Whole animal copper flux assessed by positron emission tomography in the Long-Evans cinnamon rat - a feasibility study
Whole animal copper flux assessed by positron emission tomography in the Long-Evans cinnamon rat - a feasibility study
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DOI：
10.1007/s10534-004-1800-0
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发表时间：
2005-02-01
期刊：
影响因子：
3.5
通讯作者：
Solioz, M
中科院分区：
文献类型：
--
作者：
Bissig, KD;Honer, M;Solioz, M
铜是人体必需的微量元素。然而，过量的铜会导致生物分子的氧化和细胞损伤，因此必须小心控制铜的水平。虽然铜稳态已被广泛研究在细胞水平上，短期的身体铜通量知之甚少。在这里，我们首次评估了使用Cu-64通过正电子发射断层扫描测量全身铜通量的可行性。选择比较Long-Evans肉桂（LEC）大鼠与野生型的比较方法。LEC大鼠是威尔逊病的公认模型，威尔逊病是人类铜排泄的遗传性疾病。在LEC大鼠和Wilson患者中，铜转运ATP酶ATP 7 B是有缺陷的。这种ATP酶主要在肝脏中表达，并通过胆汁分泌铜。ATP 7 B功能障碍导致铜在肝脏中积累。对照组和LEC大鼠经胃注射10 μ g Cu-64和铜通量，随后进行3小时的全动物PET和伴随的胆汁收集，以及断层扫描后的组织分析。如PET所见，施用的铜大部分被截留在胃和近端肠中，并且在对照和LEC大鼠之间没有显著差异。由于PET技术的动态范围不足，铜被全身吸收并主要转运至肝脏，因此只能进行采样和β计数。胆汁铜排泄随后在对照组大鼠15分钟后，但在LEC大鼠缺席。铜给药后1小时胆汁排泄达到饱和。口服给药的铜在胃肠道中的捕获可能是在突然、过量的铜负荷的条件下预防铜毒性的重要机制，这不能通过增加胆汁分泌来缓解。然而，这种捕获确实限制了PET测量整个动物铜通量的实用性。
Copper is an essential trace element. However, excess copper can lead to oxidation of biomolecules and cell damage and copper levels must be carefully controlled. While copper homeostasis has been studied extensively at the cellular level, short-term body copper fluxes are poorly understood. Here, we assessed for the first time the feasibility of measuring whole body copper flux by positron emission tomography, using Cu-64. A comparative approach comparing the Long-Evans cinnamon (LEC) rat to the wild type was chosen. LEC rats are an accepted model for Wilson disease, an inherited disorder of copper excretion in humans. In LEC rats as well as in Wilson patients, the copper transporting ATPase, ATP7B, is defective. This ATPase is primarily expressed in the liver and serves in copper secretion via the bile. Dysfunction of ATP7B leads to accumulation of copper in the liver. A control and an LEC rat were transgastrically injected with 10 mu g of Cu-64 and the copper flux followed for three hours by whole animal PET and concomitant collection of bile, as well as the analysis of tissue following tomography. As seen by PET, the administered copper was largely trapped in the stomach and the proximal intestine, and without a significant difference between control and LEC rat. Due to an insufficient dynamic range of the PET technology, copper which was systemically absorbed and primarily transported to the liver could only be followed by sampling and by beta-counting. Biliary copper excretion ensued after 15 min in the control rat, but was absent in the LEC rat. Biliary excretion reached saturation one hour after copper administration. The trapping of orally administered copper in the gastrointestinal tract may be an important mechanism to prevent copper toxicity under conditions of a sudden, excessive copper load, which cannot be alleviated by increased biliary secretion. This trapping does however limit the utility of PET to measure whole animal copper flux.