Reduction of copper and metallothionein in toxic milk mice by tetrathiomolybdate, but not deferiprone
Reduction of copper and metallothionein in toxic milk mice by tetrathiomolybdate, but not deferiprone
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DOI：
10.1016/s0162-0134(01)00383-x
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发表时间：
2002-01-15
影响因子：
3.9
通讯作者：
Koropatnick, J
中科院分区：
文献类型：
--
作者：
Czachor, JD;Cherian, MG;Koropatnick, J
铜既是生命所必需的，也是有毒的。细胞内运输水平上铜的异常调节与遗传性疾病有关，包括人类威尔逊氏病（WND）。 WND 导致铜以及铜和锌结合蛋白金属硫蛋白 (MT) 在肝脏和其他组织中积累。肝脏变性、神经功能障碍。小鼠体内的毒奶（TX）突变导致模仿人类 WND 的表型，并且 TX 已被提议作为该疾病的模型。我们将 TX 小鼠描述为在发育期间以及用金属离子螯合剂四硫代钼酸盐 (TTM) 和去铁酮 (L1) 治疗后金属离子和 MT 水平发生改变的模型。我们报告说，3 个月和 12 个月大的 TX 小鼠的肝、肾和脑铜和 MT 均升高。在两个时间点，TX 小鼠肝脏中的锌含量均显着升高，但大脑和肾脏中的锌含量则没有显着升高。 8-12 个月时，TX 小鼠肝脏中自发出现结节，维持高铜水平，但形态更加正常，MT 水平降低。用 TTM 治疗 TX 小鼠可显着降低升高的肝铜和 MT。 TTM 治疗伴随着血液和肾铜的短暂增加，表明肾脏排泄是重要的清除途径。另一方面，L1 治疗对肝或肾铜和 MT 没有影响，但导致脑铜和 MT 水平增加。这些数据表明，TTM（而非 L1）可能有助于治疗包括 WND 在内的铜超载疾病。 (C) 2002 Elsevier Science B.V. 保留所有权利。
Copper is both essential for life and toxic. Aberrant regulation of copper at the level of intracellular transport has been associated with inherited diseases, including Wilson's disease (WND) in humans. WND results in accumulation of copper and the copper and zinc-binding protein metallothionein (MT) in liver and other tissues. liver degeneration, and neurological dysfunction. The toxic milk (TX) mutation in mice results in a phenotype that mimics human WND, and TX has been proposed to be a model of the disease. We characterized TX mice as a model of altered metal ion and MT levels during development, and after treatment with the metal ion chelators tetrathiomolybdate (TTM) and deferiprone (L1). We report that hepatic, renal and brain copper and MT are elevated in TX mice at 3 and 12 months of age. Zinc was significantly higher in TX mouse liver, but not brain and kidney, at both time points. Nodules appeared spontaneously in TX mouse livers at 8-12 months that maintained high copper levels, but with more normal morphology and decreased MT levels. Treatment of TX mice with TTM significantly reduced elevated hepatic copper and MT. Transient increases in blood and kidney copper accompanied TTM treatment and indicated that renal excretion was a significant route of removal. Treatment with L1, on the other hand, had no effect on liver or kidney copper and MT, but resulted in increased brain copper and MT levels. These data indicate that TTM, but not L1, may be useful in treating diseases of copper overload including WND. (C) 2002 Elsevier Science B.V. All rights reserved.