厚生労働科学研究費補助金（難治性疾患克服研究事業） 「Menkes 病・occipital horn 症候群の実態調査、早期診断基準確立、治療法開発に関する研究」 平成23年度 総括・分担研究報告書（page 19/118）[厚生労働科学研究費補助金（難治性疾患克服研究事業） 「Menkes 病・occipital horn 症候群の実態調査、早期診断基準確立、治療法開発に関する研究」 平成23年度 総括・分担研究報告書]

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serum, liver, and brain, and high copper concentrations in the intestine and kidney. Copperconcentrations in the cerebellum, liver, and serum of treated macular mice were significantly higherthan thos....

serum, liver, and brain, and high copper concentrations in the intestine and kidney. Copperconcentrations in the cerebellum, liver, and serum of treated macular mice were significantly higherthan those of control macular mice, suggesting that disulfiram improved intestinal copperabsorption. The activity of cytochrome c oxidase, a copper-dependent enzyme, is reduced in thebrain of macular mice [12]. Combination therapy improved cytochrome c oxidase activity (Fig. 3).Dopamineβ-hydroxylase is also a copper-dependent enzyme. Copper is incorporated intodopamineβ-hydroxylase in the Golgi apparatus in normal cells. Dopamineβ-hydroxylase activity isdecreased in the brain of the brindled mouse, an animal model of MD [13]. Furthermore, even inpatients with MD, the activity of this enzyme is reduced and cannot be improved by parenteralcopper administration [14]. These findings indicate that copper cannot be incorporated intodopamineβ-hydroxylase in MD-affected cells due to ATP7A defects. Given that dopamineβ-hydroxylase converts dopamine to noradrenaline, which is subsequently metabolized toadrenaline, the ratios of noradrenaline and adrenaline to dopamine serve as indicators of dopamineβ-hydroxylase activity. As shown in Fig. 4, the ratios of noradrenaline and adrenaline to dopaminewere higher in treated macular mice, suggesting that dopamineβ-hydroxylase activity wasimproved by the therapy. The results of our study suggest that disulfiram facilitates copper transportinto the Golgi apparatus of affected cells, including cells in the intestines and blood-brain barrier,thereby making it available to copper-dependent enzymes.MD patients and macular mice exhibit high renal copper concentrations [1]. Indeed, controlmacular mice exhibited a high concentration of copper in the kidney. The renal copperconcentration of treated macular mice was higher than that of control macular mice. Serumcreatinine levels were normal (normal, 0.08?0.24 mg/dL) in 23 treated mice; one treated mouseexhibited a slightly higher serum creatinine level (0.3 mg/dL). Serum BUN, AST, and ALT levelswere normal in all treated macular mice. To apply the combination therapy to patients with MD, theeffects of long-term combination treatment must be investigated in mouse models of MD.