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J. Biol. Chem., Vol. 283, Issue 46, 31385-31393, November 14, 2008

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Defining the in Vivo Role for Cytochrome b₅ in Cytochrome P450 Function through the Conditional Hepatic Deletion of Microsomal Cytochrome b₅^*

Robert D. Finn, Lesley A. McLaughlin, Sebastien Ronseaux, Ian Rosewell, J. Brian Houston^¶, Colin J. Henderson, and C. Roland Wolf¹

From the Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Institute, Level 5, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom, Cancer Research UK Transgenic Services, Clare Hall Laboratories, Blanche Lane, South Mimms, Potters Bar, Herts EN6 3LD, United Kingdom, and the ^¶School of Pharmacy and Pharmaceutical Sciences, University of Manchester, M13 9PT, United Kingdom

In vitro, cytochrome b₅ modulates the rate of cytochrome P450-dependent mono-oxygenation reactions. However, the role of this enzyme in determining drug pharmacokinetics in vivo and the consequential effects on drug absorption distribution, metabolism, excretion, and toxicity are unclear. In order to resolve this issue, we have carried out the conditional deletion of microsomal cytochrome b₅ in the liver to create the hepatic microsomal cytochrome b₅ null mouse. These mice develop and breed normally and have no overt phenotype. In vitro studies using a range of substrates for different P450 enzymes showed that in hepatic microsomal cytochrome b₅ null NADH-mediated metabolism was essentially abolished for most substrates, and the NADPH-dependent metabolism of many substrates was reduced by 50–90%. This reduction in metabolism was also reflected in the in vivo elimination profiles of several drugs, including midazolam, metoprolol, and tolbutamide. In the case of chlorzoxazone, elimination was essentially unchanged. For some drugs, the pharmacokinetics were also markedly altered; for example, when administered orally, the maximum plasma concentration for midazolam was increased by 2.5-fold, and the clearance decreased by 3.6-fold in hepatic microsomal cytochrome b₅ null mice. These data indicate that microsomal cytochrome b₅ can play a major role in the in vivo metabolism of certain drugs and chemicals but in a P450- and substrate-dependent manner.

Received for publication, May 7, 2008 , and in revised form, September 19, 2008.

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^* This work was supported by Cancer Research UK Programme Grant C4639/A5661 (to C. R. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–5 and Tables 1–5.

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¹ To whom correspondence should be addressed: Cancer Research UK Molecular Pharmacology Unit, Biomedical Research Institute, Level 5, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK. Tel.: 44-1382-632621; Fax: 44-1382-66993; E-mail: c.r.wolf{at}dundee.ac.uk.

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