Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers.
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.
Okada
Kosuke
K
Dept. of Gastroenterology, Graduate School of Comprehensive Human Sciences, Univ. of Tsukuba, 1-1-1 Tennodai, Tsukuba-shi, Ibaraki 305-8575, Japan.
Shoda
Junichi
J
Kano
Masahito
M
Suzuki
Sachiko
S
Ohtake
Nobuhiro
N
Yamamoto
Masahiro
M
Takahashi
Hiroshi
H
Utsunomiya
Hirotoshi
H
Oda
Koji
K
Sato
Kimi
K
Watanabe
Ayaka
A
Ishii
Tetsuro
T
Itoh
Ken
K
Yamamoto
Masayuki
M
Yokoi
Tsuyoshi
T
Yoshizato
Katsutoshi
K
Sugiyama
Yuichi
Y
Suzuki
Hiroshi
H
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
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