Skip to main content
SpringerLink
Log in

Copper binding components of blood plasma and organs, and their responses to influx of large doses of 65Cu, in the mouse

  • Published:
BioMetals Aims and scope Submit manuscript

Abstract

To establish for the first time how mice might differ from rats and humans in terms of copper transport, excretion, and copper binding proteins, plasma and organ cytosols from adult female C57CL6 mice were fractionated and analyzed by directly coupled size exclusion HPLC-ICP-MS, before and after i.p. injection of large doses of 65Cu. Plasma from untreated mice had different proportions of Cu associated with transcuprein/macroglobulin, ceruloplasmin and albumin than in humans and rats, and two previously undetected copper peaks (Mr 700 k and 15 k) were observed. Cytosols had Cu peaks seen previously in rat liver (Mr > 1000 k, 45 k and 11 k) plus one of 110 kDa. 65Cu (141 μg) administered over 14 h, initially loaded plasma albumin and mainly entered liver and kidney (especially 28 kDa and 11 kDa components). Components of other organs were less (but still significantly) enriched. 63Cu/65Cu ratios returned almost to normal by 14 days, indicating a robust system for excreting excess copper. We conclude that there are significant differences but also strong similarities in copper metabolism between mice, rats and humans; that the liver is able to buffer enormous changes in copper status; and that a large number of mammalian copper proteins remain to be identified.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

Abbreviations

Mr:

Apparent molecular weight

k:

Thousands (as in apparent molecular weight)

References

  • Amaravadi R, Glerum DM, Tzagoloff A (1997) Isolation of a cDNA encoding the human homolog of COX17, a yeast gene essential for mitochondrial copper recruitment. Hum Genet 99(3):329–333

    Article  PubMed  CAS  Google Scholar 

  • Arredondo M, Nunez MT (2005) Iron and copper metabolism. Mol Aspects Med 26(4–5):313–327

    Article  PubMed  CAS  Google Scholar 

  • Barrow L, Tanner MS (1988) Copper distribution among serum proteins in paediatric liver disorders and malignancies. Eur J Clin Invest 18(6):555–560

    Article  PubMed  CAS  Google Scholar 

  • Bethin KE, Cimato TR, Ettinger MJ (1995) Copper binding to mouse liver S-adenosylhomocysteine hydrolase and the effects of copper on its levels. J Biol Chem 270(35):20702–20711

    Google Scholar 

  • Bielli P, Calabrese L (2002) Structure to function relationships in ceruloplasmin:a ‘moonlighting’ protein. Cell Mol Life Sci 59(9):381–387

    Article  Google Scholar 

  • Burstein E, Hoberg JE, Wilkinson AS, Rumble JM, Csomos RA, Komarck CM, Maine GN, Wilkinson JC, Mayo MW, Duckett CS (2005) COMMD proteins, a novel family of structural and functional homologs of MURR1. J Biol Chem 280(23):22222–22232

    Article  PubMed  CAS  Google Scholar 

  • Camakaris J, Voskoboinik I, Mercer JFB (1999) Molecular mechanisms of copper homeostasis. Biochem Biophys Res Comm 261(2):225–232

    Article  PubMed  CAS  Google Scholar 

  • Campbell CH, Brown R, Linder MC (1981) Circulating ceruloplasmin is an important source of copper for normal and malignant cells. Biochim Biophys Acta 678(1):27–38

    PubMed  CAS  Google Scholar 

  • Culotta VC, Klomp LW, Strain J, Casareno RL, Krems B, Gitlin JD (1997) The copper chaperone for superoxide dismutase. J Biol Chem 272(38):23469–23472

    Article  PubMed  CAS  Google Scholar 

  • Donley SA, Ilagan BJ, Rim H, Linder MC (2002) Copper transport to mammary gland and milk during lactation in rats. Am J Physiol 284:G739–G747

    Google Scholar 

  • Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC (1998) Nramp2 is mutated in the anemic Belgrade (b) rat: evidence of a role for Nramp2 in endosomal iron transport. Proc Natl Acad Sci USA 95(3):1148–1153

    Article  PubMed  CAS  Google Scholar 

  • Freedman JH, Ciriolo MR, Peisach J (1989) The role of glutathione in copper metabolism and toxicity. J Biol Chem 264(10):5598–5606

    PubMed  CAS  Google Scholar 

  • Frieden E (1970) Ceruloplasmin, a link between copper and iron metabolism. Nutr Rev 28(1):87–91

    CAS  Google Scholar 

  • Garvey JS, Chang CC (1981) Detection of circulating metallothionein in rats injected with zinc or cadmium. Science 214(1):805–807

    Article  PubMed  CAS  Google Scholar 

  • Gless U, Schmitt Y, Ziegler S, Kruse-Jarres JD (1992) chromatographic separation of serum proteins and estimation of their zinc and copper content. J Trace Elem Electrolytes Health Dis 6(4):245–250

    PubMed  CAS  Google Scholar 

  • Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, BoronWF, Nussberger S, Gollan JL, Hediger MA (1997) Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388(6641):482–488

    Article  PubMed  CAS  Google Scholar 

  • Harada M, Kawaguchi T, Kumemura H, Terada K, Ninomiya H, Taniguchi E, Hanada S, Baba S, Maeyama M, Koga H, Ueno T, Furuta K, Suganuma T, Sugiyama T, Sata M (2005) The Wilson disease protein ATP7B resides in the late endosomes with Rab7 and the Niemann-Pick C1 protein. Am J Path 166(2):499–510

    PubMed  CAS  Google Scholar 

  • Harris ED (2000) Cellular copper transport and metabolism. Annu Rev Nutri 20:291–310

    Article  CAS  Google Scholar 

  • Harris ZL, Takahashi Y, Miyajima H, Serizawa M, MacGillivray RTA, Gitlin JD (1995) Aceruloplasminemia: molecular characterization of this disorder of iron metabolism. Proc Natl Acad Sci USA 92(7):2539–2543

    Article  PubMed  CAS  Google Scholar 

  • Harris ZL, Klomp LW, Gitlin JD (1998) Aceruloplasminemia: an inherited neurodegenerative disease with impaired iron homeostasis. Am J Clin Nutr 67(5 Suppl):972S–977S

    PubMed  CAS  Google Scholar 

  • Harris ZL, Durley AP, Man TM, Gitlin JD (1999) Targeted gene disruption reveals an essential role for ceruloplasmin in cellular iron efflux. Proc Natl Acad Sci USA 96(19):10812–10817

    Article  PubMed  CAS  Google Scholar 

  • Huffman DL, O’Halloran TV (2001) Function, structure and mechanism of intracellular copper trafficking proteins. Annu Rev Biochem 70:677–701

    Article  PubMed  CAS  Google Scholar 

  • Kagi KHR, Nordberg M (eds) (1979) Metallothionein. Birkhauser Verlag, Basel

    Google Scholar 

  • Kataoka M, Tavassoli M (1985) Identification of ceruloplasmin receptors on the surface of human blood monocytes, granulocytes, and lymphocytes. Exp Hematol 13(8):806–810

    PubMed  CAS  Google Scholar 

  • Klomp LW, Lin SJ, Yuan DS, Klausner RD, Culotta VC, Gitlin JD (1997) Identification and functional expression of HAH1: a novel human gene involved in copper homeostasis. J Biol Chem 272(14):9221–9226

    Article  PubMed  CAS  Google Scholar 

  • Klomp AE, van der Sluis B, Klomp LWJ, Wijmenga C (2003) The ubiquitously expressed MURR1 protein is absent in canine copper toxicosis. J Hepatol 39(5):703–709

    Article  PubMed  CAS  Google Scholar 

  • Kuo YM, Zhou B, Cosco D, Gitschier J (2001) The copper transporter CTR1 provides an essential function in mammalian embryonic development. Proc Natl Acad Sci USA 98(12):6836–6841

    Article  PubMed  CAS  Google Scholar 

  • Lee S, Lancey R, Montaser A, Madani N, Linder MC (1993) Transfer of copper from mother to fetus during the latter part of gestation in the rat. Proc Soc Exp Biol Med 203(6):428–439

    PubMed  CAS  Google Scholar 

  • Lee J, Prohaska JR, Thiele DJ (2001) Essential role for mammalian copper transproter Ctr1 in copper homeostasis and embryonic development. Proc Natl Acad Sci USA 98(12):6842–6847

    Article  PubMed  CAS  Google Scholar 

  • Linder MC (1991) Biochemistry of copper. Plenum Press, New York

    Google Scholar 

  • Linder MC (2001) Copper and genomic stability in mammals. Mutation Res 475(1–2):141–152

    PubMed  CAS  Google Scholar 

  • Linder MC (2002) Biochemistry and molecular biology of copper in mammals. In: Massoro EJ (ed) Handbook of copper pharmacology and toxicology. Humana Press, Totowa NJ

    Google Scholar 

  • Linder MC, Roboz M (1986) Turnover and excretion of copper in rats as measured with 67Cu. Am J Physiol 251(11):E551–E555

    PubMed  CAS  Google Scholar 

  • Liu NM, Lo LSL, Askary SH, Goforth J, Vivas EM, Tsai M, Linder MC (2007) Transcuprein is a macroglobulin regulated by copper and iron availability. J Nutr Biochem 18:597–608

    Article  PubMed  CAS  Google Scholar 

  • Lonberg-Holm K, Reed DL, Roberts RC, Damato-McCabe D (1987) Three high molecular weight protease inhibitors of rat plasma. Reactions with trypsin. J Biol Chem 262(10):4844–4853

    PubMed  CAS  Google Scholar 

  • Mason AZ, Borja MR (2002) A study of Cu turnover in proteins of the visceral complex of Littoria littorea by stable isotopic analysis using coupled HPLC-ICP-MS. Mar Environ Res 54(3–5):351–355

    Article  PubMed  CAS  Google Scholar 

  • Ma Z-Y, Guan Y-P, Liu H-Z (2005) Affinity adsorption of albumin on Cibacron Blue F3GA-coupled non-porous micrometered-sized magnetic polymer microspheres. React Funct Polym 66(6):618–624

    Article  CAS  Google Scholar 

  • Masuoka J, Hegenauer J, Van Dyke BR, Saltman P (1993) Intrinsic stoichiometric equilibrium constants for the binding of zinc(II) and copper (II) to the high affinity site of serum albumin. J Biol Chem 268(29):21533–21537

    PubMed  CAS  Google Scholar 

  • Mehra RK, Bremner I (1983) Development of a radioimmunoassay for rat liver metallothionein-1 and its application to the analysis of rat plasma and kidneys. Biochem J 213(2):459–465

    PubMed  CAS  Google Scholar 

  • Mercer JF (2001) The molecular basis of copper-transport diseases. Trends Mol Med 7(2):64–69

    Article  PubMed  CAS  Google Scholar 

  • Meyer LA, Durley AP, Prohaska JR, Harris ZL (2001) Copper transport and metabolism are normal in aceruloplasminemic mice. J Biol Chem 276(39):36857–36861

    Article  PubMed  CAS  Google Scholar 

  • Montaser A, Tetreault C, Linder MC (1992) Comparison of copper binding proteins in dog serum with those in other species. Proc Soc Ex Biol Med 200(4):321–329

    CAS  Google Scholar 

  • Nishikawa T, Lee ISM, Shiraishi N, Ishikawa T, Ohta Y, Mishikimi M (1997) Identification of S100b protein as copper-binding protein and its suppression of copper-induced cell damage. J Biol Chem 272(37):23037–23041

    Article  PubMed  CAS  Google Scholar 

  • Norton DS, Heaton FW (1980) Distribution of copper and zinc among protein fractions in the cytoplasm or rat tissues. J Inorg Biochem 13(1):1–9

    Article  PubMed  CAS  Google Scholar 

  • Ohta Y, Sharaishi N, Inai Y, Lee IS, Ishihashi H, Nishikimi M (2001) Ascorbate-induced high-affinity binding of copper to cytosolic proteins. Biochem Biophys Res Comm 287(4):888–894

    Article  PubMed  CAS  Google Scholar 

  • Osaki S, Johnson DA (1969) The possible significance of the ferrous oxidase activity of ceruloplasmin in normal human serum. J Biol Chem 244(20):5757–5761

    PubMed  CAS  Google Scholar 

  • Owen CA Jr, Randall RV, Goldstein NP (1975) Effect of dietary D-penicillamine on metabolism of copper in rats. Am J Physiol 228(1):88–91

    PubMed  CAS  Google Scholar 

  • Prohaska JR (1983) Changes in tissue growth, concentrations of copper, iron, cytochrome oxidase and superoxide dismutase subsequent to dietary or genetic copper deficiency in mice. J Nutr 113(8):2148–2158

    Google Scholar 

  • Puig S, Thiele DJ (2002) Molecular mechanisms of copper uptake and distribution. Curr Opin Chem Biol 6(2):171–180

    Article  PubMed  CAS  Google Scholar 

  • Rae TD, Schmidt PJ, Pufahl RA, Culotta VC, O’Halloran TV (1999) Undetectable intracellular free copper: the requirement of a copper chaperone for superoxide dismutase. Science 284(5415):805–808

    Article  PubMed  CAS  Google Scholar 

  • Ragan HA, Nacht S, Lee GR, Bishop CR, Cartwright GE (1969) Effect of ceruloplasmin on plasma iron in copper deficiency swine. Am J Physiol 217(5):1320–1323

    PubMed  CAS  Google Scholar 

  • Roelofsen J, Wolters H, Van Luyn JA, Miura N, Kuipers F, Vonk RJ (2000) Copper-induced apical trafficking of ATP7B in polarized hepatoma cells provides a mechanism for biliary copper excretion. Gastroenterol 119(3):782–793

    Article  CAS  Google Scholar 

  • Roeser HP, Lee GR, Nacht S, Cartwright GE (1980) The role of ceruloplasmin in iron metabolism. J Clin Invest 49(12):2408–2417

    Article  Google Scholar 

  • Schaefer M, Roelofsen J, Wolters H, Hofmann WJ, Muller M, Kuipers F, Stremmel W, Vonk RJ (1999) Localization of the Wilson’s disease protein in human liver. Gastroenterology 117(6):1380–1385

    Article  PubMed  CAS  Google Scholar 

  • Sharma RP, McQueen EG (1981) Effects of gold sodium thiomalate on cytosolic copper and zinc in the rat kidney and liver tissues. Clin Exp Pharmacol Physiol 8(6):591–599

    Article  PubMed  CAS  Google Scholar 

  • Sottrup-Jensen L (1989) Alpha-macroglobulins: structure, shape, and mechanisms of proteinase complex formation. J Biol Chem 264(20):11539–11542

    PubMed  CAS  Google Scholar 

  • Stevens MD, DiSilvestro RA, Harris ED (1984) Specific receptor for ceruloplasmin in membrane fragments from aortic and heart tissues. Biochem 23(2):261–266

    Article  CAS  Google Scholar 

  • Terao T, Owen CA Jr (1973) Nature of copper compounds in liver supernate and bile of rats: studies with 67Cu. Am J Physiol 224(3):682–686

    PubMed  CAS  Google Scholar 

  • Ting BTG, Lee CC, Janghobani M, Prohaska JR (1990) Development of the stable isotope tracer approach for studies of copper turnover in the rat and mouse. J Nutr Biochem 1(5):249–255

    Article  PubMed  CAS  Google Scholar 

  • Turnlund JR, Keyes WR, Anderson HL, Acord LL (1989) Copper absorption and retention in young men at three levels of dietary copper using the stable isotope, 65Cu. Am J Clin Nutr 49(5):870–878

    PubMed  CAS  Google Scholar 

  • Turnlund JR, Keyes WR, Peiffer GL, Scott KC (1998) Copper absorption, excretion, and retention by young men consuming low dietary copper determined by using the stable isotope 65Cu. Am J Clin Nutr 67(6 Suppl):1219–1225

    PubMed  CAS  Google Scholar 

  • van den Berghe PV, Folmer DE, Malingre HE, van Beurden E, Klomp AE, van de Sluis B, Merkx M, Klomp LW (2007) Human copper transporter 2 is localized in late endosomes and lysosomes and facilitates cellular copper uptake. Biochem J 407:49–59

    Article  PubMed  Google Scholar 

  • Vargas EJ, Shoho AR, Linder MC (1994) Copper transport in the Nagase analbuminemic rat. Am J Physiol 267(2):G259–G269

    PubMed  CAS  Google Scholar 

  • Weiss KC, Linder MC (1985) Copper transport in rats involving a new plasma protein. Am J Physiol 249(1):E77–E88

    PubMed  CAS  Google Scholar 

  • Wirth PL, Linder MC (1985) Distribution of copper among multiple components of human serum. J Natl Cancer Inst 75(2):277–284

    PubMed  CAS  Google Scholar 

  • Yoshida K, Furihata K, Takeda S, Nakamura A, Yamamoto K, Hiyamuta S, Ikeda S, Shimizu N, Yanagisawa N (1995) A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans. Nat Genet 9(3):267–272

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported in part by USPHS Grant RO1 HD46949 and NSF REU grant CHE 0354159 to M. C. Linder; and NSF grants DBI-9978806 and OCE-9977564 to A. Z. Mason. We are grateful to Dr. Z. Leah Harris for the breeding pairs for our colony of ceruloplasmin knockout mice.

Author information

Authors and Affiliations

  1. Department of Chemistry and Biochemistry, California State University, Fullerton, CA, 92834-6866, USA

    Anthony Cabrera, Erin Alonzo, Eric Sauble, Yu Ling Chu, Dionne Nguyen & Maria C. Linder

  2. Department of Biological Science, California State University, Long Beach, CA, 90840, USA

    Dee S. Sato & Andrew Z. Mason

  3. Institute for Integrated Research in Materials, Environments and Societies, California State University, Long Beach, CA, 90840, USA

    Andrew Z. Mason

Authors
  1. Anthony Cabrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Erin Alonzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eric Sauble
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Ling Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dionne Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria C. Linder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Dee S. Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Andrew Z. Mason
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria C. Linder.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cabrera, A., Alonzo, E., Sauble, E. et al. Copper binding components of blood plasma and organs, and their responses to influx of large doses of 65Cu, in the mouse. Biometals 21, 525–543 (2008). https://doi.org/10.1007/s10534-008-9139-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10534-008-9139-6

Keywords

Search

Navigation