title: Copper is taken up efficiently from albumin and alpha2-macroglobulin by cultured human cells by more than one mechanism.
abstract: Ionic copper entering blood plasma binds tightly to albumin and the macroglobulin transcuprein. It then goes primarily to the liver and kidney except in lactation, where a large portion goes directly to the mammary gland. Little is known about how this copper is taken up from these plasma proteins. To examine this, the kinetics of uptake from purified human albumin and alpha(2)-macroglobulin, and the effects of inhibitors, were measured using human hepatic (HepG2) and mammary epithelial (PMC42) cell lines. At physiological concentrations (3-6 muM), both cell types took up copper from these proteins independently and at rates similar to each other and to those for Cu-dihistidine or Cu-nitrilotriacetate (NTA). Uptakes from alpha(2)-macroglobulin indicated a single saturable system in each cell type, but with different kinetics, and 65-80% inhibition by Ag(I) in HepG2 cells but not PMC42 cells. Uptake kinetics for Cu-albumin were more complex and also differed with cell type (as was the case for Cu-histidine and NTA), and there was little or no inhibition by Ag(I). High Fe(II) concentrations (100-500 microM) inhibited copper uptake from albumin by 20-30% in both cell types and that from alpha(2)-macroglobulin by 0-30%, and there was no inhibition of the latter by Mn(II) or Zn(II). We conclude that the proteins mainly responsible for the plasma-exchangeable copper pool deliver the metal to mammalian cells efficiently and by several different mechanisms. alpha(2)-Macroglobulin delivers it primarily to copper transporter 1 in hepatic cells but not mammary epithelial cells, and additional as-yet-unidentified copper transporters or systems for uptake from these proteins remain to be identified.
authors.affiliation: Department of Chemistry and Biochemistry and Institute for Molecular Biology and Nutrition, California State University, Fullerton, California 92834-6866, USA.
authors.forename: Mizue
authors.initials: M
authors.lastname: Moriya
authors.forename: Yi-Hsuan
authors.initials: YH
authors.lastname: Ho
authors.forename: Anne
authors.initials: A
authors.lastname: Grana
authors.forename: Linh
authors.initials: L
authors.lastname: Nguyen
authors.forename: Arrissa
authors.initials: A
authors.lastname: Alvarez
authors.forename: Rita
authors.initials: R
authors.lastname: Jamil
authors.forename: M Leigh
authors.initials: ML
authors.lastname: Ackland
authors.forename: Agnes
authors.initials: A
authors.lastname: Michalczyk
authors.forename: Pia
authors.initials: P
authors.lastname: Hamer
authors.forename: Danny
authors.initials: D
authors.lastname: Ramos
authors.forename: Stephen
authors.initials: S
authors.lastname: Kim
authors.forename: Julian F B
authors.initials: JF
authors.lastname: Mercer
authors.forename: Maria C
authors.initials: MC
authors.lastname: Linder
mesh_terms: D001667:Binding, Competitive; D001943:Breast Neoplasms / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D003300:Copper / Q000378:metabolism*; D000079923:Copper Transporter 1; D005260:Female; D006639:Histidine / Q000031:analogs & derivatives / Q000378:metabolism; D006801:Humans; D017136:Ion Transport; D007501:Iron / Q000378:metabolism; D007700:Kinetics; D008113:Liver Neoplasms / Q000378:metabolism; D008345:Manganese / Q000378:metabolism; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D009942:Organometallic Compounds / Q000378:metabolism; D011485:Protein Binding; D012709:Serum Albumin / Q000378:metabolism*; D012834:Silver / Q000378:metabolism; D015032:Zinc / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; D000079923:Copper Transporter 1; D009942:Organometallic Compounds; C490079:SLC31A1 protein, human; D012709:Serum Albumin; D000511:alpha-Macroglobulins; D012834:Silver; D008345:Manganese; D006639:Histidine; D003300:Copper; C098468:copper histidine; C060581:cupric nitrilotriacetate; D007501:Iron; D015032:Zinc; D009571:Nitrilotriacetic Acid