Skip to main content
Log in

Positron Emission Tomography of Copper Metabolism in the Atp7b −/− Knock-out Mouse Model of Wilson’s Disease

  • Research Article
  • Published:
Molecular Imaging and Biology Aims and scope Submit manuscript

Abstract

Purpose

This study aims to determine feasibility and utility of copper-64(II) chloride (64CuCl2) as a tracer for positron emission tomography (PET) of copper metabolism imbalance in human Wilson’s disease (WD).

Procedures

Atp7b −/− mice, a mouse model of human WD, were injected with 64CuCl2 intravenously and subjected to PET scanning using a hybrid PET-CT (computerized tomography) scanner, with the wild-type C57BL mice as a normal control. Quantitative PET analysis was performed to determine biodistribution of 64Cu radioactivity and radiation dosimetry estimates of 64Cu were calculated for PET of copper metabolism in humans.

Results

Dynamic PET analysis revealed increased accumulation and markedly reduced clearance of 64Cu from the liver of the Atp7b −/− mice, compared to hepatic uptake and clearance of 64Cu in the wild-type C57BL mice. Kinetics of copper clearance and retention was also altered for kidneys, heart, and lungs in the Atp7b −/− mice. Based on biodistribution of 64Cu in wild-type C57BL mice, radiation dosimetry estimates of 64Cu in normal human subjects were obtained, showing an effective dose (ED) of 32.2 μ (micro)Sv/MBq (weighted dose over 22 organs) and the small intestine as the critical organ for radiation dose (61 μGy/MBq for males and 69 μGy/MBq for females). Radiation dosimetry estimates for the patients with WD, based on biodistribution of 64Cu in the Atp7b −/− mice, showed a similar ED of 32.8 μ (micro)Sv/MBq (p = 0.53), with the liver as the critical organ for radiation dose (120 μSv/MBq for male and 161 μSv/MBq for female).

Conclusions

Quantitative PET analysis demonstrates abnormal copper metabolism in the mouse model of WD with improved time–resolution. Human radiation dosimetry estimates obtained in this preclinical study encourage direct radiation dosimetry of 64CuCl2 in human subjects. The results suggest feasibility of utilizing 64CuCl2 as a tracer for noninvasive assessment of copper metabolism in WD with PET.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Olivares M, Uauy R (1996) Copper as an essential nutrient. Am J Clin Nutr 63(5):791S–6S

    PubMed  CAS  Google Scholar 

  2. Uauy R, Olivares M, Gonzalez M (1998) Essentiality of copper in humans. Am J Clin Nutr 67(5 Suppl):952S–959S

    PubMed  CAS  Google Scholar 

  3. Cartwright GE, Wintrobe MM (1964) Copper metabolism in normal subjects. Am J Clin Nutr 14:224–32

    PubMed  CAS  Google Scholar 

  4. Turnlund JR (1998) Human whole-body copper metabolism. Am J Clin Nutr 67(5):960S–964S

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  6. Lutsenko S (2010) Human copper homeostasis: a network of interconnected pathways. Curr Opin Chem Biol 14:1–7

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  8. Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW (1993) The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet 5:327–337

    Article  PubMed  CAS  Google Scholar 

  9. Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W, Ross B et al (1993) The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. Nat Genet 5:344–350

    Article  PubMed  CAS  Google Scholar 

  10. Vulpe C, Levinson B, Whitney S, Packman S, Gitschier J (1993) Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting. Nat Genet 3:7–13

    Article  PubMed  CAS  Google Scholar 

  11. Mercer JF, Livingston J, Hall B, Paynter JA, Begy C, Chandrasekharappa S et al (1993) Isolation of a partial candidate gene for Menkes disease by positional cloning. Nat Genet 3:20–25

    Article  PubMed  CAS  Google Scholar 

  12. Chelly J, Tumer Z, Tonnesen T, Petterson A, Ishikawa-Brush Y, Tommerup N et al (1993) Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein. Nat Genet 3:14–19

    Article  PubMed  CAS  Google Scholar 

  13. Olivarez L, Caggana M, Pass KA, Ferguson P, Brewer GJ (2001) Estimate of the frequency of Wilson’s disease in the US Caucasian population: a mutation analysis approach. Ann Hum Genet 65:459–463

    Article  PubMed  CAS  Google Scholar 

  14. Multhaup G (1997) Amyloid precursor protein, copper and Alzheimer’s disease. Biomed Pharmacother 51(3):105–11

    Article  PubMed  CAS  Google Scholar 

  15. Theophanides T, Anastassopoulou J (2002) Copper and carcinogenesis. Crit Rev Oncol Hematol 1:57–64

    Article  Google Scholar 

  16. Kusleikaite M, Masironi R (1996) Trace elements in prognosis of myocardial infarction and sudden coronary death. J Trace Elem Exp Med 9(2):57–62

    Article  Google Scholar 

  17. Owen CA Jr (1964) Distribution of copper in the rat. Am J Physiol 207:446–448

    PubMed  CAS  Google Scholar 

  18. Owen CA Jr (1965) Metabolism of radiocopper (Cu64) in the rat. Am J Physiol 209:900–904

    PubMed  CAS  Google Scholar 

  19. Dunn MA, Green MH, Leach RM Jr (1991) Kinetics of copper metabolism in rats: a compartmental model. Am J Physiol 261:E115–125

    PubMed  CAS  Google Scholar 

  20. Que EL, Chang CJ (2006) A smart magnetic resonance contrast agent for selective copper sensing. J Am Chem Soc 128:15942–15943

    Article  PubMed  CAS  Google Scholar 

  21. Que EL, Gianolio E, Baker SL, Wong AP, Aime S, Chang CJ (2009) Copper-responsive magnetic resonance imaging contrast agents. J Am Chem Soc 131(24):8527–8536

    Article  PubMed  CAS  Google Scholar 

  22. Chaudhry AF, Verma M, Morgan MT, Henary MM, Siegel N, Hales JM et al (2010) Kinetically controlled photoinduced electron transfer switching in Cu(I)-responsive fluorescent probes. J Am Chem Soc 132(2):737–747

    Article  PubMed  CAS  Google Scholar 

  23. Domaille DW, Zeng L, Chang CJ (2010) Visualizing ascorbate-triggered release of labile copper within living cells using a ratiometric fluorescent sensor. J Am Chem Soc 132(4):1194–1195

    Article  PubMed  CAS  Google Scholar 

  24. Blower PJ, Lewis JS, Zweit J (1996) Copper radionuclides and radiopharmaceuticals in nuclear medicine. Nucl Med Biol 23:957–980

    Article  PubMed  CAS  Google Scholar 

  25. Peng F, Xin Lu, Janisse J, Muzik O, Shields AF (2006) Positron emission tomography of human prostate cancer xenografts in mice with increased uptake of copper (II)-64 chloride. J Nucl Med 47(10):1649–1652

    PubMed  CAS  Google Scholar 

  26. Liu J, Hajibeigi A, Ren G, Lin M, Siyambalapitiyage W, Liu Z et al (2009) Retention of the radiotracers 64Cu-ATSM and 64Cu-PTSM in human and murine tumors is influenced by MDR1 protein expression. J Nucl Med 50:1332–1339

    Article  PubMed  CAS  Google Scholar 

  27. Stabin MG (1996) MIRDOSE: personal computer software for internal dose assessment in nuclear medicine. J Nucl Med 37:538–46

    PubMed  CAS  Google Scholar 

  28. Stabin MB, Siegel JA (2003) Physical models and dose factors for use in internal dose assessment. Health Phys 85:294–310

    Article  PubMed  CAS  Google Scholar 

  29. Osborn SB, Szaz KF, Walshe JM (1969) Studies with radioactive copper (64Cu and 67Cu): abdominal scintiscans in patients with Wilson’s disease. Q J Med 38:467–474

    PubMed  CAS  Google Scholar 

  30. Walshe JM, Potter G (1977) The pattern of the whole body distribution of radioactive copper (67Cu, 64Cu) in Wilson’s disease and various control groups. Q J Med 46:445–462

    PubMed  CAS  Google Scholar 

  31. Hays MT, Watson EE, Thomas SR, Stabin (2002) Radiation absorbed dose estimates from 18 F-FDG. J Nucl Med 43:210–214

    PubMed  CAS  Google Scholar 

  32. Bush JA, Mahoney JP, Markowitz H, Gubler CJ, Cartwright GE, Wintrobe MM (1955) Studies on copper metabolism. XVI. Radioactive copper studies in normal subjects and in patients with hepatolenticular degeneration. J Clin Invest 34:1766–1778

    Article  PubMed  CAS  Google Scholar 

  33. Skromne-Kadlubik G, Diaz JF, Celis C (1975) Basal ganglia scans in the human. J Nucl Med 16(8):787–788

    PubMed  CAS  Google Scholar 

  34. Bissig KD, Honer M, Zimmermann K, Summer KH, Solioz M (2005) Whole animal copper flux assessed by positron emission tomography in the Long–Evans cinnamon rat—a feasibility study. Biometals 18(1):83–88

    Article  PubMed  CAS  Google Scholar 

  35. Wahl RL, Quint LE, Cieslak RD, Aisen AM, Koeppe RA, Meyer CR (1993) Anatometabolic tumor imaging: fusion of FDG PET with CT or MRI to localize foci of increased activity. J Nucl Med 34:1190–1197

    PubMed  CAS  Google Scholar 

  36. Judenhofer MS, Wehrl HF, Newport DF, Catana C, Siegel SB, Becker M et al (2008) Simultaneous PET-MRI: a new approach for functional and morphological imaging. Nat Med 14(4):459–465

    Article  PubMed  CAS  Google Scholar 

  37. Huster D, Finegold MJ, Morgan CT, Burkhead JL, Nixon R, Vanderwerf SM, Gilliam CT, Lutsenko S (2006) Consequences of copper accumulation in the livers of the Atp7b-/(Wilson disease gene) knockout mice. Am J Pathol 168(2):423–434

    Article  PubMed  CAS  Google Scholar 

  38. Lee SH, Lancey R, Montaser A, Madani N, Linder MC (1993) Ceruloplasmin and copper transport during the latter part of gestation in the rat. Proc Soc Exp Biol Med 203(4):428–39

    PubMed  CAS  Google Scholar 

  39. Harris ZL, Durley AP, Man TK, 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 

  40. Linz R, Barnes NL, Zimnicka AM, Kaplan JH, Eipper B, Lutsenko S (2008) The intracellular targeting of copper-transporting ATPase ATP7A in a normal and ATP7b −/− kidney. Am J Physiol Renal Electrolyte Physiol 294(1):F53–61

    Article  CAS  Google Scholar 

  41. Buiakova OI, Xu J, Lutsenko S, Zeitlin S, Das K, Das S, Ross BM, Mekios C, Scheinberg IH, Gilliam TC (1999) Null mutation of the murine ATP7B (Wilson disease) gene results in intracellular copper accumulation and late-onset hepatic nodular transformation. Hum Mol Genet 8(9):1665–71

    Article  PubMed  CAS  Google Scholar 

  42. Li Y, Wang L, Schuschke DA, Zhou Z, Saari JT, Kang YJ (2005) Marginal dietary copper restriction induces cardiomyopathy in rats. J Nutr 135(9):2130–2136

    PubMed  CAS  Google Scholar 

  43. Juhasz-Pocsine K, Rudnicki SA, Archer RL, Harik SI (2007) Neurologic complications of gastric bypass surgery for morbid obesity. Neurology 68(21):1843–1850

    Article  PubMed  Google Scholar 

  44. Turnlund JR, KeyesWR EHL, 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 49:870–878

    PubMed  CAS  Google Scholar 

  45. Fueger BJ, Czernin J, Hildebrandt I, Tran C, Halpern BS, Stout D et al (2006) Impact of animal handling on the results of 18 F-FDG PET studies in mice. J Nucl Med 47:999–1006

    PubMed  CAS  Google Scholar 

  46. Brewer GJ, Dick RD, Grover DK, LeClaire V, Tseng M, Wicha M et al (2000) Treatment of metastatic cancer with tetrathiomolybdate, an anticopper, antiangiogenic agent: phase I study. Clin Cancer Res 6:1–10

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Jon Anderson and Anjali Gupta for technical support in calibration of PET-CT scanner and PET-CT scanning, and Guiyang Hao for help in tracer injection. This project was funded partially by National Institutes of Health, USA (R21EB005331-01A2 to F.P; R56DK084510 to SL) and the Department of Radiology and Harold C. Simmons Comprehensive Cancer Center, at University of Texas Southwestern Medical Center at Dallas, TX, USA. The production of Cu-64 at Washington University School of Medicine is supported by NCI grant R24 CA86307. The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Fangyu Peng.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peng, F., Lutsenko, S., Sun, X. et al. Positron Emission Tomography of Copper Metabolism in the Atp7b −/− Knock-out Mouse Model of Wilson’s Disease. Mol Imaging Biol 14, 70–78 (2012). https://doi.org/10.1007/s11307-011-0476-4

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11307-011-0476-4

Key words

Navigation