Distribution of exogenous metallothionein following intraperitoneal and intramuscular injection of metallothionein-deficient mice
Distribution of exogenous metallothionein following intraperitoneal and intramuscular injection of metallothionein-deficient mice
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DOI：
10.14670/hh-27.1459
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发表时间：
2012-11-01
影响因子：
2
通讯作者：
Chuah, Meng Inn
中科院分区：
文献类型：
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作者：
Lewis, Katherine E.;Chung, Roger S.;Chuah, Meng Inn
金属硫蛋白i /II （MT-I/II）是一种具有抗氧化和神经保护作用的小金属结合蛋白，在多种情况下被实验用作神经治疗剂。因此，确定外源性MT-I/II在肌肉和腹腔注射后是保留在特定器官中还是排出体外是很重要的。通过组织样本的免疫组化和尿样的western blotting检测外源性MT-IIA（主要的人类MT-I/II亚型）在MT-I/II缺陷小鼠中的分布。肌内或腹腔注射1小时后，在肾皮质和髓小管上皮细胞内检测到MT-IIA。此外，注射后1小时尿液中检测到MT-IIA，表明其快速吸收进入循环并通过肾小球滤过。一部分肌内注射的MT-IIA在注射后至少在肌肉内停留24小时。单次注射或连续注射MT-IIA后，肝脏或大脑内均未观察到MT-IIA。这些结果与早期的报道一致，即外源性给药MT-IIA不能穿过完整的血脑屏障，尽管在脉络膜丛中存在MT-I/II （meggalin）的受体。我们假设，由于通过尿液的损失，循环MT-IIA水平在注射后迅速下降，不允许通过脉络膜丛运输。具有类似神经活性特性的MT-I/II肽类似物（emtin）可能更适合于中枢神经系统递送。
Metallothionein-I/II (MT-I/II) is a small metal-binding protein with antioxidant and neuroprotective properties, which has been used experimentally as a neurotherapeutic agent in multiple conditions. Therefore it is important to determine whether exogenous MT-I/II is retained in specific organs or expelled from the body following intramuscular and intraperitoneal injection. The distribution of exogenous MT-IIA (the major human MT-I/II isoform) was examined in MT-I/II-deficient mice, by immunohistochemistry of tissue samples and western blotting of urine samples. MT-IIA was detected within epithelial cells of the kidney cortical and medullary tubules within 1 hour of either intramuscular or intraperitoneal injection. Additionally, MT-IIA was detected within the urine at 1 hour after injection, indicating rapid absorbance into the circulation and filtration through the kidney glomerulus. A portion of the intramuscularly-injected MT-IIA remained within the muscle for at least 24 hours after injection. No MT-IIA was observed within the liver or the brain after either a single injection or a series of MT-IIA injections. These results are consistent with earlier reports that exogenously administered MT-IIA does not cross the intact blood-brain barrier, although a receptor for MT-I/II (megalin) is present in the choroid plexus. We postulate that due to losses through the urine, circulating MT-IIA levels drop rapidly after injection and do not permit transport across the choroid plexus. Peptide analogues of MT-I/II with similar neuroactive properties (emtins) may be more suited for CNS delivery.