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Research ArticleArticle

RNA-Sequencing Quantification of Hepatic Ontogeny of Phase-I Enzymes in Mice

Lai Peng, Julia Y. Cui, Byunggil Yoo, Sumedha S. Gunewardena, Hong Lu, Curtis D. Klaassen and Xiao-bo Zhong
Drug Metabolism and Disposition December 2013, 41 (12) 2175-2186; DOI: https://doi.org/10.1124/dmd.113.054635
Lai Peng
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.)
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Julia Y. Cui
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.)
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Byunggil Yoo
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.)
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Sumedha S. Gunewardena
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.)
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Hong Lu
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.)
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Curtis D. Klaassen
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.)
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Xiao-bo Zhong
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.)
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Abstract

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.

Footnotes

    • Received August 30, 2013.
    • Accepted September 30, 2013.
  • This study was supported by the National Institutes of Health National Institute for Environmental Health Sciences [Grant R01ES-019487] (to X.B.Z., C.D.K., and H.L.); the National Institutes of Health National Institute of General Medical Sciences [Grant R01GM-087376] (to X.B.Z.); and the National Institutes of Health National Institute for Environmental Health Sciences [Grant R01ES-009649] (to C.D.K.).

  • dx.doi.org/10.1124/dmd.113.054635.

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (12)
Drug Metabolism and Disposition
Vol. 41, Issue 12
1 Dec 2013
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Research ArticleArticle

Ontogeny of Phase-I Enzymes in Mouse Livers

Lai Peng, Julia Y. Cui, Byunggil Yoo, Sumedha S. Gunewardena, Hong Lu, Curtis D. Klaassen and Xiao-bo Zhong
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2175-2186; DOI: https://doi.org/10.1124/dmd.113.054635

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Research ArticleArticle

Ontogeny of Phase-I Enzymes in Mouse Livers

Lai Peng, Julia Y. Cui, Byunggil Yoo, Sumedha S. Gunewardena, Hong Lu, Curtis D. Klaassen and Xiao-bo Zhong
Drug Metabolism and Disposition December 1, 2013, 41 (12) 2175-2186; DOI: https://doi.org/10.1124/dmd.113.054635
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