Application of chimeric mice with human hepatocytes for the evaluation of metabolically activated genotoxic...

The in vivo micronucleus (MN) assay is used for evaluation of chromosomal aberration induced by chemicals, and the liver MN assay can detect genotoxic compounds which require metabolic activation to induce micronucleus formation. However, species differences in liver metabolism are known, and therefore results obtained from mouse and rat liver MN assays may not always be directly extrapolated to humans. Chimeric mouse with human hepatocytes (the PXB-mouse®) is expected to be used in genotoxicity studies as an animal model of metabolic reactions in humans. To date, the use of the liver MN assay with PXB-mice has been reported, but its application has been limited to compounds that do not require metabolic activation to induce chromosomal aberrations.

In this study, we used the liver MN assay in PXB-mice to evaluate diethylnitrosamine (DEN) and N-nitrosodimethylamine (NDMA), both of which require metabolic activation to induce chromosomal aberrations. After repeated administration of DEN for 14 days or NDMA for 28 days, statistically significant increases in micronucleus frequency were observed.

From the results of this examination, it was demonstrated that the liver MN assay using PXB-mice can detect the genotoxicity of compounds that require metabolic activation to exert genotoxicity. Although some issues remain, such as the presence of residual mouse hepatocytes, the liver MN assay using PXB-mice is expected to provide supportive information for more accurate evaluation of chemical genotoxicity in humans.