Characterization of novel cytochrome P450 2E1 knockout rat model generated by CRISPR/Cas9.
Characterization of novel cytochrome P450 2E1 knockout rat model generated by CRISPR/Cas9.
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DOI：
10.1016/j.bcp.2016.03.001
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发表时间：
2016-04
影响因子：
5.8
通讯作者：
Xin Wang;Yu Tang;Jian Lu;Yanjiao Shao;Xuan Qin;Yongmei Li;Liren Wang;Dali Li;Mingyao Liu
中科院分区：
文献类型：
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作者：
Xin Wang;Yu Tang;Jian Lu;Yanjiao Shao;Xuan Qin;Yongmei Li;Liren Wang;Dali Li;Mingyao Liu
来自化脓性链球菌的细菌CRISPR相关蛋白-9核酸酶（CRISPR/Cas9）作为编辑靶基因组的新工具产生了相当大的兴奋。细胞色素P450（CYP）2 E1不仅在外源性物质的代谢和化学毒性中起重要作用，而且与酒精性肝病、糖尿病等多种疾病有关。尽管其重要性，很少有动物模型用于预测CYP 2 E1在生理学，病理学以及致癌物活化方面的特性。为了建立一种研究CYP 2 E1在体内功能的新模型，本研究利用CRISPR/Cas9系统成功建立了Cyp 2 e1基因敲除（KO）大鼠模型。Cyp 2 e1基因敲除大鼠能存活并具有生育能力，未显示任何明显的生理异常。KO大鼠中CYP 2 E1表达的缺失也导致CYP 2 E1底物代谢的失活行为。Cyp 2 e1基因敲除大鼠作为一种新型的啮齿类动物模型，为研究CYP 2 E1的化学代谢、毒性、致癌性及其在药物相互作用中的核心作用提供了有力的工具。
A bacterial CRISPR-associated protein-9 nuclease (CRISPR/Cas9) fromStreptococcus pyogeneshas generated considerable excitement as a new tool to edit the targeted genome. Cytochrome P450 (CYP) 2E1 not only plays an important role in the xenobiotic metabolism and chemical toxicity, but also is involved in many kinds of diseases, such as alcoholic liver diseases and diabetes. Despite its importance, few animal models are used to predict CYP2E1 properties in physiology, pathology, as well as carcinogen activation. To establish a novel model for investigating the functions of CYP2E1in vivo, this study has successfully generated theCyp2e1knockout (KO) rat model without detectable off-target effects using CRISPR/Cas9 system. TheCyp2e1KO rats were viable and fertile and did not display any obvious physiological abnormities. The absent expression of CYP2E1 in KO rats also resulted in inactive behaviors in the metabolism of CYP2E1 substrates. TheCyp2e1KO rats as a novel and available rodent animal model provide a powerful tool for the study of CYP2E1 in the chemical metabolism, toxicity, carcinogenicity, and its core factor in drug–drug interactions.