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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >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.
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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.

机译：具有可逆的亚型细胞色素P450还原酶基因的小鼠模型的产生：用于组织特异性还原酶的拯救，以及从整体抑制肝外组织中P450还原酶表达的小鼠模型中获得的见解。

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摘要

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.
机译：最近生成了一种称为Cpr-low（CL）的小鼠模型，其中细胞色素P450还原酶（Cpr）基因的表达被全面下调。 CPR表达降低伴有表型改变，包括胚胎存活率降低，循环胆固醇降低，肝P450表达升高和女性不育（伴有血清睾丸激素和孕酮水平升高）。在本研究中，生成了一种互补的小鼠模型[命名为可逆CL（r-CL）]，其中降低的CPR表达可以以器官特异性方式逆转。可通过Cre重组酶删除插入r-CL小鼠中最后一个Cpr内含子的neo盒，从而使Cre表达细胞中的Cpr基因结构（从而恢复CPR表达）恢复正常。所有先前确定的CL小鼠表型均保留在r-CL小鼠中。作为r-CL模型的首次应用，我们已经生产了肝外CL（xh-CL）小鼠，用于测试所有肝外组织中CPR依赖性酶的功能。通过将r-CL小鼠与白蛋白-Cre小鼠交配而产生的xh-CL小鼠在肝细胞中具有正常的CPR表达，但在其他地方却下调了CPR表达。它们与野生型小鼠的体重和肝重，循环胆固醇水平以及肝微粒体P450的表达和活性没有区别。然而，它们仍然显示出女性的血清睾丸激素和孕激素水平升高以及不育。男性的胚胎致死性得到了预防，但女性并未如此，这表明胎儿肝CPR依赖性酶在胚胎发育中起着至关重要的作用，至少在男性中如此。

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