Peng Lai, Piekos Stephanie, Guo Grace L, Zhong Xiao-Bo
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA; Key Laboratory of System Biomedicine, Center for Comparative Biomedicine, Institute of Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.
Acta Pharm Sin B. 2016 Sep;6(5):453-459. doi: 10.1016/j.apsb.2016.07.015. Epub 2016 Aug 10.
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.
出生后肝脏成熟过程中，肝脏中I相药物代谢酶的表达会发生显著变化。法尼酯X受体（FXR）对肝脏中的胆汁酸和脂质稳态至关重要。然而，FXR在调节I相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基因敲除小鼠和对照（C57BL/6）小鼠肝脏中I相基因的发育表达。使用了从产前到成年6个不同年龄的雄性C57BL/6和FXR基因敲除小鼠的肝脏样本。FXR基因敲除显示出总体上减少I相基因表达“第1天激增”的作用，包括新生儿期的细胞色素P450。在来自12个不同家族的185个I相基因中，有136个表达，并且在发育过程中所有12个I相家族的基因都发生了差异表达，包括水解作用：羧酸酯酶（CES）、对氧磷酶（PON）和环氧水解酶（EH）；还原作用：醛酮还原酶（AKR）、醌氧化还原酶（QR）和二氢嘧啶脱氢酶（DPYD）；以及氧化作用：乙醇脱氢酶（ADH）、醛脱氢酶（ALDH）、黄素单加氧酶（FMO）、钼羟化酶（MAO和AOX）、细胞色素P450（P450）和细胞色素P450氧化还原酶（POR）。数据还表明了FXR可能靶向的新的I相基因。这些结果揭示了FXR在调节I相基因个体发育中的重要作用。
