Accumulating evidence suggests that species differences between mice and humans can compromise drug efficacy studies. In humans, the pharmacological activity of many small molecules is altered by activity of the cytochrome P450 (CYP) system. Humans have eight genes within the CYP1A, CYP2C, CYP2D and CYP3A subfamilies, while mice have 34 genes within the CYP system. These species differences lead to major differences in metabolism between human and mouse drug metabolism, with mice metabolizing drugs more rapidly than humans. A new study in PNAS shows that the use of humanized mice for the CYP system can circumvent the limitations of the mouse models and improve the translation of preclinical drug discovery to humans. To create this model, the researchers replaced 33 mouse CYP genes, together with Pxr and Car genes, with human CYP1A1, CYP1A2, CYP2C9, CYP2D6, CYP3A4, CYP3A7, PXR, and CAR. Humanization of the mice removed species differences in drug metabolism, supporting the use of this new model in early and preclinical drug development.

Original reference: MacLeod A.K. et al. Proc. Natl Acad. Sci. USA 121, e2315069121 (2024)

越来越多的证据表明，小鼠和人类之间的物种差异可能会影响药物功效研究。在人类中，许多小分子的药理活性会因细胞色素 P450 (CYP) 系统的活性而改变。人类在 CYP1A、CYP2C、CYP2D 和 CYP3A 亚家族中有 8 个基因，而小鼠在 CYP 系统中有 34 个基因。这些物种差异导致人类和小鼠药物代谢存在重大差异，小鼠的药物代谢速度比人类更快。PNAS的一项新研究表明，使用 CYP 系统人源化小鼠可以规避小鼠模型的局限性，并改善临床前药物发现向人类的转化。为了创建这个模型，研究人员将 33 个小鼠 CYP 基因以及Pxr和Car基因替换为人类CYP1A1、CYP1A2、CYP2C9、CYP2D6、CYP3A4、CYP3A7、PXR和CAR。小鼠的人源化消除了药物代谢的物种差异，支持这种新模型在早期和临床前药物开发中的使用。

原始参考文献： MacLeod AK et al.过程。国家科学院。科学。美国 121，e2315069121 (2024)