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LIVER AND BILIARY TRACT

Inchinkoto, a herbal medicine, and its ingredients dually exert Mrp2/MRP2-mediated choleresis and Nrf2-mediated antioxidative action in rat livers

¹Department of Gastroenterology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki; ²Pharmacogical Department, Central Research Laboratories, Tsumura and Company, Ibaraki; ³Department of Anesthesiology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki; ⁴Department of Pathology, Wakayama Medical University, Wakayama; ⁵Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Aichi; ⁶Department of Molecular and Cellular Physiology, Graduate School of Comprehensive Human Sciences, and ⁷Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Science, University of Tsukuba, Ibaraki; ⁸Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa; ⁹Department of Biological Science, Developmental Biology Laboratory, Graduate School of Science, Hiroshima University, Hiroshima (Yoshizato Project, Cooperative Link of Unique Science and Technology for Economy Revitalization, Hiroshima Prefectual Institute of Industrial Science and Technology, Hiroshima); and ¹⁰Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, and ¹¹Department of Pharmacy, University of Tokyo Hospital, Faculty of Medicine, University of Tokyo, Tokyo, Japan

Submitted 10 July 2006 ; accepted in final form 27 September 2006

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.

multidrug resistance-associated proteins; bilirubin; gluthathione; heme oxygenase-1; chimeric mice with humanized liver; nuclear factor-E2-related factor

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