title: 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 bothFxr-null and control (C57BL/6) mouse livers during development. Liver samples of male C57BL/6 andFxr-null mice at 6 different ages from prenatal to adult were used. TheFxr-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 (AoxandXdh), 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.
authors.affiliation: 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.
authors.forename: Lai
authors.initials: L
authors.lastname: Peng
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Piekos
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, CT 06269, USA.
authors.forename: Xiao-Bo
authors.initials: XB
authors.lastname: Zhong
keywords: ADH, alcohol dehydrogenase; AKR, aldoketo reductase; ALDH, aldehyde dehydrogenase; CES, carboxylesterase (Ces); DPYD, dihydropyrimidine dehydrogenase; Drug metabolizing  enzymes; EPHX, epoxide hydrolase; FMO, flavin monooxygenases, Farnesoid X receptor (FXR); Farnesoid X receptor; Fxr-null mouse; Gene expression; Liver; NQO, quinone oxidoreductase; Ontogeny; P450, cytochrome P450; PON, paraoxonase; POR, cytochrome P450 oxidoreductase