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



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.


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.


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.


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.



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)


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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

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