- Kouichi Yoshinari (Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka / Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University / firstname.lastname@example.org)
1) Laboratory of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka , 2) Laboratory of Health Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University
The nuclear receptor pregnane X receptor (PXR, NR1I2) regulates several liver functions such as xenobiotic metabolism, energy metabolism, inflammation or cell growth, which are associated with drug-drug interactions and some diseases. It is well known that there are large species differences between human PXR and mouse PXR (mPXR) ligands. Although mouse models are often used in biological research, the number of mPXR ligands are limited. In the present study, we have thus searched mPXR activators from 190 industrial chemicals and 161 agricultural chemicals by reporter assay system with a promoter region of PXR target gene, and mouse primary hepatocytes and mice were treated with the candidates to confirm mPXR activation. Thirty-eight chemicals were selected after reporter assay screening. Among them, seven chemicals were selected as potential mPXR activators since their treatment increased mRNA levels of Cyp3a11, a representative PXR target gene, in mouse primary hepatocytes. Finally, in in vivo experiments using mice, hepatic Cyp3a11 mRNA levels were induced by treatment with flusilazole and metconazole. These results suggest that these two chemicals function as mPXR activators in vitro and in vivo.