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Research ArticleArticle

Evidence That Cytochrome b5 and Cytochrome b5 Reductase Can Act as Sole Electron Donors to the Hepatic Cytochrome P450 System

Colin J. Henderson, Lesley A. McLaughlin and C. Roland Wolf
Molecular Pharmacology June 2013, 83 (6) 1209-1217; DOI: https://doi.org/10.1124/mol.112.084616
Colin J. Henderson
Division of Cancer Research, Medical Research Institute, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom
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Lesley A. McLaughlin
Division of Cancer Research, Medical Research Institute, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom
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C. Roland Wolf
Division of Cancer Research, Medical Research Institute, University of Dundee, Jacqui Wood Cancer Centre, Ninewells Hospital and Medical School, Dundee, United Kingdom
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Abstract

We previously described the development of genetic models to study the in vivo functions of the hepatic cytochrome P450 (P450) system, through the hepatic deletion of either cytochrome P450 oxidoreductase [POR; HRN (hepatic reductase null) line] or cytochrome b5 [HBN (hepatic cytochrome b5 null) line]. However, HRN mice still exhibit low levels of mono-oxygenase activity in spite of the absence of detectable reductase protein. To investigate whether this is because cytochrome b5 and cytochrome b5 reductase can act as the sole electron donor to the P450 system, we crossed HRN with HBN mice to generate a line lacking hepatic expression of both electron donors (HBRN). HBRN mice exhibited exacerbation of the phenotypic characteristics of the HRN line: liver enlargement, hepatosteatosis, and increased expression of certain P450s. Also, drug metabolizing activities in vitro were further reduced relative to the HRN model, in some cases to undetectable levels. Pharmacokinetic studies in vivo demonstrated that midazolam half-life, Cmax, and area under the concentration-time curve were increased, and clearance was decreased, to a greater extent in the HBRN line than in either the HBN or HRN model. Microsomal incubations using NADPH concentrations below the apparent Km of cytochrome b5 reductase, but well above that for POR, led to the virtual elimination of 7-benzyloxyquinoline turnover in HRN samples. These data provide strong evidence that cytochrome b5/cytochrome b5 reductase can act as a sole electron donor to the P450 system in vitro and in vivo.

Footnotes

    • Received December 20, 2012.
    • Accepted March 25, 2013.
  • This work was funded by the Cancer Research UK Programme [Grant C4639/A12330].

  • C.H. and L.M. are joint first authors.

  • ↵dx.doi.org/10.1124/mol.112.084616.

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

  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (6)
Molecular Pharmacology
Vol. 83, Issue 6
1 Jun 2013
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Research ArticleArticle

Drug Metabolism and Disposition in HBN, HRN, and HBRN Mice

Colin J. Henderson, Lesley A. McLaughlin and C. Roland Wolf
Molecular Pharmacology June 1, 2013, 83 (6) 1209-1217; DOI: https://doi.org/10.1124/mol.112.084616

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Research ArticleArticle

Drug Metabolism and Disposition in HBN, HRN, and HBRN Mice

Colin J. Henderson, Lesley A. McLaughlin and C. Roland Wolf
Molecular Pharmacology June 1, 2013, 83 (6) 1209-1217; DOI: https://doi.org/10.1124/mol.112.084616
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