Role of farnesoid X receptor in establishment of ontogeny of phase-I drug metabolizing enzyme genes in mouse liver

ABSTRACT

The expression of phase-I drug metabolizing enzymes in liver changes dramatically during postnatal liver maturation. Farnesoid X receptor (FXR) is critical for bile acid and lipid homeostasis in liver. However, the role of FXR in regulating ontogeny of phase-I drug metabolizing genes is not clear. Hence, we applied RNA-sequencing to quantify the developmental expression of phase-I genes in both-null and control (C57BL/6) mouse livers during development. Liver samples of male C57BL/6 and-null mice at 6 different ages from prenatal to adult were used. The-null showed an overall effect to diminish the "day-1 surge" of phase-I gene expression, including cytochrome P450s at neonatal ages. Among the 185 phase-I genes from 12 different families, 136 were expressed, and differential expression during development occurred in genes from all 12 phase-I families, including hydrolysis carboxylesterase (), paraoxonase (), and epoxide hydrolase (); reduction aldoketo reductase (), quinone oxidoreductase (), and dihydropyrimidine dehydrogenase (); and oxidation alcohol dehydrogenase (), aldehyde dehydrogenase (), flavin monooxygenases (), molybdenum hydroxylase (and), cytochrome P450 (P450), and cytochrome P450 oxidoreductase (). The data also suggested new phase-I genes potentially targeted by FXR. These results revealed an important role of FXR in regulation of ontogeny of phase-I genes.