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Research ArticleArticle

RNA-Sequencing Quantification of Hepatic Ontogeny and Tissue Distribution of mRNAs of Phase II Enzymes in Mice

Hong Lu, Sumedha Gunewardena, Julia Y. Cui, Byunggil Yoo, Xiao-bo Zhong and Curtis D. Klaassen
Drug Metabolism and Disposition April 2013, 41 (4) 844-857; DOI: https://doi.org/10.1124/dmd.112.050211
Hong Lu
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York (H.L.); Department of Medicine (J.Y.C., C.D.K.) and Kansas Intellectual and Developmental Disabilities Research Center (S.G., B.Y.), University of Kansas Medical Center, Kansas City, Kansas; and Department of Pharmaceutical Sciences, University of Connecticut School of Pharmacy, Storrs, Connecticut (X.Z.)
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Sumedha Gunewardena
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York (H.L.); Department of Medicine (J.Y.C., C.D.K.) and Kansas Intellectual and Developmental Disabilities Research Center (S.G., B.Y.), University of Kansas Medical Center, Kansas City, Kansas; and Department of Pharmaceutical Sciences, University of Connecticut School of Pharmacy, Storrs, Connecticut (X.Z.)
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Julia Y. Cui
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York (H.L.); Department of Medicine (J.Y.C., C.D.K.) and Kansas Intellectual and Developmental Disabilities Research Center (S.G., B.Y.), University of Kansas Medical Center, Kansas City, Kansas; and Department of Pharmaceutical Sciences, University of Connecticut School of Pharmacy, Storrs, Connecticut (X.Z.)
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Byunggil Yoo
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York (H.L.); Department of Medicine (J.Y.C., C.D.K.) and Kansas Intellectual and Developmental Disabilities Research Center (S.G., B.Y.), University of Kansas Medical Center, Kansas City, Kansas; and Department of Pharmaceutical Sciences, University of Connecticut School of Pharmacy, Storrs, Connecticut (X.Z.)
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Xiao-bo Zhong
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York (H.L.); Department of Medicine (J.Y.C., C.D.K.) and Kansas Intellectual and Developmental Disabilities Research Center (S.G., B.Y.), University of Kansas Medical Center, Kansas City, Kansas; and Department of Pharmaceutical Sciences, University of Connecticut School of Pharmacy, Storrs, Connecticut (X.Z.)
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Curtis D. Klaassen
Department of Pharmacology, SUNY Upstate Medical University, Syracuse, New York (H.L.); Department of Medicine (J.Y.C., C.D.K.) and Kansas Intellectual and Developmental Disabilities Research Center (S.G., B.Y.), University of Kansas Medical Center, Kansas City, Kansas; and Department of Pharmaceutical Sciences, University of Connecticut School of Pharmacy, Storrs, Connecticut (X.Z.)
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Abstract

Phase II conjugating enzymes play key roles in the metabolism of xenobiotics. In the present study, RNA sequencing was used to elucidate hepatic ontogeny and tissue distribution of mRNA expression of all major known Phase II enzymes, including enzymes involved in glucuronidation, sulfation, glutathione conjugation, acetylation, methylation, and amino acid conjugation, as well as enzymes for the synthesis of Phase II cosubstrates, in male C57BL/6J mice. Livers from male C57BL/6J mice were collected at 12 ages from prenatal to adulthood. Many of these Phase II enzymes were expressed at much higher levels in adult livers than in perinatal livers, such as Ugt1a6b, -2a3, -2b1, -2b5, -2b36, -3a1, and -3a2; Gsta1, -m1, -p1, -p2, and -z1; mGst1; Nat8; Comt; Nnmt; Baat; Ugdh; and Gclc. In contrast, hepatic mRNA expression of a few Phase II enzymes decreased during postnatal liver development, such as mGst2, mGst3, Gclm, and Mat2a. Hepatic expression of certain Phase II enzymes peaked during the adolescent stage, such as Ugt1a1, Sult1a1, Sult1c2, Sult1d1, Sult2as, Sult5a1, Tpmt, Glyat, Ugp2, and Mat1a. In adult mice, the total transcripts for Phase II enzymes were comparable in liver, kidney, and small intestine; however, individual Phase II enzymes displayed marked tissue specificity among the three organs. In conclusion, this study unveils for the first time developmental changes in mRNA abundance of all major known Phase II enzymes in mouse liver, as well as their tissue-specific expression in key drug-metabolizing organs. The age- and tissue-specific expression of Phase II enzymes indicate that the detoxification of xenobiotics is highly regulated by age and cell type.

Footnotes

  • This work was supported by the National Institutes of Health National Institute of Environmental Health Sciences [Grant ES-019487]; and the National Institutes of Health National Center for Research Resources [Grant RR-021940].

  • dx.doi.org/10.1124/dmd.112.050211.

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

  • Received November 19, 2012.
  • Accepted January 31, 2013.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (4)
Drug Metabolism and Disposition
Vol. 41, Issue 4
1 Apr 2013
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Research ArticleArticle

Hepatic Ontogeny and Tissue Distribution of Phase II Enzymes

Hong Lu, Sumedha Gunewardena, Julia Y. Cui, Byunggil Yoo, Xiao-bo Zhong and Curtis D. Klaassen
Drug Metabolism and Disposition April 1, 2013, 41 (4) 844-857; DOI: https://doi.org/10.1124/dmd.112.050211

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Research ArticleArticle

Hepatic Ontogeny and Tissue Distribution of Phase II Enzymes

Hong Lu, Sumedha Gunewardena, Julia Y. Cui, Byunggil Yoo, Xiao-bo Zhong and Curtis D. Klaassen
Drug Metabolism and Disposition April 1, 2013, 41 (4) 844-857; DOI: https://doi.org/10.1124/dmd.112.050211
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