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: Kosuke Okada, Junichi Shoda, Masahito Kano, Sachiko Suzuki, Nobuhiro Ohtake, Masahiro Yamamoto, Hiroshi Takahashi, Hirotoshi Utsunomiya, Koji Oda, Kimi Sato, Ayaka Watanabe, Tetsuro Ishii, Ken Itoh, Masayuki Yamamoto, Tsuyoshi Yokoi, Katsutoshi Yoshizato, Yuichi Sugiyama, Hiroshi Suzuki
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 292 Issue 5 Pg. G1450-63 (May 2007) ISSN: 0193-1857 [Print] United States
• PMID: 17038627 (Publication Type: Journal Article)

Chemical References

• ATP-Binding Cassette Transporters
• Abcc2 protein, rat
• Antioxidants
• Cholagogues and Choleretics
• Drugs, Chinese Herbal
• Iridoid Glycosides
• Iridoids
• NF-E2-Related Factor 2
• Nfe2l2 protein, rat
• Organic Anion Transporters
• inchinko-to
• genipin
• Heme Oxygenase (Decyclizing)
• Hmox1 protein, rat
• Glutathione

Topics

• ATP-Binding Cassette Transporters (physiology)
• Animals
• Antioxidants (physiology)
• Bile (metabolism)
• Cells, Cultured
• Cholagogues and Choleretics (pharmacology)
• Drugs, Chinese Herbal (pharmacology)
• Glutathione (biosynthesis)
• Heme Oxygenase (Decyclizing) (biosynthesis)
• Iridoid Glycosides
• Iridoids (pharmacology)
• Kidney (drug effects, metabolism)
• Liver (drug effects, metabolism)
• Male
• Mice
• NF-E2-Related Factor 2 (physiology)
• Organic Anion Transporters (biosynthesis)
• Rats
• Rats, Sprague-Dawley