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Journal of Pharmacology and Experimental Therapeutics

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Conditional Deletion of Cytochrome P450 Oxidoreductase in the Liver and Gastrointestinal Tract: A New Model for Studying the Functions of the P450 System

Robert D. Finn, Aileen W. McLaren, Dianne Carrie, Colin J. Henderson and C. Roland Wolf
Journal of Pharmacology and Experimental Therapeutics July 2007, 322 (1) 40-47; DOI: https://doi.org/10.1124/jpet.107.121780
Robert D. Finn
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Aileen W. McLaren
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Dianne Carrie
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Colin J. Henderson
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C. Roland Wolf
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Abstract

We have previously described a mouse model, where hepatic cytochrome P450 oxidoreductase (POR) expression has been deleted, resulting in almost complete ablation of hepatic P450 function [Hepatic P450 Reductase Null (HRN)]. HRN mice grow normally but develop fatty livers, and they have increased cytochrome P450 levels. Associated with the hepatic lipid accumulation are significant changes in the expression of genes controlling lipid homeostasis. We have characterized this model extensively and demonstrated its value in drug efficiency testing, in toxicokinetics, and in evaluating the role of the hepatic P450 system in drug pharmacokinetics. To extend the deletion of POR, and P450 inactivation, to other tissues, and to develop the utility of this model, we have generated a mouse where POR can be deleted conditionally in the liver and gastrointestinal tract using the rat cytochrome P450 CYP1A1 promoter to drive Cre recombinase expression. Administration of the CYP1A1 inducers tetrachlorodibenzo-p-dioxin or β-naphthoflavone resulted in both hepatic and gastrointestinal deletion of POR, whereas administration of 3-methylcholanthrene resulted specifically in loss of hepatic POR expression. In all cases, the resulting hepatic phenotype seemed identical to that of the HRN model, including increased cytochrome P450 expression. Hepatic deletion of POR and the subsequent increase in P450 expression were dependent on inducer dose, with maximal POR deletion occurring at a single dose of 3-methylcholanthrene of 40 mg/kg. This model provides a powerful approach for studying the functions of POR as well as in the evaluation of the role of hepatic and gastrointestinal P450s in drug deposition and chemical toxicity.

Footnotes

  • This work was supported by a Cancer Research UK program grant to C.R.W.

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

  • doi:10.1124/jpet.107.121780.

  • ABBREVIATIONS: P450, cytochrome P450; POR, cytochrome P450 oxidoreductase; HRN, Hepatic Reductase Null; Ah, Aryl hydrocarbon; BNF, β-naphthoflavone; TCDD, tetrachlorodibenzo-p-dioxin; 3MC, 3-methylcholanthrene; BFC, 7-benzyloxy-4-(trifluoromethly)-coumarin; g.i., gastrointestinal; SKF-525A, 2-diethylaminoethyl-2,2-diphenylpropylacetate.

    • Received February 22, 2007.
    • Accepted April 12, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 385 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 385, Issue 1
1 Apr 2023
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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Conditional Deletion of Cytochrome P450 Oxidoreductase in the Liver and Gastrointestinal Tract: A New Model for Studying the Functions of the P450 System

Robert D. Finn, Aileen W. McLaren, Dianne Carrie, Colin J. Henderson and C. Roland Wolf
Journal of Pharmacology and Experimental Therapeutics July 1, 2007, 322 (1) 40-47; DOI: https://doi.org/10.1124/jpet.107.121780

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Research ArticleGASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Conditional Deletion of Cytochrome P450 Oxidoreductase in the Liver and Gastrointestinal Tract: A New Model for Studying the Functions of the P450 System

Robert D. Finn, Aileen W. McLaren, Dianne Carrie, Colin J. Henderson and C. Roland Wolf
Journal of Pharmacology and Experimental Therapeutics July 1, 2007, 322 (1) 40-47; DOI: https://doi.org/10.1124/jpet.107.121780
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