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Research ArticleArticle

RNA Sequencing Reveals Dynamic Changes of mRNA Abundance of Cytochromes P450 and Their Alternative Transcripts during Mouse Liver Development

Lai Peng, Byunggil Yoo, Sumedha S. Gunewardena, Hong Lu, Curtis D. Klaassen and Xiao-bo Zhong
Drug Metabolism and Disposition June 2012, 40 (6) 1198-1209; DOI: https://doi.org/10.1124/dmd.112.045088
Lai Peng
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Byunggil Yoo
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Sumedha S. Gunewardena
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Hong Lu
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Curtis D. Klaassen
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Xiao-bo Zhong
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Abstract

Cytochromes P450 (P450s) are a superfamily of enzymes that have critical functions in liver to catalyze the biotransformation of numerous drugs. However, the functions of most P450s are not mature at birth, which can markedly affect the metabolism of drugs in newborns. Therefore, characterization of the developmental profiles and regulatory mechanisms of P450 expression is needed for more rational drug therapy of pediatric patients. An animal model is indispensable for studying the mechanisms of postnatal development of the P450s. Hence we used RNA sequencing (RNA-Seq) to provide a “true quantification” of mRNA expression of all P450s in mouse liver during development. Liver samples of male C57BL/6 mice at 12 different ages from prenatal to adulthood were used. Total mRNAs of the 103 mouse P450s displayed two rapid increasing stages after birth, reflecting critical functional transition of liver during development. Four ontogenic expression patterns were identified among the 71 significantly expressed P450s, which categorized genes into neonatal-, adolescent-, adolescent/adult-, and adult-enriched groups. The 10 most highly expressed subfamilies of mouse P450s in livers of adult mice were CYP2E, -2C, -2D, -3A, -4A, -2F, -2A, -1A, -4F, and -2B, which showed diverse expression profiles during development. The expression patterns of multiple members within a P450 subfamily were often classified to different groups. RNA-Seq also enabled the quantification of known transcript variants of CYP2C44, CYP2C50, CYP2D22, CYP3A25, and CYP26B1 and identification of novel transcripts for CYP2B10, CYP2D26, and CYP3A13. In conclusion, this study reveals the mRNA abundance of all the P450s in mouse liver during development and provides a foundation for mechanistic studies in the future.

Footnotes

  • This study was supported by the National Institutes of Health National Institute for Environmental Health Sciences [Grant ES-019487] (to X.Z., C.D.K., and H.L.); the National Institutes of Health National Institute of General Medical Sciences [Grant GM-087376] (to X.Z.); the National Institutes of Health National Institute for Environmental Health Sciences [Grant ES-009649] (to C.D.K.); and the National Institutes of Health National Center for Research Resources [Grant RR-021940] (to C.D.K. and X.Z.).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    http://dx.doi.org/10.1124/dmd.112.045088.

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    RNA-Seq
    RNA sequencing
    bp
    base pairs
    NCBI
    National Center for Biotechnology Information
    FPKM
    fragments per kilobase of exon per million reads mapped
    FDR-BH
    Benjamini-Hochberg-adjusted false discovery rate
    PCR
    polymerase chain reaction
    3′RACE
    rapid amplification of cDNA 3′ end
    UTR
    untranslated region.

  • Received February 14, 2012.
  • Accepted March 20, 2012.
  • Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 40 (6)
Drug Metabolism and Disposition
Vol. 40, Issue 6
1 Jun 2012
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Research ArticleArticle

ONTOGENY OF P450s IN MOUSE LIVER REVEALED BY RNA-Seq

Lai Peng, Byunggil Yoo, Sumedha S. Gunewardena, Hong Lu, Curtis D. Klaassen and Xiao-bo Zhong
Drug Metabolism and Disposition June 1, 2012, 40 (6) 1198-1209; DOI: https://doi.org/10.1124/dmd.112.045088

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Research ArticleArticle

ONTOGENY OF P450s IN MOUSE LIVER REVEALED BY RNA-Seq

Lai Peng, Byunggil Yoo, Sumedha S. Gunewardena, Hong Lu, Curtis D. Klaassen and Xiao-bo Zhong
Drug Metabolism and Disposition June 1, 2012, 40 (6) 1198-1209; DOI: https://doi.org/10.1124/dmd.112.045088
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