タイトル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23-24年度 総合研究報告書

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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23-24年度 総合研究報告書

W. Bhadhprasit et al. / Journal of Trace Elements in Medicine and Biology 26 (2012) 105?108 107Consistent with a previous report [12], control macular mice exhibitedlow copper concentrations in serum, liver, and brain, and highcopper concentrations in the intestine and kidney. Copper concentrationsin the cerebellum, liver, and serum of treated macular micewere significantly higher than those of control macular mice, suggestingthat disulfiram improved intestinal copper absorption. Theactivity of cytochrome c oxidase, a copper-dependent enzyme, isreduced in the brain of macular mice [12]. Combination therapyimproved cytochrome c oxidase activity (Fig. 3).Dopamine ?-hydroxylase is also a copper-dependent enzyme.Copper is incorporated into dopamine ?-hydroxylase in the Golgiapparatus in normal cells. Dopamine ?-hydroxylase activity isdecreased in the brain of the brindled mouse, an animal model ofMD [13]. Furthermore, even in patients with MD, the activity ofthis enzyme is reduced and cannot be improved by parenteral copperadministration [14]. These findings indicate that copper cannotbe incorporated into dopamine ?-hydroxylase in MD-affected cellsdue to ATP7A defects. Given that dopamine ?-hydroxylase convertsdopamine to noradrenaline, which is subsequently metabolized toadrenaline, the ratios of noradrenaline and adrenaline to dopamineserve as indicators of dopamine ?-hydroxylase activity. As shownin Fig. 4, the ratios of noradrenaline and adrenaline to dopaminewere higher in treated macular mice, suggesting that dopamineFig. 3. Cytochrome c oxidase (CCO) activity in the cerebrum and cerebellum ofnormal mice (n = 4), control macular mice (n = 3), and treated macular mice (n = 4).*p < 0.05.?-hydroxylase activity was improved by the therapy. The resultsof our study suggest that disulfiram facilitates copper transportinto the Golgi apparatus of affected cells, including cells in theintestines and blood?brain barrier, thereby making it available tocopper-dependent enzymes.Fig. 4. Ratios of noradrenaline/dopamine and adrenaline/dopamine in the cerebrum (A and B) and cerebellum (C and D) of normal mice (n = 7), control macular mice (n = 7),and treated macular mice (n = 7). *p < 0.05; **p < 0.01.12