A mouse model termed
Cpr-low (CL) was recently generated, in which the expression of the
cytochrome P450 reductase (
Cpr) gene was globally down-regulated. The decreased
CPR expression was accompanied by phenotypical changes, including reduced embryonic survival, decreases in circulating
cholesterol, increases in hepatic P450 expression, and
female infertility (accompanied by elevated serum
testosterone and
progesterone levels). In the present study, a complementary mouse model [named reversible-CL (r-CL)] was generated, in which the reduced
CPR expression can be reversed in an organ-specific fashion. The neo cassette, which was inserted into the last
Cpr intron in r-CL mice, can be deleted by
Cre recombinase, thus returning the structure of the
Cpr gene (and hence
CPR expression) to normal in Cre-expressing cells. All previously identified phenotypes of the CL mice were preserved in the r-CL mice. As a first application of the r-CL model, we have generated an extrahepatic-CL (xh-CL) mouse for testing of the functions of
CPR-dependent
enzymes in all extrahepatic tissues. The xh-CL mice, generated by mating of r-CL mice with
albumin-Cre mice, had normal
CPR expression in hepatocytes but down-regulated
CPR expression elsewhere. They were indistinguishable from wild-type mice in body and liver weights, circulating
cholesterol levels, and hepatic microsomal P450 expression and activities; however, they still showed elevated serum
testosterone and
progesterone levels and
sterility in females. Embryonic lethality was prevented in males, but apparently not in females, indicating a critical role for fetal hepatic
CPR-dependent
enzymes in embryonic development, at least in males.