Host: The Japanese Society of Toxicology
Name : The 51st Annual Meeting of the Japanese Society of Toxicology
Date : July 03, 2024 - July 05, 2024
The liver is a primary target of toxicity of chemical substances such as pharmaceuticals and pesticides, and species differences are often observed in the hepatotoxicity of chemicals. Therefore, understanding the mechanisms of hepatotoxicity is essential for developing mechanism-based evaluation systems for risk assessment of chemicals, considering species differences.
The nuclear receptor CAR has been identified as essential for phenobarbital-dependent enzyme induction and hepatocarcinogenesis, but the carcinogenic mechanism remained unclear for a long time. In addition, the molecular mechanism for the species differences in this CAR-mediated hepatocarcinogenesis also remained unknown. We have demonstrated that CAR induces hepatocyte proliferation in mice by activating the transcriptional co-activator YAP, an effector molecule of the Hippo pathway involved in cell and organ size control. Furthermore, identifying the YAP-binding motif of CAR has revealed a one amino acid difference between the motifs of human and rodent CAR, which determines the rodent specificity in the CAR-mediated hepatocyte proliferation.
We have also demonstrated that although the nuclear receptor PXR does not show liver cancer-promoting activity, it enhances hepatocyte proliferation induced by CAR, PPARα, or hepatocellular injury. In contrast, PXR markedly suppressed the progression of CAR-dependent liver cancer in a two-stage liver carcinogenesis model. These results indicate that CAR and PXR have similar functions in inducing drug-metabolizing enzymes but have different roles in hepatocyte proliferation and hepatocarcinogenesis.
Our findings provide valuable information not only from the basic toxicology of carcinogenesis but also from a regulatory science perspective.
