Abstract
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, 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.
Highlights
The hepatic cytochrome P450 (CYP)1-dependent monoxygenase system plays a central role in mammalian defense against harmful environmental chemicals [1]; it is a major deter
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
The data presented in the current study is based on the generation of mice from targeted ES cells such that these mice retain all three loxP sites and the selectable marker, as shown in Fig. 1a, either at both CPR alleles (CPRlox/lox) or at one allele with the other CPR allele deleted (CPRlox/Ϫ), tissuespecific deletion being achieved by crossing in the CreALB transgene
Summary
The hepatic cytochrome P450 (CYP)1-dependent monoxygenase system plays a central role in mammalian defense against harmful environmental chemicals [1]; it is a major deter-. We describe the generation and characterization of mice carrying a deletion of hepatic CPR, and lacking P450 activity in the liver. Such mice exhibited many intriguing phenotypes, and remarkably they were viable and healthy. Hepatic CPR-null mice had a severely compromised ability to metabolize the narcotic drug pentobarbital or the analgesic acetaminophen, demonstrating the predominant role of the hepatic P450 enzymes in the pharmacology and toxicology of these compounds and demonstrating the power of this model for understanding P450 functions
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