Conditional deletion of cytochrome P450 oxidoreductase in the liver and gastrointestinal tract: A new model for studying the functions of the P450 system
Conditional deletion of cytochrome P450 oxidoreductase in the liver and gastrointestinal tract: A new model for studying the functions of the P450 system
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DOI：
10.1124/jpet.107.121780
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发表时间：
2007-07-01
影响因子：
3.5
通讯作者：
Wolf, C. Roland
中科院分区：
文献类型：
--
作者：
Finn, Robert D.;McLaren, Aileen W.;Wolf, C. Roland
我们之前已经描述了一个小鼠模型，其中肝细胞色素P450氧化还原酶（POR）表达被删除，导致肝脏P450功能几乎完全消融[肝P450还原酶缺失（HRN）]。HRN小鼠生长正常，但出现脂肪肝，细胞色素P450水平升高。与肝脏脂质积累相关的是控制脂质稳态的基因表达的显著变化。我们对该模型进行了广泛的描述，并证明了其在药物效率测试、毒性动力学和评估肝脏P450系统在药物代动力学中的作用方面的价值。为了将POR的缺失和P450的失活扩展到其他组织，并开发该模型的实用性，我们利用大鼠细胞色素P450 CYP1A1启动子来驱动Cre重组酶的表达，构建了一种可以在肝脏和胃肠道中有条件地删除POR的小鼠。使用CYP1A1诱导剂四氯二苯并-对二恶英或-萘黄酮可导致肝脏和胃肠道的POR缺失，而使用3-甲基胆蒽可特异性地导致肝脏POR表达缺失。在所有情况下，所得的肝脏表型似乎与HRN模型相同，包括细胞色素P450表达增加。POR的肝脏缺失和P450表达的增加依赖于诱导剂量，单剂量3-甲基胆蒽的POR缺失最大，为研究POR的功能以及评估肝脏和胃肠道P450在药物沉积和化学毒性中的作用提供了有力的方法。
We have previously described a mouse model, where hepatic cytochrome P450 oxidoreductase ( POR) expression has been deleted, resulting in almost complete ablation of hepatic P450 function [ Hepatic P450 Reductase Null ( HRN)]. HRN mice grow normally but develop fatty livers, and they have increased cytochrome P450 levels. Associated with the hepatic lipid accumulation are significant changes in the expression of genes controlling lipid homeostasis. We have characterized this model extensively and demonstrated its value in drug efficiency testing, in toxicokinetics, and in evaluating the role of the hepatic P450 system in drug pharmacokinetics. To extend the deletion of POR, and P450 inactivation, to other tissues, and to develop the utility of this model, we have generated a mouse where POR can be deleted conditionally in the liver and gastrointestinal tract using the rat cytochrome P450 CYP1A1 promoter to drive Cre recombinase expression. Administration of the CYP1A1 inducers tetrachlorodibenzo- p- dioxin or beta-naphthoflavone resulted in both hepatic and gastrointestinal deletion of POR, whereas administration of 3- methylcholanthrene resulted specifically in loss of hepatic POR expression. In all cases, the resulting hepatic phenotype seemed identical to that of the HRN model, including increased cytochrome P450 expression. Hepatic deletion of POR and the subsequent increase in P450 expression were dependent on inducer dose, with maximal POR deletion occurring at a single dose of 3- methylcholanthrene of 40 mg/ kg. This model provides a powerful approach for studying the functions of POR as well as in the evaluation of the role of hepatic and gastrointestinal P450s in drug deposition and chemical toxicity.