Advertisement

Journal of Inherited Metabolic Disease

, Volume 41, Issue 6, pp 1285–1291 | Cite as

Disulfiram enhanced delivery of orally administered copper into the central nervous system in Menkes disease mouse model

  • Takao HoshinaEmail author
  • Satoshi Nozaki
  • Takashi Hamazaki
  • Satoshi Kudo
  • Yuka Nakatani
  • Hiroko Kodama
  • Haruo Shintaku
  • Yasuyoshi Watanabe
Original Article
  • 148 Downloads

Abstract

Introduction

Menkes disease (MD) is an X-linked recessive disorder caused by dysfunction of a copper-transporting protein, leading to severe neurodegeneration in early childhood. We investigated whether a lipophilic copper chelator, disulfiram, could enhance copper absorption from the intestine and transport copper across the blood–brain barrier in MD model mice.

Methods

Wild type and MD model mice were pretreated with disulfiram for 30 min before oral administration of 64CuCl2. Each organ was sequentially analyzed for radioactivity with γ counting. Copper uptake into the brain parenchyma was assessed by ex vivo autoradiography.

Results

In wild type mice, orally administered copper was initially detected in the intestine within 2 h, reaching a maximum level in the liver (19.6 ± 3.8 percentage injected dose per gram [%ID/g]) at 6 h. In MD model mice, the copper reached the maximum level in the liver (5.3 ± 1.5 %ID/g) at 4 h, which was lower than that of wild type mice (19.0 ± 7.4 %ID/g) (P < 0.05). Pretreatment of disulfiram in MD model mice increased the copper level in the brain (0.59 ± 0.28 %ID/g) at 24 h compared with MD model mice without disulfiram (0.07 ± 0.05 %ID/g) (P < 0.05). Ex vivo autoradiography revealed that high levels of copper uptake was observed in the cerebral cortex upon disulfiram pretreatment.

Conclusion

Our data demonstrated that disulfiram enhanced the delivery of orally administered copper into the central nervous system in MD model mice. The administration of disulfiram will enable patients to avoid unpleasant subcutaneous copper injection in the future.

Notes

Funding

This study was supported by a grant for research on intractable diseases from the Ministry of Health, Labour and Welfare (MHLW) of Japan (H23nannchi-ippann-091) and the Japan Society for the Promotion of Science (JSPS) KAKENHI grant 24591523.

Compliance with ethical standards

The experimental protocols were planned and performed according to the international standards for animal use and institutional guidelines and were approved by the animal care and use committees of Osaka City University, Osaka, Japan, and RIKEN Center for Biosystems Dynamics Research and Center for Life Science Technologies, Kobe, Hyogo, Japan.

Conflict of interest

Takao Hoshina, Satoshi Nozaki, Takashi Hamazaki, Satoshi Kudo, Yuka Nakatani, Hiroko Kodama, Haruo Shintaku, and Yasuyoshi Watanabe declare that they have no competing interests.

Supplementary material

10545_2018_239_MOESM1_ESM.docx (21 kb)
ESM 1 (DOCX 20 kb)

References

  1. Bhadhprasit W, Kodama H, Fujisawa C, Hiroki T, Ogawa E (2012) Effect of copper and disulfiram combination therapy on the macular mouse, a model of Menkes disease. J Trace Elem Med Biol 26:105–108CrossRefGoogle Scholar
  2. Danks DM, Cartwright E, Stevens BJ, Townley RR (1973) Menkes’ kinky hair disease: further definition of the defect in copper transport. Science 179:1140–1142CrossRefGoogle Scholar
  3. Huang J, Campian JL, Gujar AD et al (2018) Final results of a phase I dose-escalation, dose-expansion study of adding disulfiram with or without copper to adjuvant temozolomide for newly diagnosed glioblastoma. J Neurooncol 138:105–111CrossRefGoogle Scholar
  4. Johansson B (1992) A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites. Acta Psychiatr Scand Suppl 369:15–26CrossRefGoogle Scholar
  5. Kaler SG (2014) Neurodevelopment and brain growth in classic Menkes disease is influenced by age and symptomatology at initiation of copper treatment. J Trace Elem Med Biol 28:427–430CrossRefGoogle Scholar
  6. Kodama H, Fujisawa C (2009) Copper metabolism and inherited copper transport disorders: molecular mechanisms, screening, and treatment. Metallomics 1:42–52CrossRefGoogle Scholar
  7. Kodama H, Murata Y (1999) Molecular genetics and pathophysiology of Menkes disease. Pediatr Int 41:430–435CrossRefGoogle Scholar
  8. Kodama H, Meguro Y, Abe T et al (1991) Genetic expression of Menkes disease in cultured astrocytes of the macular mouse. J Inherit Metab Dis 14:896–901CrossRefGoogle Scholar
  9. Kodama H, Abe T, Takama M, Takahashi I, Kodama M, Nishimura M (1993) Histochemical localization of copper in the intestine and kidney of macular mice: light and electron microscopic study. J Histochem Cytochem 41:1529–1535CrossRefGoogle Scholar
  10. Kodama H, Sato E, Gu YH, Shiga K, Fujisawa C, Kozuma T (2005) Effect of copper and diethyldithiocarbamate combination therapy on the macular mouse, an animal model of Menkes disease. J Inherit Metab Dis 28:971–978CrossRefGoogle Scholar
  11. Kodama H, Fujisawa C, Bhadhprasit W (2012) Inherited copper transport disorders: biochemical mechanisms, diagnosis, and treatment. Curr Drug Metab 13:237–250CrossRefGoogle Scholar
  12. Kowal M, Lenartowicz M, Pecio A, Gołas A, Błaszkiewicz T, Styrna J (2010) Copper metabolism disorders affect testes structure and gamete quality in male mice. Syst Biol Reprod Med 56:431–444CrossRefGoogle Scholar
  13. Kreuder J, Otten A, Fuder H et al (1993) Clinical and biochemical consequences of copper-histidine therapy in Menkes disease. Eur J Pediatr 152:828–832CrossRefGoogle Scholar
  14. Kuo Y-M, Gybina AA, Pyatskowit JW, Gitschier J, Prohaska JR (2006) Copper transport protein (Ctr1) levels in mice are tissue specific and dependent on copper status. J Nutr 136:21–26CrossRefGoogle Scholar
  15. La Fontaine S, Mercer JFB (2007) Trafficking of the copper-ATPases, ATP7A and ATP7B: role in copper homeostasis. Arch Biochem Biophys 463:149–167CrossRefGoogle Scholar
  16. Lee J, Peña MMO, Nose Y, Thiele DJ (2002) Biochemical characterization of the human copper transporter Ctr1. J Biol Chem 277:4380–4387CrossRefGoogle Scholar
  17. Lenartowicz M, Krzeptowski W, Lipiński P et al (2015) Mottled mice and non-mammalian models of Menkes disease. Front Mol Neurosci 8:72CrossRefGoogle Scholar
  18. Lutsenko S, Barnes NL, Bartee MY, Dmitriev OY (2007) Function and regulation of human copper-transporting ATPases. Physiol Rev 87:1011–1046CrossRefGoogle Scholar
  19. Menkes JH, Alter M, Steigleder GK, Weakley DR, Sung JH (1962) A sex-linked recessive disorder with retardation of growth, peculiar hair, and focal cerebral and cerebellar degeneration. Pediatrics 29:764–779Google Scholar
  20. Mori M, Nishimura M (1997) A serine-to-proline mutation in the copper-transporting P-type ATPase gene of the macular mouse. Mamm Genome 8:407–410CrossRefGoogle Scholar
  21. Murata Y, Kodama H, Abe T et al (1997) Mutation analysis and expression of the mottled gene in the macular mouse model of Menkes disease. Pediatr Res 42:436–442CrossRefGoogle Scholar
  22. Nomura S, Nozaki S, Hamazaki T et al (2014) PET imaging analysis with 64Cu in disulfiram treatment for aberrant copper biodistribution in Menkes disease mouse model. J Nucl Med 55:845–851CrossRefGoogle Scholar
  23. Qian Y, Tiffany-Castiglioni E, Welsh J, Harris ED (1998) Copper efflux from murine microvascular cells requires expression of the menkes disease cu-ATPase. J Nutr 128:1276–1282CrossRefGoogle Scholar
  24. Sarkar B, Lingertat-Walsh K, Clarke JTR (1993) Copper-histidine therapy for Menkes disease. J Pediatr 123:828–830CrossRefGoogle Scholar
  25. Szerdahelyi P, Kása P (1987) Regional differences in the uptake of exogenous copper into rat brain after acute treatment with sodium diethyldithiocarbamate. A histochemical and atomic absorption spectrophotometric study. Histochemistry 86:627–632CrossRefGoogle Scholar
  26. Tümer Z, Møller LB (2010) Menkes disease. Eur J Hum Genet 18:511–518CrossRefGoogle Scholar
  27. 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 ATPase. Nat Genet 3:7–13CrossRefGoogle Scholar

Copyright information

© SSIEM 2018

Authors and Affiliations

  1. 1.Department of PediatricsOsaka City University Graduate School of MedicineOsakaJapan
  2. 2.Laboratory for Pathophysiological and Health ScienceRIKEN Center for Biosystems Dynamics Research and Center for Life Science TechnologiesKobeJapan
  3. 3.Department of PediatricsTeikyo University School of MedicineTokyoJapan

Personalised recommendations