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J. Biol. Chem., Vol. 278, Issue 15, 13480-13486, April 11, 2003
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From the Cancer Research UK Molecular Pharmacology Unit, Biomedical
Research Centre, Level 5, Ninewells Hospital & Medical School, Dundee
DD1 9SY, United Kingdom
Cytochrome P450 (CYP) monooxygenases catalyze the
oxidation of a large number of endogenous compounds and the majority of ingested environmental chemicals, leading to their elimination and
often to their metabolic activation to toxic products. This enzyme
system therefore provides our primary defense against xenobiotics and
is a major determinant in the therapeutic efficacy of pharmacological agents. To evaluate the importance of hepatic P450s in normal homeostasis, drug pharmacology, and chemical toxicity, we have conditionally deleted the essential electron transfer protein, NADH:ferrihemoprotein reductase (EC 1.6.2.4, cytochrome P450 reductase,
CPR) in the liver, resulting in essentially complete ablation of
hepatic microsomal P450 activity. Hepatic CPR-null mice could no longer
break down cholesterol because of their inability to produce bile
acids, and whereas hepatic lipid levels were significantly increased,
circulating levels of cholesterol and triglycerides were severely
reduced. Loss of hepatic P450 activity resulted in a 5-fold increase in
P450 protein, indicating the existence of a negative feedback pathway
regulating P450 expression. Profound changes in the in vivo
metabolism of pentobarbital and acetaminophen indicated that
extrahepatic metabolism does not play a major role in the disposition
of these compounds. Hepatic CPR-null mice developed normally and
were able to breed, indicating that hepatic microsomal P450-mediated
steroid hormone metabolism is not essential for fertility,
demonstrating that a major evolutionary role for hepatic P450s is to
protect mammals from their environment.
Inactivation of the Hepatic Cytochrome P450 System
by Conditional Deletion of Hepatic Cytochrome P450 Reductase*
,,
*
This work was supported by Cancer Research UK.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
These authors contributed equally to the work.
§
Present address: Dept. of Molecular Physiology and Biophysics,
Vanderbilt School of Medicine, 702 Light Hall, Nashville, TN 37232. E-mail: mark.magnuson@vanderbilt.edu.
¶
Present address: Cancer Research UK Transgenic Services, Clare
Hall Laboratories, Blanche Lane, South Mimms, Potters Bar, Herts, EN6
3LD, UK. E-mail: ian.rosewell@cancer.org.uk.
To whom correspondence should be addressed. Tel.:
01382-632621; Fax: 01382-669993; E-mail:
roland.wolf@cancer.org.uk.
Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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