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

108 W. Bhadhprasit et al. / Journal of Trace Elements in Medicine and Biology 26 (2012) 105?108MD patients and macular mice exhibit high renal copper concentrations[1]. Indeed, control macular mice exhibited a highconcentration of copper in the kidney. The renal copper concentrationof treated macular mice was higher than that of controlmacular mice. Serum creatinine levels were normal (normal,0.08?0.24 mg/dL) in 23 treated mice; one treated mouse exhibiteda slightly higher serum creatinine level (0.3 mg/dL). Serum BUN,AST, and ALT levels were normal in all treated macular mice. Toapply the combination therapy to patients with MD, the effects oflong-term combination treatment must be investigated in mousemodels of MD.ConclusionsA combination therapy comprising copper injection and oraldisulfiram improved copper concentrations in serum, liver, andbrain, and enhanced cytochrome c oxidase activity and catecholaminemetabolism in the brain of the macular mouse,a model of MD. These results suggest that the lipophiliccopper?disulfiram complex can penetrate cellular membranes,including the blood?brain barrier and Golgi membranes, inMD-affected cells, thereby making copper available to copperdependentenzymes. Connective tissue disorders, including arterialabnormalities, bladder diverticula, and osteoporosis, are also seriousproblems in patients with MD. These disorders are caused byreduced activity of lysyl oxidase, a secretory copper-dependentenzyme. Thus, the copper?disulfiram combination therapy mayalso be effective in treating connective tissue disorders associatedwith MD.AcknowledgmentsThis work was in part by a Grant of Research on IntractableDiseases from Ministry of Health, Labor and Welfare of Japan(23-326) and a memorial fund for Naoki, a former patient withMenkes disease.References[1] Kodama H, Fujisawa C. Copper metabolism and inherited copper transportdisorders: molecular mechanisms, screening, and treatment. Metallomics2009;1:42?52.[2] Kodama H, Meguro Y, Abe T, Rayner MH, Suzuki KT, Kobayashi S, et al. Geneticexpression of Menkes disease in cultured astrocytes of the macular mouse. JInherit Metab Dis 1991;14:896?901.[3] Kodama H. Recent developments in Menkes disease. J Inherit Metab Dis1993;16:791?9.[4] Qian Y, Tiffany-Castigloini E, Welsh J, Harris ED. Copper efflux from murinemicrovascular cells requires expression of the Menkes disease Cu-ATPase. JNutr 1998;128:1276?82.[5] Sarker B, Lingertat-walse K, Clark JT. Copper?histidine therapy for Menkesdisease. Pediatrics 1993;123:828?30.[6] Kodama H, Fujisawa C, Bhadhprasit W. Pathology, clinical features and treatmentof congenital copper metabolic diseases?focus on neurologic aspects.Brain Dev 2011;33:243?51.[7] Kodama H, Sato E, Gu YH, Shiga K, Fujisawa C, Kozuma T. Effect of copper anddiethydithiocarbamate combination therapy on the macular mouse, an animalmodel of Menkes disease. J Inherit Metab Dis 2005;28:971?8.[8] Pike MG, Mays DC, Macomber DW, Lipsky JJ. Metabolism of a disulfirammetabolite, S-methyl N,N-diethyldithiocarbamate, by flavin monooxygenasein human renal microsomes. Drug Metab Dispos 2001;29:127?32.[9] Benvenuto JA, Connor TH, Monteith DK, Laidlaw JL, Adams SC, Matney TS, et al.Degradation and inactivation of antitumor drugs. J Pharm Sci 1993;82:988?91.[10] Sofuoglu M, Kosten T. Novel approaches to the treatment of cocaine addiction.NCS Drugs 2005;19:13?5.[11] Murata Y, Kodama H, Abe T. Mutation analysis and expression of the mottledgene in the macular mouse model of Menkes disease. Pediatr Res1997;42:436?42.[12] Meguro Y, Kodama H, Abe T, Kobayashi S, Kodama Y, Nishimura M. Changes ofcopper level and cytochrome c oxidase activity in the macular mouse with age.Brain Dev 1991;13:184?6.[13] Nagara H, Yajima K, Suzuki K. The effect of copper supplementation onthe brindled mouse. A clinicopathological study. J Neuropathol Exp Neurol1981;40:428?46.[14] Christodoulou J, Danks DM, Sarkar B, Baerlocher KE, Casey R, Horn N, et al.Early treatment of Menkes disease with parenteral copper?histidine: longtermfollow-up of four treated patients. Am J Med Genet 1998;76:154?64.13