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Molecular Pharmacology

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Research ArticleArticle

Deletion of Microsomal Cytochrome b5 Profoundly Affects Hepatic and Extrahepatic Drug Metabolism

Lesley A. McLaughlin, Sebastien Ronseaux, Robert D. Finn, Colin J. Henderson and C. Roland Wolf
Molecular Pharmacology August 2010, 78 (2) 269-278; DOI: https://doi.org/10.1124/mol.110.064246
Lesley A. McLaughlin
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Sebastien Ronseaux
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Robert D. Finn
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Colin J. Henderson
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C. Roland Wolf
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This article has a correction. Please see:

  • Correction to “Deletion of Microsomal Cytochrome b5 Profoundly Affects Hepatic and Extrahepatic Drug Metabolism” - January 01, 2014

Abstract

We demonstrated recently that cytochrome b5 plays an important in vivo role in hepatic cytochrome P450 (P450) function [J Biol Chem 283:31385–31393, 2008]. We have now generated a model in which cytochrome b5 has been deleted in all tissues [cytochrome b5 complete null (BCN)], which surprisingly results in a viable mouse despite the putative in vivo roles of this protein in lipid and steroid hormone metabolism and the reduction of methemoglobin. In contrast to the liver-specific deletion, complete deletion of cytochrome b5 leads to a neonatal increase in the expression of many hepatic P450s at both the protein and mRNA level. In extrahepatic tissues, some changes in P450 expression were also observed that were isoform-dependent. In vitro cytochrome P450 activities in liver, kidney, lung, and small intestine of BCN mice were determined for a range of model substrates and probe drugs; a profound reduction in the metabolism of some substrates, particularly in lung, kidney, and small intestine, was observed. In vivo, the metabolism of metoprolol was significantly altered in BCN mice, in contrast to the previous finding in the liver-specific cytochrome b5 deletion, suggesting that extrahepatic cytochrome b5 plays a significant role in its disposition. Testicular Cyp17 hydroxylase and lyase activities were also significantly reduced by cytochrome b5 deletion, leading to significantly lower levels of testicular testosterone. The BCN mouse provides an additional model system with which to further investigate the functions of cytochrome b5, particularly in extrahepatic tissues.

Footnotes

  • This work was supported by the Cancer Research UK Programme [Grant C4639/A5661].

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

    doi:10.1124/mol.110.064246.

  • ABBREVIATIONS:

    P450
    cytochrome P450
    BCN
    cytochrome b5 complete knockout mice, Cytb 5(−/−)
    BFC
    7-benzyloxy-4-trifluoromethylcoumarin
    BR
    benzyloxyresorufin
    EFC
    7-ethoxy-4-trifluoromethylcoumarin
    ER
    ethoxyresorufin
    HPLC
    high-performance liquid chromatography
    LC/MS-MS
    liquid chromatography/tandem mass spectrometry
    MFC
    7-methoxy-4-trifluoromethylcoumarin
    MR
    methoxyresorufin
    POR
    cytochrome P450 oxidoreductase
    PR
    pentoxyresorufin
    WT
    wild type, Cytb5(+/+)
    PCR
    polymerase chain reaction.

  • Received February 17, 2010.
  • Accepted April 29, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (2)
Molecular Pharmacology
Vol. 78, Issue 2
1 Aug 2010
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Research ArticleArticle

Deletion of Microsomal Cytochrome b5 Profoundly Affects Hepatic and Extrahepatic Drug Metabolism

Lesley A. McLaughlin, Sebastien Ronseaux, Robert D. Finn, Colin J. Henderson and C. Roland Wolf
Molecular Pharmacology August 1, 2010, 78 (2) 269-278; DOI: https://doi.org/10.1124/mol.110.064246

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Research ArticleArticle

Deletion of Microsomal Cytochrome b5 Profoundly Affects Hepatic and Extrahepatic Drug Metabolism

Lesley A. McLaughlin, Sebastien Ronseaux, Robert D. Finn, Colin J. Henderson and C. Roland Wolf
Molecular Pharmacology August 1, 2010, 78 (2) 269-278; DOI: https://doi.org/10.1124/mol.110.064246
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