Laboratory of Clinical Pharmaceutics & Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12-jo, Nishi-6-chome, Kita-ku, Sapporo 060-0812, Japan.
Int J Pharm. 2013 Aug 16;452(1-2):36-41. doi: 10.1016/j.ijpharm.2013.04.019. Epub 2013 Apr 20.
Multidrug resistance protein 2 (MRP2, ABCC2) is localized to the apical membrane of hepatocytes and played an important role in the biliary excretion of a broad range of endogenous and xenobiotic compounds and drugs, such as pravastatin. However, the effects of statins on MRP2 in the liver and the precise mechanisms of their actions have been obscure. The goal of this study was to determine the regulatory molecular mechanism for statin-induced MRP2 expression in hepatocytes. In vitro and in vivo studies suggested that pitavastatin increased MRP2 expression. Pitavastatin promoted liver X receptor (LXR) α/β translocation from the cytosol to nuclei, resulting in LXR activation. Deletion and mutational analysis suggested that the potential sterol regulatory element (SRE) played a major role in the observed modulation of MRP2 expression by pitavastatin. Furthermore pitavastatin increased the protein-DNA complex, and when SRE was mutated, stimulation of the protein-DNA complex by pitavastatin was decreased. It was demonstrated that pitavastatin upregulated MRP2 expression by an SREBP regulatory pathway in hepatocytes and that the actions of statins may lead to improve the biliary excretion of MRP2 substrates.
多药耐药蛋白 2（MRP2，ABCC2）定位于肝细胞的顶膜，在胆汁排泄广泛的内源性和外源性化合物和药物方面发挥重要作用，如普伐他汀。然而，他汀类药物对肝脏中 MRP2 的作用及其确切作用机制仍不清楚。本研究旨在确定他汀类药物诱导肝细胞中 MRP2 表达的调节分子机制。体外和体内研究表明，匹伐他汀增加了 MRP2 的表达。匹伐他汀促进肝 X 受体（LXR）α/β从细胞质向核内易位，导致 LXR 激活。缺失和突变分析表明，潜在的固醇调节元件（SRE）在观察到的匹伐他汀对 MRP2 表达的调节中起主要作用。此外，匹伐他汀增加了蛋白-DNA 复合物，当 SRE 发生突变时，匹伐他汀对蛋白-DNA 复合物的刺激减少。结果表明，匹伐他汀通过肝细胞中的 SREBP 调节途径上调 MRP2 表达，他汀类药物的作用可能导致改善 MRP2 底物的胆汁排泄。
