RNA-sequencing quantification of hepatic ontogeny of phase-I enzymes in mice.
Phase-I drug metabolizing enzymes catalyze reactions of hydrolysis, reduction, and oxidation of drugs and play a critical role in drug metabolism. However, the functions of most phase-I enzymes are not mature at birth, which markedly affects drug metabolism in newborns. Therefore, characterization of the expression profiles of phase-I enzymes and the underlying regulatory mechanisms during liver maturation is needed for better estimation of using drugs in pediatric patients. The mouse is an animal model widely used for studying the mechanisms in the regulation of developmental expression of phase-I genes. Therefore, we applied RNA sequencing to provide a "true quantification" of the mRNA expression of phase-I genes in the mouse liver during development. Liver samples of male C57BL/6 mice at 12 different ages from prenatal to adulthood were used for defining the ontogenic mRNA profiles of phase-I families, including hydrolysis: carboxylesterase (Ces), paraoxonase (Pon), and epoxide hydrolase (Ephx); reduction: aldo-keto 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). Two rapidly increasing stages of total phase-I gene expression after birth reflect functional transition of the liver during development. Diverse expression patterns were identified, and some large gene families contained the mRNA of genes that are enriched at different stages of development. Our study reveals the mRNA abundance of phase-I genes in the mouse liver during development and provides a valuable foundation for mechanistic studies in the future.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut (L.P., X.B.Z.); Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas (J.Y.C., C.D.K.); Kansas Intellectual and Developmental Disabilities Research Center, Kansas City, Kansas (B.Y., S.S.G.); Department of Pharmacology, Upstate Medical University, State University of New York, Syracuse, New York (H.L.).
Lai
L
Peng
Julia Y
JY
Cui
Byunggil
B
Yoo
Sumedha S
SS
Gunewardena
Hong
H
Lu
Curtis D
CD
Klaassen
Xiao-Bo
XB
Zhong
D000818:Animals; D015870:Gene Expression / Q000235:genetics; D006868:Hydrolysis; D008099:Liver / Q000201:enzymology*; D008297:Male; D050216:Metabolic Detoxication, Phase I / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics*; D017423:Sequence Analysis, RNA / Q000379:methods
D012333:RNA, Messenger