Hepatotoxicity

Main characteristics

• TK-NOG Humanization

  TK-NOG immunodeficient mice are pre-conditioned with ganciclovir, which activates the thymidine kinase (TK) transgene, selectively inducing apoptosis of mouse hepatocytes and creating space for human cell engraftment. This is followed by intrasplenic injection of healthy primary human hepatocytes, enabling efficient seeding and repopulation of the liver. Approximately 8 weeks post-engraftment, mice are quality controlled by measuring human albumin levels in the blood, which serves as a surrogate marker for the Replacement Index (RI)—a key indicator of the extent of human liver reconstitution.

• Healthy animals

  Unlike other humanized liver mouse models, humanized TK-NOG mice do not develop liver tumors for up to one year of age, allowing for a more stable and physiologically relevant liver environment. This extended tumor-free window enables longer-term studies and ensures that liver function and architecture remain closer to the human physiological state, enhancing the model’s translational value for drug metabolism, toxicity, and liver disease research.

• Readouts

  In our humanized liver mouse model, hepatotoxicity can be evaluated through several robust and clinically relevant readouts. These include measurement of serum biomarkers such as ALT, AST, bilirubin, and albumin to assess liver function, alongside histological analysis to detect hepatocellular damage, necrosis, or fibrosis. Additionally, immunohistochemistry (IHC) and gene expression analysis can further elucidate molecular mechanisms of drug-induced liver injury (DILI), ensuring comprehensive evaluation of hepatic safety in a fully human liver context.

• Human Metabolite Production

  Assessment of human-specific metabolite production is reliably achievable, facilitating accurate evaluation of drug metabolism pathways and pharmacokinetics. Frequent blood sampling allows detailed PK/PD profiling, including time-dependent measurement of drug concentration and metabolite generation, closely mirroring clinical conditions. This approach enables precise characterization of human hepatic drug processing, enhancing translational relevance and predictive accuracy of preclinical studies.

• The Fialuridine Case Study

  A landmark example is fialuridine (FIAU), an antiviral compound that passed standard preclinical tests but caused fatal liver failure in humans. In conventional animal models, FIAU appeared safe due to species-specific differences in mitochondrial toxicity. However, studies using humanized liver mice have successfully recapitulated FIAU’s mitochondrial toxicity and hepatotoxic profile, making this model a gold standard for assessing human-relevant liver safety and preventing late-stage failures.