TY - JOUR
T1 - Regulation of multidrug resistance protein 2 (MRP2, ABCC2) expression by statins
T2 - Involvement of SREBP-mediated gene regulation
AU - Kobayashi, Masaki
AU - Gouda, Keisuke
AU - Chisaki, Ikumi
AU - Asada, Koji
AU - Ogura, Jiro
AU - Takahashi, Natsuko
AU - Konishi, Toru
AU - Koshida, Yusuke
AU - Sasaki, Shotaro
AU - Yamaguchi, Hiroaki
AU - Iseki, Ken
N1 - Funding Information:
This work was supported by Nakatomi Foundation .
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - Hepatocytes
KW - Multidrug resistance protein 2
KW - Statin
KW - Sterol regulatory element-binding protein
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U2 - 10.1016/j.ijpharm.2013.04.019
DO - 10.1016/j.ijpharm.2013.04.019
M3 - Article
C2 - 23612356
AN - SCOPUS:84884131005
VL - 452
SP - 36
EP - 41
JO - International Journal of Pharmaceutics
JF - International Journal of Pharmaceutics
SN - 0378-5173
IS - 1-2
ER -