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Papers In Press, published online ahead of print February 3, 2003
Biomedical Research Centre, University of Dundee, Dundee, Tayside DD1 9SY
Corresponding Author: margaret.rooney{at}cancer.org.uk
Cytochrome P450 (CYP) monooxygenases catalyse 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 defence 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 (EC1.6.2.4, 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 due to their inability to produce bile acids, and while hepatic lipid levels were significantly increased, circulating levels of cholesterol and triglycerides were severely reduced. Loss of hepatic P450 activity resulted in a five-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.
J. Biol. Chem, 10.1074/jbc.M212087200
Submitted on November 27, 2002
Revised on January 23, 2003
Accepted on February 3, 2003
Inactivation of the hepatic cytochrome P450 system by conditional deletion of hepatic cytochrome P450 reductase
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