Univ. Grenoble Alpes, CEA, CNRS, IRIG, LCBM, F-38000 Grenoble, France and Univ. Grenoble Alpes, CEA, CNRS, IRIG, SyMMES, F-38000 Grenoble, France.
Univ. Lyon, CNRS, ENS de Lyon, LGLTPE, F-69007 Lyon, France.
Metallomics. 2020 Jun 24;12(6):1000-1008. doi: 10.1039/d0mt00069h.
Copper chelation is the most commonly used therapeutic strategy nowadays to treat Wilson's disease, a genetic disorder primarily inducing a pathological accumulation of Cu in the liver. The mechanism of action of Chel2, a liver-targeting Cu(i) chelator known to promote intracellular Cu chelation, was studied in hepatic cells that reconstitute polarized epithelia with functional bile canaliculi, reminiscent of the excretion pathway in the liver. The interplay between Chel2 and Cu localization in these cells was demonstrated through confocal microscopy using a fluorescent derivative and nano X-ray fluorescence. The Cu(i) bound chelator was found in vesicles potentially excreted in the canaliculi. Moreover, injection of Chel2 either intravenously or subcutaneously to a murine model of Wilson's disease increased excretion of Cu in the faeces, confirming in vivo biliary excretion. Therefore, Chel2 turns out to be a possible means to collect and excrete hepatic Cu in the faeces, hence restoring the physiological pathway.
铜螯合是目前治疗威尔逊病（一种主要导致肝脏内铜病理性积累的遗传性疾病）最常用的治疗策略。本研究旨在研究 Chel2（一种已知能促进细胞内铜螯合的肝脏靶向 Cu(i)螯合剂）在具有功能性胆小管的重组极化上皮的肝细胞中的作用机制，这些细胞类似于肝脏中的排泄途径。通过使用荧光衍生物和纳米 X 射线荧光的共聚焦显微镜，证明了 Chel2 与细胞内 Cu 定位之间的相互作用。用荧光衍生物检测到与 Cu(i)结合的 Chel2 位于可能分泌到胆小管中的小泡中。此外，将 Chel2 注射到威尔逊病的小鼠模型的静脉或皮下，增加了粪便中 Cu 的排泄，证实了体内胆排泄。因此，Chel2 可能成为一种在粪便中收集和排泄肝脏 Cu 的方法，从而恢复生理途径。
