| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Department of Gastroenterology, Graduate School of Comprehensive Human Sciences, The University of Tsukuba, Tsukuba, Ibaraki, Japan
2 Tsukuba, Ibaraki, Japan; Department of Gastroenterology, Graduate School of Comprehensive Human Sciences, The University of Tsukuba, Tsukuba, Ibaraki, Japan
3 Department of Gastroenterology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan
4 Pharmacogical Department, Central Research Laboratories, Tsumura & Co., Tsukuba, Ibaraki, Japan
5 Pharmacogical Department, Central Research Laboratories, Tsumura & Co., Ibaraki, Japan
6 Department of Anesthesiology, Graduate School of Comprehensive Human Sciences, The University of Tsukuba, Tsukuba, Ibaraki, Japan
7 Department of Pathology, Wakayama Medical University, Wakayama , Japan
8 Division of Surgical Oncology, Department of Surgery, Nagoya University Graduate School of Medicine, Aichi, Japan
9 Department of Molecular and Cellular Physiology, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaraki, Japan
10 Department of molecular and Cellular physiology, Graduate School of Comprehensive Human Sciences, The University of Tsukuba, Ibaraki, Japan
11 Department of Molecular and Cellular Physiology, Graduate School of Comprehensive Human Science, The University of Tsukuba, Ibaraki, Japan
12 The Center for Tsukuba Advanced Research Alliance and Institute of Basic Medical Science, The uNiversity of Tsukuba, United States
13 The Center for Tsukuba Advanced Resarch Alliance and Institute of Basic Medical Science, The University of Tsukuba, Ibaraki, Japan
14 Division of Drug Metabolism, Faculty of Pharmaceutical Sciences, Kanazawa University, Ishikawa, Japan
15 Department of Biological Science, Developmental Biology Laboratory, Graduate School of Science, Hiroshima University, Hiroshima, Japan
16 Department of Biopharmaceutics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
17 Department of Pharmacy, The University of Tokyo Hospital, Faculty of medicine, Tokyo, Japan
* To whom correspondence should be addressed. E-mail: shodaj{at}md.tsukuba.ac.jp.
Inchinkoto (ICKT), an 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-week 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. The Mrp2 protein and mRNA levels and the Mrp2 membrane densities in the bile canaliculi and the renal proximal tubules were significantly increased in the ICKT- or genipin-treated rat livers and kidneys. ICKT and genipin, thereby, accelerated the disposal of intravenously infused bilirubin. The treatment also increased the 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 the 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 the Mrp2/MRP2-mediated secretory capacities in both livers and kidneys, as well as Nrf2-mediated antioxidative action, in the treatment of cholestatic liver diseases associated with jaundice.
This article has been cited by other articles:
|
|
 |
|
  K. Okada, J. Shoda, K. Taguchi, J. M. Maher, K. Ishizaki, Y. Inoue, M. Ohtsuki, N. Goto, K. Takeda, H. Utsunomiya, et al. Ursodeoxycholic acid stimulates Nrf2-mediated hepatocellular transport, detoxification, and antioxidative stress systems in mice Am J Physiol Gastrointest Liver Physiol, October 1, 2008; 295(4): G735 - G747. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Makino, N. Ohtake, A. Watanabe, N. Tsuchiya, S. Imamura, S. Iizuka, M. Inoue, and H. Mizukami Down-Regulation of a Hepatic Transporter Multidrug Resistance-Associated Protein 2 Is Involved in Alteration of Pharmacokinetics of Glycyrrhizin and Its Metabolites in a Rat Model of Chronic Liver Injury Drug Metab. Dispos., July 1, 2008; 36(7): 1438 - 1443. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Visit Other APS Journals Online |
