title: Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers.
abstract: Inchinkoto (ICKT), a herbal medicine, has been recognized in Japan and China as a "magic bullet" for jaundice. To explore potent therapeutic agents for cholestasis, the effects of ICKT or its ingredients on multidrug resistance-associated protein 2 (Mrp2/ MRP2)-mediated choleretic activity, as well as on antioxidative action, were investigated using rats and chimeric mice with livers that were almost completely repopulated with human hepatocytes. Biliary excretion of Mrp2 substrates and the protein mass, subcellular localization, and mRNA level of Mrp2 were assessed in rats after 1-wk oral administration of ICKT or genipin, a major ingredient of ICKT. Administration of ICKT or genipin to rats for 7 days increased bile flow and biliary excretion of bilirubin conjugates. Mrp2 protein and mRNA levels and Mrp2 membrane densities in the bile canaliculi and renal proximal tubules were significantly increased in ICKT- or genipin-treated rat livers and kidneys. ICKT and genipin, thereby, accelerated the disposal of intravenously infused bilirubin. The treatment also increased hepatic levels of heme oxygenase-1 and GSH by a nuclear factor-E2-related factor (Nrf2)-dependent mechanism. Similar effects of ICKT on MRP2 expression levels were observed in humanized livers of chimeric mice. In conclusion, these findings provide the rationale for therapeutic options of ICKT and its ingredients that should potentiate bilirubin disposal in vivo by enhancing Mrp2/MRP2-mediated secretory capacities in both livers and kidneys as well as Nrf2-mediated antioxidative actions in the treatment of cholestatic liver diseases associated with jaundice.
authors.affiliation: Dept. of Gastroenterology, Graduate School of Comprehensive Human Sciences, Univ. of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Okada
authors.forename: Junichi
authors.initials: J
authors.lastname: Shoda
authors.forename: Masahito
authors.initials: M
authors.lastname: Kano
authors.forename: Sachiko
authors.initials: S
authors.lastname: Suzuki
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Ohtake
authors.forename: Masahiro
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takahashi
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Utsunomiya
authors.forename: Koji
authors.initials: K
authors.lastname: Oda
authors.forename: Kimi
authors.initials: K
authors.lastname: Sato
authors.forename: Ayaka
authors.initials: A
authors.lastname: Watanabe
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Ishii
authors.forename: Ken
authors.initials: K
authors.lastname: Itoh
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
authors.forename: Katsutoshi
authors.initials: K
authors.lastname: Yoshizato
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sugiyama
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Suzuki
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D000975:Antioxidants / Q000502:physiology*; D001646:Bile / Q000378:metabolism*; D002478:Cells, Cultured; D002756:Cholagogues and Choleretics / Q000494:pharmacology*; D004365:Drugs, Chinese Herbal / Q000494:pharmacology*; D005978:Glutathione / Q000096:biosynthesis; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis; D057889:Iridoid Glycosides; D039823:Iridoids / Q000494:pharmacology; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000502:physiology*; D027361:Organic Anion Transporters / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018528:ATP-Binding Cassette Transporters; C423013:Abcc2 protein, rat; D000975:Antioxidants; D002756:Cholagogues and Choleretics; D004365:Drugs, Chinese Herbal; D057889:Iridoid Glycosides; D039823:Iridoids; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D027361:Organic Anion Transporters; C078038:inchinko-to; C007834:genipin; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D005978:Glutathione