在出生后肝脏成熟期间,肝脏中I期药物代谢酶的表达发生了显着变化。法尼醇X受体(FXR)对肝脏胆汁酸和脂质稳态至关重要。然而,FXR在调节I期药物代谢基因个体发育中的作用尚不清楚。因此,我们应用RNA测序来量化发育过程中Fxr-null和对照(C57BL/6)小鼠肝脏中I期基因的发育表达。使用从产前到成年的6个不同年龄的雄性C57BL/6和Fxr-null小鼠的肝脏样品。Fxr-null显示出减少I期基因表达的“第1天激增”的总体效果,包括新生儿年龄的细胞色素P450。在来自12个不同家族的185个I期基因中,136表示,发育过程中差异表达发生在所有12个I期家族的基因中,包括水解:羧酸酯酶(Ces),对氧磷酶(Pon),和环氧化物水解酶(Ephx);还原:醛酮还原酶(Akr),醌氧化还原酶(Nqo),和二氢嘧啶脱氢酶(Dpyd);和氧化:醇脱氢酶(Adh),醛脱氢酶(Aldh),黄素单加氧酶(Fmo),钼羟化酶(Aox和Xdh),细胞色素P450(P450),和细胞色素P450氧化还原酶(Por)。数据还表明FXR可能靶向的新的I期基因。这些结果揭示了FXR在I期基因个体发育调控中的重要作用。
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 Fxr-null and control (C57BL/6) mouse livers during development. Liver samples of male C57BL/6 and Fxr-null mice at 6 different ages from prenatal to adult were used. The Fxr-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 (Ces), paraoxonase (Pon), and epoxide hydrolase (Ephx); reduction: aldoketo reductase (Akr), quinone oxidoreductase (Nqo), and dihydropyrimidine dehydrogenase (Dpyd); and oxidation: alcohol dehydrogenase (Adh), aldehyde dehydrogenase (Aldh), flavin monooxygenases (Fmo), molybdenum hydroxylase (Aox and Xdh), cytochrome P450 (P450), and cytochrome P450 oxidoreductase (Por). 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.