title: The effect of dimerumic acid on LPS-induced downregulation of Mrp2 in the rat.
abstract: Oxidative stress is known to be a common feature of cholestatic syndrome. Lipopolysaccharide (LPS) induces cholestasis, causing multidrug resistance-associated protein 2 (Mrp2) downregulation in two different ways: early retrieval from the canalicular membrane and the latter event of reduced mRNA expression. However, the triggering factor for LPS-induced cholestasis is not fully understood. In this study, we examined the effect of dimerumic acid (DMA), an antioxidant and traditional Chinese medicine, on endotoxin-induced Mrp2 downregulation in rat liver. At 3h following LPS injection (4mg/kg body weight), canalicular Mrp2 localization was disrupted without changing the expression of Mrp2 protein or the integrity of tight junctions in the liver. Pretreatment with DMA (12mg/kg body weight) counteracted LPS-induced subcellular distribution, and decreased the bile flow rate and biliary glutathione (GSH) excretion. At 12h following LPS injection, Mrp2 protein and mRNA expression were significantly decreased by 58% and 7%, respectively. In contrast, pretreatment with DMA did not have any effect on the decreased Mrp2 expression and biliary excretion of GSH induced by LPS exposure. Taken together, our data clearly indicate that LPS-induced short-term rapid retrieval of Mrp2 from the canalicular surface resulted from LPS-induced oxidative stress, while the long-term transcriptional regulation of Mrp2 expression did not depend on the intracellular redox status.
authors.affiliation: Chiba University, Inohana, Chuo-ku, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Yano
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sekine
authors.forename: Kanako
authors.initials: K
authors.lastname: Nemoto
authors.forename: Toru
authors.initials: T
authors.lastname: Fuwa
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Horie
mesh_terms: D000818:Animals; D015536:Down-Regulation / Q000187:drug effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D008297:Male; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D008070:Lipopolysaccharides; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010879:Piperazines; C001011:dimerum acid