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Regulation of multidrug resistance protein 2 (MRP2, ABCC2) expression by statins: Involvement of SREBP-mediated gene regulation

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Title: Regulation of multidrug resistance protein 2 (MRP2, ABCC2) expression by statins: Involvement of SREBP-mediated gene regulation
Authors: Kobayashi, Masaki Browse this author →KAKEN DB
Gouda, Keisuke Browse this author
Chisaki, Ikumi Browse this author
Asada, Koji Browse this author
Ogura, Jiro Browse this author →KAKEN DB
Takahashi, Natsuko Browse this author
Konishi, Toru Browse this author
Koshida, Yusuke Browse this author
Sasaki, Shotaro Browse this author
Yamaguchi, Hiroaki Browse this author →KAKEN DB
Iseki, Ken Browse this author →KAKEN DB
Keywords: Statin
Hepatocytes
Multidrug resistance protein 2
Sterol regulatory element-binding protein
Issue Date: 16-Aug-2013
Publisher: Elsevier science bv
Journal Title: International journal of pharmaceutics
Volume: 452
Issue: 1-2
Start Page: 36
End Page: 41
Publisher DOI: 10.1016/j.ijpharm.2013.04.019
PMID: 23612356
Abstract: 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) alpha/beta 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. (C) 2013 Elsevier B.V. All rights reserved.
Type: article (author version)
URI: http://hdl.handle.net/2115/54671
Appears in Collections:薬学研究院 (Faculty of Pharmaceutical Sciences) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 小林 正紀

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