title: Regulation of multidrug resistance protein 2 (MRP2, ABCC2) expression by statins: involvement of SREBP-mediated gene regulation.
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.
authors.affiliation: 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.
authors.forename: Masaki
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Keisuke
authors.initials: K
authors.lastname: Gouda
authors.forename: Ikumi
authors.initials: I
authors.lastname: Chisaki
authors.forename: Koji
authors.initials: K
authors.lastname: Asada
authors.forename: Jiro
authors.initials: J
authors.lastname: Ogura
authors.forename: Natsuko
authors.initials: N
authors.lastname: Takahashi
authors.forename: Toru
authors.initials: T
authors.lastname: Konishi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Koshida
authors.forename: Shotaro
authors.initials: S
authors.lastname: Sasaki
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yamaguchi
authors.forename: Ken
authors.initials: K
authors.lastname: Iseki
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000069059:Atorvastatin; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051779:Sterol Regulatory Element Binding Proteins / Q000378:metabolism*
chemical_list: D018528:ATP-Binding Cassette Transporters; D000069059:Atorvastatin; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000071518:Liver X Receptors; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D057093:Orphan Nuclear Receptors; D011758:Pyrroles; D011804:Quinolines; D012333:RNA, Messenger; D051779:Sterol Regulatory Element Binding Proteins; C000715087:ABCC2 protein, human; C423013:Abcc2 protein, rat; C000605213:NR1H3 protein, human; C000605215:Nr1h3 protein, rat; C108475:pitavastatin