Deletion of 30 Murine Cytochrome p450 Genes Results In Viable Mice With Compromised Drug Metabolism

Nico Scheer, Lesley A. McLaughlin, Anja Rode, A.K. MacLeod, Colin J. Henderson, C. Roland Wolf (Lead / Corresponding author)

    Research output: Contribution to journalArticle

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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.
    Original languageEnglish
    Pages (from-to)1022-1030
    Number of pages9
    JournalDrug Metabolism and Disposition
    Volume42
    Issue number6
    Early online date26 Mar 2014
    DOIs
    Publication statusPublished - Jun 2014

    Fingerprint

    Cytochrome P-450 Enzyme System
    Pharmaceutical Preparations
    Genes
    Multigene Family
    Liver
    Enzymes
    Pharmacokinetics
    Cytochrome P-450 CYP3A
    Body Size
    Substrate Specificity
    Mixed Function Oxygenases
    Caffeine
    Drug-Related Side Effects and Adverse Reactions
    Isoenzymes
    Blood Glucose
    Phenotype

    Cite this

    Scheer, Nico ; McLaughlin, Lesley A. ; Rode, Anja ; MacLeod, A.K. ; Henderson, Colin J. ; Wolf, C. Roland. / Deletion of 30 Murine Cytochrome p450 Genes Results In Viable Mice With Compromised Drug Metabolism. In: Drug Metabolism and Disposition. 2014 ; Vol. 42, No. 6. pp. 1022-1030.
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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.",
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    Deletion of 30 Murine Cytochrome p450 Genes Results In Viable Mice With Compromised Drug Metabolism. / Scheer, Nico; McLaughlin, Lesley A.; Rode, Anja; MacLeod, A.K.; Henderson, Colin J.; Wolf, C. Roland (Lead / Corresponding author).

    In: Drug Metabolism and Disposition, Vol. 42, No. 6, 06.2014, p. 1022-1030.

    Research output: Contribution to journalArticle

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    AU - McLaughlin, Lesley A.

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