<p>If chemical-induced carcinogenesis is observed in rodent carcinogenicity studies due to compound administration, it is necessary to elucidate the mode of action (MOA) and to analyze the relevance of tumors to humans based on the MOA. In the liver, it is known that activation of constitutive androstane receptor (CAR) enhances hepatocyte proliferation and induces hepatocellular tumors in rodents. Our previous studies in chimeric mouse with humanized liver (PXB mice) have shown no increase in cell proliferation, and thus the MOA is considered not plausible for humans. Recently, it has been shown that CAR causes hepatocyte proliferation in rodents via YAP activation but not in humans. However, it is uncertain whether the PXB mouse well reflects YAP-mediated mechanism in humans. To investigate the utility of the PXB mouse, 100 mg/kg/day of Phenobarbital (PB), which indirectly activates CAR, was administered to CD-1 or PXB mice for up to 8 continuous days and differences in hepatic gene expression related to YAP activation between CD-1 and PXB mice were examined. Altered gene expressions of Ki-67, cell cycle-related genes, and YAP target genes were observed at early phase of treatment, suggesting YAP activation and increased cell proliferation occurred in CD-1 mice. Next, these gene expressions in PXB mice were examined at the peak point of YAP activation, showing no significant changes. We revealed that PB administration did not induce YAP activation in PXB mice, suggesting that the PXB mouse is a useful human model to evaluate relevancy of CAR-mediated MOA to humans.</p>