A mouse model with a hypomorphic
NADPH-cytochrome P450 reductase (
Cpr) gene (designated
Cpr(low) allele) was generated and characterized in this study. The
Cpr gene in these mice was disrupted by the insertion of a neo gene in intron 15, which led to 74 to 95% decreases in
CPR expression in all tissues examined, including olfactory mucosa, adrenal gland, brain, testis, ovary, lung, kidney, liver, and heart. In the liver, a pattern of pericentral distribution of
CPR protein was preserved in the
Cpr(low/low) mice, despite an overall reduction in
CPR expression. Genotype distribution in F2 pups indicated limited embryonic lethality associated with the
Cpr(low) allele, a finding that confirms the role of
CPR-dependent
enzymes in development. Adult male homozygotes had decreased
body weight and decreased heart, lung, and kidney weights, whereas homozygous
Cpr(low) females, which had increased serum
testosterone and
progesterone and decreased copulatory activities, were infertile. Furthermore, adult
Cpr(low/low) mice had decreased plasma
cholesterol, and some mice developed mild centrilobular hepatic
lipidosis. In addition, despite apparently compensatory increases in total microsomal
cytochrome P450 content in the liver and kidney, the decreases in
CPR expression were accompanied by reductions in systemic clearance of
pentobarbital, as well as in hepatic microsomal metabolism of
acetaminophen and
testosterone. These phenotypes illustrate the potential impact of a globally decreased
CPR activity in human adults, and this novel knock-in mouse model provides a unique opportunity for further explorations of the in vivo roles of
CPR and
CPR-dependent
enzymes.