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Research ArticleArticle

Deletion of 30 Murine Cytochrome P450 Genes Results In Viable Mice With Compromised Drug Metabolism

Nico Scheer, Lesley A. McLaughlin, Anja Rode, A. Kenneth MacLeod, Colin J. Henderson and C. Roland Wolf
Drug Metabolism and Disposition June 2014, 42 (6) 1022-1030; DOI: https://doi.org/10.1124/dmd.114.057885
Nico Scheer
TaconicArtemis, Köln, Germany (N.S., A.R.); and Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (L.A.M., A.K.M., C.J.H., C.R.W.)
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Lesley A. McLaughlin
TaconicArtemis, Köln, Germany (N.S., A.R.); and Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (L.A.M., A.K.M., C.J.H., C.R.W.)
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Anja Rode
TaconicArtemis, Köln, Germany (N.S., A.R.); and Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (L.A.M., A.K.M., C.J.H., C.R.W.)
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A. Kenneth MacLeod
TaconicArtemis, Köln, Germany (N.S., A.R.); and Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (L.A.M., A.K.M., C.J.H., C.R.W.)
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Colin J. Henderson
TaconicArtemis, Köln, Germany (N.S., A.R.); and Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (L.A.M., A.K.M., C.J.H., C.R.W.)
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C. Roland Wolf
TaconicArtemis, Köln, Germany (N.S., A.R.); and Medical Research Institute, University of Dundee, Ninewells Hospital and Medical School, University of Dundee, Dundee, United Kingdom (L.A.M., A.K.M., C.J.H., C.R.W.)
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Abstract

In humans, 75% of all drugs are metabolized by the cytochrome P450-dependent monooxygenase system. Enzymes encoded by the CYP2C, CYP2D, and CYP3A gene clusters account for ∼80% of this activity. There are profound species differences in the multiplicity of cytochrome P450 enzymes, and the use of mouse models to predict pathways of drug metabolism is further complicated by overlapping substrate specificity between enzymes from different gene families. To establish the role of the hepatic and extrahepatic P450 system in drug and foreign chemical disposition, drug efficacy, and toxicity, we created a unique mouse model in which 30 cytochrome P450 genes from the Cyp2c, Cyp2d, and Cyp3a gene clusters have been deleted. Remarkably, despite a wide range of putative important endogenous functions, Cyp2c/2d/3a KO mice were viable and fertile, demonstrating that these genes have evolved primarily as detoxification enzymes. Although there was no overt phenotype, detailed examination showed Cyp2c/2d/3a KO mice had a smaller body size (15%) and larger livers (20%). Changes in hepatic morphology and a decreased blood glucose (30%) were also noted. A five-drug cocktail of cytochrome P450 isozyme probe substrates were used to evaluate changes in drug pharmacokinetics; marked changes were observed in either the pharmacokinetics or metabolites formed from Cyp2c, Cyp2d, and Cyp3a substrates, whereas the metabolism of the Cyp1a substrate caffeine was unchanged. Thus, Cyp2c/2d/3a KO mice provide a powerful model to study the in vivo role of the P450 system in drug metabolism and efficacy, as well as in chemical toxicity.

Footnotes

    • Received February 28, 2014.
    • Accepted March 26, 2014.
  • Program support came from Cancer Research UK [Grants C4639/A10822 to R.W.] and from ITI Life Sciences, Scotland.

  • dx.doi.org/10.1124/dmd.114.057885.

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

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 42 (6)
Drug Metabolism and Disposition
Vol. 42, Issue 6
1 Jun 2014
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Research ArticleArticle

A Mouse Model Lacking Cyp2c, Cyp2d, and Cyp3a Gene Clusters

Nico Scheer, Lesley A. McLaughlin, Anja Rode, A. Kenneth MacLeod, Colin J. Henderson and C. Roland Wolf
Drug Metabolism and Disposition June 1, 2014, 42 (6) 1022-1030; DOI: https://doi.org/10.1124/dmd.114.057885

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Research ArticleArticle

A Mouse Model Lacking Cyp2c, Cyp2d, and Cyp3a Gene Clusters

Nico Scheer, Lesley A. McLaughlin, Anja Rode, A. Kenneth MacLeod, Colin J. Henderson and C. Roland Wolf
Drug Metabolism and Disposition June 1, 2014, 42 (6) 1022-1030; DOI: https://doi.org/10.1124/dmd.114.057885
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