Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China.
Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M University Health Science Center, Houston, Texas, USA.
Sci Rep. 2017 Feb 20;7:42922. doi: 10.1038/srep42922.
Cytochrome P450 (CYP) 3A accounts for nearly 30% of the total CYP enzymes in the human liver and participates in the metabolism of over 50% of clinical drugs. Moreover, CYP3A plays an important role in chemical metabolism, toxicity, and carcinogenicity. New animal models are needed to investigate CYP3A functions, especially for drug metabolism. In this report, Cyp3a1/2 double knockout (KO) rats were generated by CRISPR-Cas9 technology, and then were characterized for viability and physiological status. The Cyp3a1/2 double KO rats were viable and fertile, and had no obvious physiological abnormities. Compared with the wild-type (WT) rat, Cyp3a1/2 expression was completely absent in the liver of the KO rat. In vitro and in vivo metabolic studies of the CYP3A1/2 substrates indicated that CYP3A1/2 was functionally inactive in double KO rats. The Cyp3a1/2 double KO rat model was successfully generated and characterized. The Cyp3a1/2 KO rats are a novel rodent animal model that will be a powerful tool for the study of the physiological and pharmacological roles of CYP3A, especially in drug and chemical metabolism in vivo.
细胞色素 P450（CYP）3A 约占人类肝脏中总 CYP 酶的 30%，参与超过 50%的临床药物代谢。此外，CYP3A 在化学代谢、毒性和致癌性方面发挥着重要作用。需要新的动物模型来研究 CYP3A 的功能，特别是药物代谢。在本报告中，我们利用 CRISPR-Cas9 技术生成了 Cyp3a1/2 双敲除（KO）大鼠，并对其生存能力和生理状态进行了特征描述。Cyp3a1/2 双 KO 大鼠具有生存能力和繁殖能力，且没有明显的生理异常。与野生型（WT）大鼠相比，KO 大鼠肝脏中 Cyp3a1/2 的表达完全缺失。CYP3A1/2 底物的体外和体内代谢研究表明，CYP3A1/2 在双 KO 大鼠中功能失活。成功构建并鉴定了 Cyp3a1/2 双 KO 大鼠模型。Cyp3a1/2 KO 大鼠是一种新型啮齿动物模型，将成为研究 CYP3A 的生理和药理学作用的有力工具，特别是在体内药物和化学代谢方面。
