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J. Biol. Chem., Vol. 278, Issue 28, 25895-25901, July 11, 2003

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Liver-specific Deletion of the NADPH-Cytochrome P450 Reductase Gene

IMPACT ON PLASMA CHOLESTEROL HOMEOSTASIS AND THE FUNCTION AND REGULATION OF MICROSOMAL CYTOCHROME P450 AND HEME OXYGENASE^*

Jun Gu, Yan Weng, Qing-Yu Zhang, Huadong Cui, Melissa Behr, Lin Wu, Weizhu Yang, Li Zhang and Xinxin Ding 

From the Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York 12201

A mouse model with liver-specific deletion of the NADPH-cytochrome P450 reductase (Cpr) gene (designated Alb-Cre/Cpr^lox mice) was generated and characterized in this study. Hepatic microsomal CPR expression was significantly reduced at 3 weeks and was barely detectable at 2 months of age in the Alb-Cre^+/–/Cpr^lox+/+ (homozygous) mice, with corresponding decreases in liver microsomal cytochrome P450 (CYP) and heme oxygenase (HO) activities, in pentobarbital clearance, and in total plasma cholesterol level. Nevertheless, the homozygous mice are fertile and are normal in gross appearance and growth rate. However, at 2 months, although not at 3 weeks, the homozygotes had significant increases in liver weight, accompanied by hepatic lipidosis and other pathologic changes. Intriguingly, total microsomal CYP content was increased in the homozygotes about 2-fold at 3 weeks and about 3-fold at 2 months of age; at 2 months, there were varying degrees of induction in protein (1–5-fold) and mRNA expression (0–67-fold) for all CYPs examined. There was also an induction of HO-1 protein (nearly 9-fold) but no induction of HO-2. These data indicate the absence of significant alternative redox partners for liver microsomal CYP and HO, provide in vivo evidence for the significance of hepatic CPR-dependent enzymes in cholesterol homeostasis and systemic drug clearance, and reveal novel regulatory pathways of CYP expression associated with altered cellular homeostasis. The Alb-Cre/Cpr^lox mouse represents a unique model for studying the in vivo function of hepatic HO and microsomal CYP-dependent pathways in the biotransformation of endogenous and xenobiotic compounds.

Received for publication, March 26, 2003

Note Added in Proof—A paper by Henderson et al. (52), which was in press during the preparation of this paper, also reports the generation and characterization of a liver-specific Cpr-null mouse model. Preliminary data from that study on the impact of hepatic CPR loss on cholesterol level, liver microsomal P450 content, in vivo pentobarbital clearance, and liver weight were also presented at the 14th International Symposium on Microsomes and Drug Oxidations, Sapporo, Japan, 2002. These findings are confirmed by the present study. However, our conditional Cpr-null mouse breeding pairs had normal fertility, whereas those described by Henderson et al. had reduced fertility and litter size (52). This discrepancy may be at least partly because of differences in the structure of the conditional Cpr alleles.

^* This work was supported in part by United States Public Health Service Grant ES07462 from the NIEHS, National Institutes of Health. 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.

To whom correspondence should be addressed: Wadsworth Center, New York State Dept. of Health, Empire State Plaza, Box 509, Albany, NY 12201-0509. Tel.: 518-486-2585; Fax: 518-486-1505; E-mail: xding{at}wadsworth.org.

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