BPB Reports

Paper Details

BPB Reports
Vol. 2 No. 2 p.29-34 2019
Regular Article
Changes in Bile Acid Concentrations in Chimeric Mice Transplanted with Different Replacement Indexes of Human Hepatocytes
  • Seigo Sanoh (Graduate School of Biomedical and Health Sciences, Hiroshima University / sanoh@hiroshima-u.ac.jp)
Chieri Fujino 1) , Seigo Sanoh 1) , Yuka Tamura 1) , Yuji Ishida 2) 3) , Chise Tateno 2) 3) , Shigeru Ohta 1) 4) , Yaichiro Kotake 1)
1) Graduate School of Biomedical and Health Sciences, Hiroshima University , 2) R&D Dept., PhoenixBio, Co., Ltd. , 3) Research Center for Hepatology and Gastroenterology, Hiroshima University , 4) Wakayama Medical University
Received: March 28, 2019;   Accepted: April 17, 2019;   Released: April 27, 2019
Keywords: chimeric mice with humanized liver, bile acids, replacement index, human hepatocytes

Chimeric mice with humanized liver that are repopulated with human hepatocytes are useful to study hepatitis B and C viruses, predict drug metabolism and pharmacokinetics (PK), and evaluate hepatotoxicity. Understanding the characteristics of chimeric mice is important for making predictions in humans. In general, chimeric mice with more than 70% of replacement indexes (RIs), a value representing the occupancy ratio of the region of the human liver to that of the mouse liver, are used. However, chimeric mice with RIs less than 70% are also useful in understanding the species differences between mice and humans. In this study, to elucidate the effects of proliferating human hepatocytes and remaining mouse hepatocytes on bile acid concentrations in detail, we investigated the differences in the total concentrations of bile acids and their compositions in chimeric mice with different RIs. The total concentrations of bile acids in their sera increased as the RIs increased. The ratios of primary to secondary bile acids, percentages of glycine conjugates, and hydrophobicity indexes, obtained upon classifying bile acids based on their compositions in the serum and comparing them with those in normal mice and humans, were found to approach the values observed in humans as the RIs increased. The percentages of taurine conjugates were high in chimeric mice with high RIs, although their values were close to those in humans. These results could be fundamental in providing knowledge to accurately predict human PK and toxicity in chimeric mice with humanized liver.