Chemical chaperones mediate increased secretion of mutant α1-antitrypsin (α1-AT) Z:: A potential pharmacological strategy for prevention of liver injury and emphysema in α1-AT deficiency
Chemical chaperones mediate increased secretion of mutant α1-antitrypsin (α1-AT) Z:: A potential pharmacological strategy for prevention of liver injury and emphysema in α1-AT deficiency
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DOI：
10.1073/pnas.97.4.1796
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发表时间：
2000-02-15
影响因子：
11.1
通讯作者：
Perlmutter, DH
中科院分区：
文献类型：
--
作者：
Burrows, JAJ;Willis, LK;Perlmutter, DH
在α 1-AT缺乏症中，错误折叠但功能活性的突变α 1-ATZ（α 1-ATZ）分子保留在肝细胞的内质网中，而不是分泌到血液和体液中。肺气肿被认为是由于缺乏循环α 1-AT来抑制肺中的中性粒细胞弹性蛋白酶而引起的。肝损伤被认为是由保留的α 1-ATZ的肝毒性作用引起的。在这项研究中，我们发现，几个“化学伴侣”，这已被证明是扭转细胞的错误定位或错误折叠的其他突变质膜，核，和细胞质蛋白，介导分泌增加α 1-ATZ。特别是，4-苯基丁酸（PBA）介导的功能活性α 1-ATZ在模型细胞培养系统中的分泌显着增加。此外，PiZ小鼠（人α 1-ATZ基因的转基因小鼠）对PEA的口服给药耐受性良好，并始终介导人α 1-AT血液水平的增加，达到PIM小鼠和正常人中存在的水平的20-50%。由于临床研究表明，在α 1-AT缺乏症中仅需要部分校正来预防肝和肺损伤，并且PEA已安全地用于人类，因此它构成了α 1-AT缺乏症中靶器官损伤的化学预防的极好候选物。
In alpha 1-AT deficiency, a misfolded but functionally active mutant alpha 1-ATZ (alpha 1-ATZ) molecule is retained in the endoplasmic reticulum of liver cells rather than secreted into the blood and body fluids. Emphysema is thought to be caused by the lack of circulating alpha 1-AT to inhibit neutrophil elastase in the lung. Liver injury is thought to be caused by the hepatotoxic effects of the retained alpha 1-ATZ. In this study, we show that several "chemical chaperones," which have been shown to reverse the cellular mislocalization or misfolding of other mutant plasma membrane, nuclear, and cytoplasmic proteins, mediate increased secretion of alpha 1-ATZ. In particular, 4-phenylbutyric acid (PBA) mediated a marked increase in secretion of functionally active alpha 1-ATZ in a model cell culture system. Moreover, oral administration of PEA was well tolerated by PiZ mice (transgenic for the human alpha 1-ATZ gene) and consistently mediated an increase in blood levels of human alpha 1-AT reaching 20-50% of the levels present in PIM mice and normal humans. Because clinical studies have suggested that only partial correction is needed for prevention of both liver and lung injury in alpha 1-AT deficiency and PEA has been used safely in humans, it constitutes an excellent candidate for chemoprophylaxis of target organ injury in alpha 1-AT deficiency.