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Molecular Pharmacology

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Research ArticleArticle

Generation and Characterization of Novel Cytochrome P450 Cyp2c Gene Cluster Knockout and CYP2C9 Humanized Mouse Lines

Nico Scheer, Yury Kapelyukh, Lynsey Chatham, Anja Rode, Sandra Buechel and C. Roland Wolf
Molecular Pharmacology December 2012, 82 (6) 1022-1029; DOI: https://doi.org/10.1124/mol.112.080036
Nico Scheer
TaconicArtemis, Koeln, Germany (N.S., A.R., S.B.); CXR Biosciences Limited, Dundee, United Kingdom (Y.K., C.R.W.); Cancer Research UK Molecular Pharmacology Unit, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.R.W.); and Division of Cancer Research, Medical Research Institute, Level 9, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee, United Kingdom (L.C.).
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Yury Kapelyukh
TaconicArtemis, Koeln, Germany (N.S., A.R., S.B.); CXR Biosciences Limited, Dundee, United Kingdom (Y.K., C.R.W.); Cancer Research UK Molecular Pharmacology Unit, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.R.W.); and Division of Cancer Research, Medical Research Institute, Level 9, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee, United Kingdom (L.C.).
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Lynsey Chatham
TaconicArtemis, Koeln, Germany (N.S., A.R., S.B.); CXR Biosciences Limited, Dundee, United Kingdom (Y.K., C.R.W.); Cancer Research UK Molecular Pharmacology Unit, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.R.W.); and Division of Cancer Research, Medical Research Institute, Level 9, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee, United Kingdom (L.C.).
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Anja Rode
TaconicArtemis, Koeln, Germany (N.S., A.R., S.B.); CXR Biosciences Limited, Dundee, United Kingdom (Y.K., C.R.W.); Cancer Research UK Molecular Pharmacology Unit, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.R.W.); and Division of Cancer Research, Medical Research Institute, Level 9, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee, United Kingdom (L.C.).
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Sandra Buechel
TaconicArtemis, Koeln, Germany (N.S., A.R., S.B.); CXR Biosciences Limited, Dundee, United Kingdom (Y.K., C.R.W.); Cancer Research UK Molecular Pharmacology Unit, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.R.W.); and Division of Cancer Research, Medical Research Institute, Level 9, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee, United Kingdom (L.C.).
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C. Roland Wolf
TaconicArtemis, Koeln, Germany (N.S., A.R., S.B.); CXR Biosciences Limited, Dundee, United Kingdom (Y.K., C.R.W.); Cancer Research UK Molecular Pharmacology Unit, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (C.R.W.); and Division of Cancer Research, Medical Research Institute, Level 9, Jacqui Wood Cancer Centre, Ninewells Hospital & Medical School, University of Dundee, Dundee, United Kingdom (L.C.).
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Abstract

Compared with rodents and many other animal species, the human cytochrome P450 (P450) Cyp2c gene cluster varies significantly in the multiplicity of functional genes and in the substrate specificity of its enzymes. As a consequence, the use of wild-type animal models to predict the role of human CYP2C enzymes in drug metabolism and drug-drug interactions is limited. Within the human CYP2C cluster CYP2C9 is of particular importance, because it is one of the most abundant P450 enzymes in human liver, and it is involved in the metabolism of a wide variety of important drugs and environmental chemicals. To investigate the in vivo functions of cytochrome P450 Cyp2c genes and to establish a model for studying the functions of CYP2C9 in vivo, we have generated a mouse model with a deletion of the murine Cyp2c gene cluster and a corresponding humanized model expressing CYP2C9 specifically in the liver. Despite the high number of functional genes in the mouse Cyp2c cluster and the reported roles of some of these proteins in different biological processes, mice deleted for Cyp2c genes were viable and fertile but showed certain phenotypic alterations in the liver. The expression of CYP2C9 in the liver also resulted in viable animals active in the metabolism and disposition of a number of CYP2C9 substrates. These mouse lines provide a powerful tool for studying the role of Cyp2c genes and of CYP2C9 in particular in drug disposition and as a factor in drug-drug interaction.

Footnotes

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

  • This work was supported in part by ITI Life Sciences, Scotland.

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

    http://dx.doi.org/10.1124/mol.112.080036.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    WT
    wild-type
    Cyp2c KO
    Cyp2c knockout
    hCYP2C9
    CYP2C9 humanized
    ES
    embryonic stem
    Flpe
    flipase
    AUC
    concentration versus time curve.

  • Received May 25, 2012.
  • Accepted August 23, 2012.
  • Copyright © 2012 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 82 (6)
Molecular Pharmacology
Vol. 82, Issue 6
1 Dec 2012
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Research ArticleArticle

Cyp2c Knockout and CYP2C9 Humanized Mice

Nico Scheer, Yury Kapelyukh, Lynsey Chatham, Anja Rode, Sandra Buechel and C. Roland Wolf
Molecular Pharmacology December 1, 2012, 82 (6) 1022-1029; DOI: https://doi.org/10.1124/mol.112.080036

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Research ArticleArticle

Cyp2c Knockout and CYP2C9 Humanized Mice

Nico Scheer, Yury Kapelyukh, Lynsey Chatham, Anja Rode, Sandra Buechel and C. Roland Wolf
Molecular Pharmacology December 1, 2012, 82 (6) 1022-1029; DOI: https://doi.org/10.1124/mol.112.080036
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