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

Masaki Kobayashi, Keisuke Gouda, Ikumi Chisaki, Koji Asada, Jiro Ogura, Natsuko Takahashi, Toru Konishi, Yusuke Koshida, Shotaro Sasaki, Hiroaki Yamaguchi, Ken Iseki

Research output: Contribution to journalArticle

10 Citations (Scopus)

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) 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.

Original languageEnglish
Pages (from-to)36-41
Number of pages6
JournalInternational Journal of Pharmaceutics
Volume452
Issue number1-2
DOIs
Publication statusPublished - 2013 Jan 1

Keywords

  • Hepatocytes
  • Multidrug resistance protein 2
  • Statin
  • Sterol regulatory element-binding protein

ASJC Scopus subject areas

  • Pharmaceutical Science

Fingerprint Dive into the research topics of 'Regulation of multidrug resistance protein 2 (MRP2, ABCC2) expression by statins: Involvement of SREBP-mediated gene regulation'. Together they form a unique fingerprint.

  • Cite this

    Kobayashi, M., Gouda, K., Chisaki, I., Asada, K., Ogura, J., Takahashi, N., Konishi, T., Koshida, Y., Sasaki, S., Yamaguchi, H., & Iseki, K. (2013). Regulation of multidrug resistance protein 2 (MRP2, ABCC2) expression by statins: Involvement of SREBP-mediated gene regulation. International Journal of Pharmaceutics, 452(1-2), 36-41. https://doi.org/10.1016/j.ijpharm.2013.04.019