| Project/Area Number |
02670466
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pediatrics
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| Research Institution | Toho University |
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Principal Investigator |
AOKI Tsugutoshi Toho University School of Medicine, Department of Pedicatrics, Professor., 医学部・小児科学, 教授 (50057585)
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| Co-Investigator(Kenkyū-buntansha) |
KAZAMA Hiromi Toho University School of Medicine, Department of Pediatrics, Associate Professo, 医学部・小児科学, 助手 (90224386)
NIHEI Koichi Toho University School of Medicine, Department of Pediatrics, Associate Professo, 医学部・小児科学, 助手 (20218241)
TATENO Akihiko Toho University School of Medicine, Department of Pediatrics, Associate Professo, 医学部・小児科学, 講師 (70163491)
SHIMATAKE Hiroyuki Toho University School of Medicine, Department of Molecular Biology, Professor., 医学部・分子生物学, 教授 (40010110)
UCHIYAMA Toshimitsu Toho University School of Medicine, Department of Pharmacology, Professor, 医学部・薬理学, 教授 (50057709)
原 まどか 東邦大学, 医学部, 助手 (60181004)
水谷 正興 東邦大学, 医学部, 講師 (50166021)
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| Project Period (FY) |
1990 – 1991
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| Project Status |
Completed (Fiscal Year 1991)
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| Budget Amount *help |
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1991: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1990: ¥900,000 (Direct Cost: ¥900,000)
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| Keywords | Wilson's disease / ceruloplasmin / copper accumulation in liver / lysosome / Long-Evans / D-penicillamine / trientine-hydrochloride / defective biliary copper excretion / 胆汁中銅排泄低下 / セルロプラスミン合成 / Dーpenicillamine / 塩酸トリエチレン / キレ-ト効果 / NMR法 / 発症前Wilson病 / 胆汁中胆汁酸分析 / 胆汁中銅含量 / 新しい銅キレ-ト剤 / トリエンー2HC1 / トリエンー4HC1 |
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| Research Abstract |
In Wilson's disease, the primary pathogenetic mechanism is the inherited metabolic defect that is always associated with the gradual and progressive accumulation of copper in the liver. The ceruloplasmin is closely related to the primary genetic defect in Wilson's disease, it isn't clear whether a genetic abnormality in the synthesis of this protein causes copper to accumulate to excess.
The aim of this study was to clarify etiologic research of the copper accumulation and the impaired ceruloplasmin synthesis in the liver of Wilson's disease.
1. The bile juices and liver tissues collected by endoscopic or surgical biopsy, on 8 cases of pre -symptomatic and 12 cases of symptomatic patients with Wilson's disease were analyzed. The concentration ratio of copper/total bile acid in the bile in both of Presymptomatic and symptomatic patients were much lower than the control subjects. These findings demonstrated the copper excre tion in the bile was disturbed-in the patients. And then, copper c
… More
oncentration in the liver of the 3 year- old presymptomatic patients were very high level more than 30-50 times normal subjects.
2. Investigation about D-penicillamine and trientine in their complexing ability toward cupricion were underway in our laboratory. The stability constant of the complex of D-penicillamine - Cu(cluster) is larger than that of trientine.
3. In the acute oral toxicity, LD_<50> of trientine-2HCI was 2494 mg/kg and 2573 mg/kg for male and female rats, respectively. In the subacute oral toxicity, no animal died in any group. Although the rewere no obvious dose-depandent changes in hematological, serum biochemical, and pathological data. The cupruretic effect of trientine-2HCI or-4HCI were evident in rats. In clinical trials, the 3 agents revealed effective cupruresis in the following order : D-penicillamine>trientine-2HCI= trientine -4HCI.
4. Serum ceruloplasmin levels of the LEC rats were greatly reduced, and copper contents in their sera were very low. Urinary copper excretion was much increased in the LEC rats : they had extreme lyincreased copper contents in the liver by more than 40-50 times the LEA rats. The LEC rats most often appear with hepatitis, and have genetically auto somal recessive inheritance. We conclude that the LEC rats are useful as the animal of Wilson's disease. Less
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