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

238 Current Drug Metabolism, 2012, Vol. 13, No. 3 Kodama et al.Copper intake(2-5 mg/day)Liver(20 mg)Portal circulation(2 mg/day)ATP7Bwhole body (100 mg)brain (20 mg),muscle (35 mg),kidney (5 mg), andconnective tissue (10 mg)kidneybile(2 mg/day)Albumin Cu Ceruloplasmin CuAmino acids Cu (4.3 mg)(0.2 mg)Blood (10 mg), RBC (5.5 mg)intestinestool(2-5 mg/day)Urine Cu(10~50 ?g/day)Fig. (1). Copper metabolism in humans.ATP7B, copper-transporting P-type ATPase. Solid and dashed arrows show main and minor pathways in copper transport, respectively. Values in parenthesesshow amounts in adult males.PlasmaCu-enzymes(LOX, DBH)PlasmaCu-enzymes(LOX, DBH)MTGolgi apparatusATP7AATOX1(HAH1)CTR1MTMTMTMTMTMTGolgi apparatusMTATP7AMTMTMTMTMTATOX1(HAH1)MTMTMTMTCTR1MTMTa:Normal cellsb:Affected cells of Menkes diseaseFig. (2). Copper metabolism in normal cells versus those affected by Menkes disease.CTR1, copper transporter 1; ATP7A, copper-transporting P-type ATPase ; ?, copper. Left, copper metabolism in normal cells. Right, copper metabolism incells affected by Menkes disease. In cells affected by Menkes disease, copper cannot be transported from the cytosol to the Golgi apparatus. As a result, copperaccumulates in the cytosol and cannot be excreted from the cells. Copper deficiency in the Golgi apparatus results in a decrease in the activities of secretorycopper enzymes such as lysyl oxidase (LOX) and dopamine ?-hydroxidase (DBH).MURR1, is also involved in copper excretion to the bile. Althoughmost intracellular copper-binding proteins, such as ATP7A andATP7B, bind copper as Cu(I), COMMD1 has been reported to bindcopper as Cu(II) [25], and may be an important component of theintracellular system for utilizing, detecting, or detoxifying Cu(II)[26]. Bedlington Terriers, for example, have a COMMD1 defectwhich causes copper toxicosis in the liver due to insufficient biliarycopper excretion [27]. Serum copper and ceruloplasmin levels inBedlington Terriers are not low, indicating that ATP7B function isintact. Tao et al showed that the carboxyl terminus of COMMD1dimerizes (and oligomerizes) as efficiently as its full-length counterpart,and attributed a major protein-protein interaction role to thisacidic residue-rich region [28]. Indeed, ATP7B and COMMD1 maycooperate to facilitate biliary copper excretion [25-29], and maythus explain why biliary copper excretion is affected in WD.27