Ikeda Kazuhiko, Hirayama Masahiro, Hirota Yuko, Asa Erika, Seki Jiro, Tanaka Yoshitaka
Division of Pharmaceutical Cell Biology, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan.
Biochem Biophys Res Commun. 2008 Dec 5;377(1):268-74. doi: 10.1016/j.bbrc.2008.09.121. Epub 2008 Oct 7.
Cationic amphiphilic drugs (CADs) cause massive intracellular accumulation of phospholipids, thereby resulting in phospholipidosis (PLD); however, the molecular mechanism underlying CAD-induced PLD remains to be resolved. Here, we found that treatment of normal rat kidney cells with CADs known to induce PLD caused redistribution of a mannose 6-phosphate/IGF-II receptor (MPR300) from the TGN to endosomes and concomitantly increased the secretion of lysosomal enzymes, resulting in a decline of intracellular lysosomal enzyme levels. These results enable the interpretation of why CADs cause excessive accumulation of undegraded substrates, including phospholipids in lysosomes, and led to the conclusion that the impaired MPR300-mediated sorting system of lysosomal enzymes reflects the general mechanism of CAD-induced PLD. In addition, our findings suggest that the measurement of lysosomal enzyme activity secreted into culture medium is useful as a rapid and convenient in vitro early screening system to predict drugs that can induce PLD.
阳离子两亲性药物（CADs）可导致磷脂在细胞内大量蓄积，从而引发磷脂沉积症（PLD）；然而，CADs诱导PLD的分子机制仍有待阐明。在此，我们发现，用已知可诱导PLD的CADs处理正常大鼠肾细胞，会导致甘露糖6-磷酸/胰岛素样生长因子II受体（MPR300）从反式高尔基体网络（TGN）重新分布至内体，并同时增加溶酶体酶的分泌，导致细胞内溶酶体酶水平下降。这些结果有助于解释为什么CADs会导致包括溶酶体中的磷脂在内的未降解底物过度蓄积，并得出结论：MPR300介导的溶酶体酶分选系统受损反映了CADs诱导PLD的一般机制。此外，我们的研究结果表明，测量分泌到培养基中的溶酶体酶活性，作为一种快速便捷的体外早期筛选系统，可用于预测能够诱导PLD的药物。
