scholarly journals Pharmacokinetics of primary oxidative metabolites of thalidomide in rats and in chimeric mice humanized with different human hepatocytes

2021 ◽  
Vol 46 (7) ◽  
pp. 311-317
Author(s):  
Tomonori Miura ◽  
Shotaro Uehara ◽  
Makiko Shimizu ◽  
Hiroshi Suemizu ◽  
Hiroshi Yamazaki
Keyword(s):  
Human Hepatocytes ◽  
Chimeric Mice ◽  
Oxidative Metabolites

Lipoprotein profiles in SCID/uPA mice transplanted with human hepatocytes become human-like and correlate with HCV infection success

2010 ◽  
Vol 299 (4) ◽  
pp. G844-G854 ◽  
Author(s):  
Rineke H. G. Steenbergen ◽  
Michael A. Joyce ◽  
Garry Lund ◽  
Jamie Lewis ◽  
Ran Chen ◽  
...  
Keyword(s):  
Critical Role ◽  
Human Hepatocytes ◽  
Hcv Infection ◽  
Strong Positive Correlation ◽  
Chimeric Mice ◽  
Human Apolipoprotein ◽  
Weakest Link ◽  
Successful Infection ◽  
Human Livers ◽  
Lipoprotein Profiles

Although multiple determinants for hepatitis C virus (HCV) infection are known, it remains partly unclear what determines the human specificity of HCV infection. Presumably, the presence of appropriate entry receptors is essential, and this may explain why HCV is unable to infect nonhuman hepatocytes. However, using mice with chimeric human livers, we show in this study that the presence of human hepatocytes, and therefore human entry receptors, is not sufficient for HCV infection. In successfully transplanted SCID/Alb-uPA mice, infection with HCV is reliable only when ∼70–80% of the liver consists of human hepatocytes. We show that chimeric mice, which are hard to infect with HCV, have significant groups of human hepatocytes that are readily infected with hepatitis B virus. Thus it is unlikely that the lack of infection with HCV can simply be attributed to low hepatocyte numbers. We investigated whether the humanization of lipoprotein profiles is positively associated with infection success. We show that the lipoprotein profiles of chimeric mice become more human-like at high levels of engraftment of human hepatocytes. This and expression of markers of human lipoprotein biosynthesis, human apolipoprotein B (ApoB) and cholesterol ester transfer protein (CETP), show a strong positive correlation with successful infection. Association of HCV in the blood of chimeric mice to ApoB-containing lipoproteins is comparable to association of HCV in patient serum and provides further support for a critical role for ApoB-containing lipoproteins in the infectious cycle of HCV. Our data suggest that the weakest link in the HCV infection chain does not appear to be the presence of human hepatocytes per se. We believe that HCV infection also depends on the presence of sufficient levels of human lipoproteins.

scholarly journals Characterization and applications of chimeric mice with humanized livers for preclinical drug development

2020 ◽  
Vol 36 (1) ◽  
Author(s):  
Chise Tateno ◽  
Yuha Kojima
Keyword(s):  
Liver Function ◽  
Drug Development ◽  
Mass Production ◽  
Human Hepatocytes ◽  
In Vitro Studies ◽  
New Drugs ◽  
Pharmaceutical Companies ◽  
Chimeric Mice ◽  
Preclinical Drug Development

AbstractWe have succeeded in stable mass production of chimeric PXB-mice, whose liver is repopulated by human hepatocytes at a ratio of more than 70%, and we are providing these mice to academia and pharmaceutical companies to support the development of new drugs or studies of liver function. Furthermore, we isolated human hepatocytes, called PXB-cells, from the chimeric mice, and provide them for clients weekly for in vitro studies. In this review, we summarize the existing characterizations of PXB-mice and PXB-cells and their present and future applications.

scholarly journals Comparison of the Hepatic Effects of Phenobarbital in Chimeric Mice Containing Either Rat or Human Hepatocytes With Humanized Constitutive Androstane Receptor and Pregnane X Receptor Mice

2020 ◽  
Vol 177 (2) ◽  
pp. 362-376
Author(s):  
Tomoya Yamada ◽  
Ayako Ohara ◽  
Naoya Ozawa ◽  
Keiko Maeda ◽  
Miwa Kondo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Liver Tumor ◽  
Constitutive Androstane Receptor ◽  
Pregnane X Receptor ◽  
Rat Hepatocytes ◽  
Global Gene Expression ◽  
Human Hepatocytes ◽  
Chimeric Mouse ◽  
Chimeric Mice ◽  
Wild Type

Abstract Using a chimeric mouse humanized liver model, we provided evidence that human hepatocytes are refractory to the mitogenic effects of rodent constitutive androstane receptor (CAR) activators. To evaluate the functional reliability of this model, the present study examined mitogenic responses to phenobarbital (PB) in chimeric mice transplanted with rat hepatocytes, because rats are responsive to CAR activators. Treatment with 1000 ppm PB for 7 days significantly increased replicative DNA synthesis (RDS) in rat hepatocytes of the chimeric mice, demonstrating that the transplanted hepatocyte model is functionally reliable for cell proliferation analysis. Treatment of humanized CAR and pregnane X receptor (PXR) mice (hCAR/hPXR mice) with 1000 ppm PB for 7 days significantly increased hepatocyte RDS together with increases in several mitogenic genes. Global gene expression analysis was performed with liver samples from this and from previous studies focusing on PB-induced Wnt/β-catenin signaling and showed that altered genes in hCAR/hPXR mice clustered most closely with liver tumor samples from a diethylnitrosamine/PB initiation/promotion study than with wild-type mice. However, different gene clusters were observed for chimeric mice with human hepatocytes for Wnt/β-catenin signaling when compared with those of hCAR/hPXR mice, wild-type mice, and liver tumor samples. The results of this study demonstrate clear differences in the effects of PB on hepatocyte RDS and global gene expression between human hepatocytes of chimeric mice and hCAR/hPXR mice, suggesting that the chimeric mouse model is relevant to humans for studies on the hepatic effects of rodent CAR activators whereas the hCAR/hPXR mouse is not.

scholarly journals Hepatitis C virus RNA kinetics in chimeric mice with human hepatocytes during antiviral therapy

Hepatology ◽  
2007 ◽  
Vol 46 (6) ◽  
pp. 2049-2050
Author(s):  
Kazuaki Inoue ◽  
Tsunamasa Watanabe ◽  
Makoto Yoshiba ◽  
Michinori Kohara
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Therapy ◽  
Human Hepatocytes ◽  
Chimeric Mice ◽  
Hepatitis C Virus Rna ◽  
Virus Rna

scholarly journals Expression and inducibility of cytochrome P450s in human hepatocytes isolated from chimeric mice with humanised livers

Xenobiotica ◽  
2018 ◽  
Vol 49 (6) ◽  
pp. 678-687 ◽  
Author(s):  
Shotaro Uehara ◽  
Yuichiro Higuchi ◽  
Nao Yoneda ◽  
Hiroshi Yamazaki ◽  
Hiroshi Suemizu
Keyword(s):  
Human Hepatocytes ◽  
Cytochrome P450s ◽  
Chimeric Mice

Predictability of metabolic activities of CYP2D6 substrates using chimeric mice transplanted with human hepatocytes

2017 ◽  
Vol 32 (1) ◽  
pp. S41
Author(s):  
Chieri Fujino ◽  
Seigo Sanoh ◽  
Akihiko Shinagawa ◽  
Chihiro Yamasaki ◽  
Yuji Ishida ◽  
...  
Keyword(s):  
Human Hepatocytes ◽  
Chimeric Mice ◽  
Metabolic Activities

Expression and induction ability of cytochrome P450 in human hepatocytes isolated from chimeric mice with humanized livers

2019 ◽  
Vol 34 (1) ◽  
pp. S44
Author(s):  
Shotaro Uehara ◽  
Yuichiro Higuchi ◽  
Nao Yoneda ◽  
Hiroshi Yamazaki ◽  
Hiroshi Suemizu
Keyword(s):  
Cytochrome P450 ◽  
Human Hepatocytes ◽  
Chimeric Mice

Prediction of human metabolism of the sedative-hypnotic zaleplon using chimeric mice transplanted with human hepatocytes

Xenobiotica ◽  
2013 ◽  
Vol 43 (11) ◽  
pp. 956-962 ◽  
Author(s):  
Chiaki Tanoue ◽  
Kazumi Sugihara ◽  
Naoto Uramaru ◽  
Yoshitaka Tayama ◽  
Yoko Watanabe ◽  
...  
Keyword(s):  
Human Hepatocytes ◽  
Human Metabolism ◽  
Chimeric Mice

Human Hepatocytes Can Repopulate Mouse Liver: Histopathology of the Liver in Human Hepatocyte-Transplanted Chimeric Mice and Toxicologic Responses to Acetaminophen

2008 ◽  
Vol 36 (4) ◽  
pp. 581-591 ◽  
Author(s):  
Yasushi Sato ◽  
Hiroshi Yamada ◽  
Kazuhide Iwasaki ◽  
Chise Tateno ◽  
Tsuyoshi Yokoi ◽  
...  
Keyword(s):  
Mouse Liver ◽  
Human Hepatocytes ◽  
Human Hepatocyte ◽  
Chimeric Mice ◽  
Liver Histopathology
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