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Mouse Models of Cancer Study

Mice have long served as models for studying human biology and pathology because of their phylogenetic and physiological similarity with humans. They are also easy to maintain and breed in the laboratory, and hence, many inbred strains are now available for research. Studies on mice have contributed immeasurably to our understanding of cancer biology.
The development of transgenic, knockout, and knock-in mice has led to an exponential increase in their use as model organisms in research,...

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Related Experiment Video

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Generation of a Humanized Mouse Liver Using Human Hepatic Stem Cells
11:44

Generation of a Humanized Mouse Liver Using Human Hepatic Stem Cells

Published on: August 29, 2016

Chimeric mice with humanized liver.

Miki Katoh1, Chise Tateno, Katsutoshi Yoshizato

  • 1Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan.

Toxicology
|February 6, 2008
PubMed
Summary

Humanized liver chimeric mice offer advanced prediction of drug pharmacokinetics and toxicity. These mice exhibit human-like drug metabolism, excretion, and transporter functions, overcoming species differences for better drug development.

Area of Science:

  • Pharmacology
  • Toxicology
  • Biotechnology

Background:

  • The liver is crucial for drug pharmacokinetics and is susceptible to drug-induced damage.
  • Predicting human pharmacokinetics and toxicity is challenging using traditional animal models or in vitro methods.
  • Human hepatocytes and liver microsomes are currently used but have limitations.

Purpose of the Study:

  • To establish and evaluate chimeric mice with humanized livers as a novel in vivo model for predicting human drug pharmacokinetics and toxicity.
  • To assess the humanized liver chimeric mice's capacity for human drug metabolism, drug interactions, and excretion.

Main Methods:

  • Transplantation of human hepatocytes into urokinase-type plasminogen activator (uPA)/severe combined immunodeficient (SCID) mice to create humanized liver chimeric mice.

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  • In vivo studies to investigate drug metabolism, including enzyme expression, genetic polymorphism, and metabolite detection.
  • Assessment of drug interactions by evaluating cytochrome P450 induction and inhibition.
  • Analysis of drug excretion pathways and drug transporter expression.
  • Main Results:

    • Chimeric mice achieved high levels of human hepatocyte engraftment (80-90%).
    • Human drug-metabolizing enzymes were expressed, reflecting donor capacities and genetic polymorphism.
    • Human-specific metabolites were detected in vivo, and drug interactions (induction/inhibition) were successfully modeled.
    • Drug excretion and transporter functions were humanized, mirroring human responses.

    Conclusions:

    • Humanized liver chimeric mice serve as a powerful in vivo tool for overcoming species differences in drug metabolism and toxicity prediction.
    • These mice enable advanced assessment of drug interactions and human pharmacokinetics, improving drug development safety and efficacy.
    • The model holds significant potential for evaluating drug toxicity related to genetic polymorphism and drug interactions.