RT Journal Article
SR Electronic
T1 Generation of a Mouse Model with a Reversible Hypomorphic Cytochrome P450 Reductase Gene: Utility for Tissue-Specific Rescue of the Reductase Expression, and Insights from a Resultant Mouse Model with Global Suppression of P450 Reductase Expression in Extrahepatic Tissues
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 69
OP 77
DO 10.1124/jpet.110.167411
VO 334
IS 1
A1 Yuan Wei
A1 Xin Zhou
A1 Cheng Fang
A1 Lei Li
A1 Kerri Kluetzman
A1 Weizhu Yang
A1 Qing-Yu Zhang
A1 Xinxin Ding
YR 2010
UL http://jpet.aspetjournals.org/content/334/1/69.abstract
AB 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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics