:Ferrous Compounds; D039661:Integrin beta3; D033862:Iron-Binding Proteins; D017895:Manganese Compounds; D010980:Platelet Membrane Glycoproteins; D011994:Recombinant Proteins; D017967:Zinc Compounds; D000099236:Solute Carrier Family 11, Member 2; C020748:ferrous sulfate; C025314:ferric citrate; C016837:zinc chloride; C025340:manganese chloride