A double transgenic mouse model expressing human pregnane X receptor and cytochrome P450 3A4.
A double transgenic mouse model expressing human pregnane X receptor and cytochrome P450 3A4.
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DOI：
10.1124/dmd.108.022723
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发表时间：
2008-12
期刊：
影响因子：
--
通讯作者：
Gonzalez FJ
中科院分区：
文献类型：
--
作者：
Ma X;Cheung C;Krausz KW;Shah YM;Wang T;Idle JR;Gonzalez FJ
细胞色素 P450 3A4 (CYP3A4) 是肝脏中最丰富的人类 P450，参与约 50% 的临床使用药物的代谢。孕烷 X 受体 (PXR) 是核受体超家族的成员，是 CYP3A4 转录的主要激活剂。然而，由于对 PXR 配体反应的物种差异，使用啮齿动物评估 CYP3A4 调节和功能存在问题。表达人 PXR 和 CYP3A4 (TgCYP3A4/hPXR) 的双转基因小鼠的产生将为解决这个问题提供一种方法。在当前的研究中，通过细菌人工染色体转基因在Pxr缺失小鼠中产生了TgCYP3A4/hPXR小鼠模型。在 TgCYP3A4/hPXR 小鼠中，CYP3A4 受到利福平（一种人类特异性 PXR 配体）的强烈诱导，但不受孕烯醇酮 16α-甲腈（一种啮齿类动物特异性 PXR 配体）的强烈诱导。与 CYP3A 表达一致，在用利福平预处理的 TgCYP3A4/hPXR 小鼠中，肝脏 CYP3A 活性增加了约五倍。大多数抗人类免疫缺陷病毒蛋白酶抑制剂是 CYP3A 底物，它们与利福霉素的相互作用是人类免疫缺陷病毒和结核分枝杆菌共同感染患者的主要关注点。通过使用TgCYP3A4/hPXR小鼠，重现了人PXR-CYP3A4介导的利福平-蛋白酶抑制剂相互作用，在用利福平预处理的TgCYP3A4/hPXR小鼠的肝微粒体中，安普那韦、奈非那韦和沙奎那韦的代谢稳定性分别降低了52%、53%和99%。在体内，利福平预处理导致 TgCYP3A4/hPXR 小鼠血清安普那韦浓度-时间曲线下面积减少约 80%。这些结果表明，TgCYP3A4/hPXR 小鼠模型可以作为研究 CYP3A4 体内转录和功能的有用工具。
Cytochrome P450 3A4 (CYP3A4), the most abundant human P450 in liver, participates in the metabolism of ∼50% of clinically used drugs. The pregnane X receptor (PXR), a member of the nuclear receptor superfamily, is the major activator of CYP3A4 transcription. However, due to species differences in response to PXR ligands, it is problematic to use rodents to assess CYP3A4 regulation and function. The generation of double transgenic mice expressing human PXR and CYP3A4 (TgCYP3A4/hPXR) would provide a means to this problem. In the current study, a TgCYP3A4/hPXR mouse model was generated by bacterial artificial chromosome transgenesis in Pxr-null mice. In TgCYP3A4/hPXR mice, CYP3A4 was strongly induced by rifampicin, a human-specific PXR ligand, but not by pregnenolone 16α-carbonitrile, a rodent-specific PXR ligand. Consistent with CYP3A expression, hepatic CYP3A activity increased ∼five-fold in TgCYP3A4/hPXR mice pretreated with rifampicin. Most anti-human immunodeficiency virus protease inhibitors are CYP3A substrates and their interactions with rifamycins are a source of major concern in patients co-infected with human immunodeficiency virus and Mycobacterium tuberculosis. By using TgCYP3A4/hPXR mice, human PXR-CYP3A4 mediated rifampicin-protease inhibitor interactions were recapitulated, as the metabolic stability of amprenavir, nelfinavir, and saquinavir decreased 52%, 53%, and 99% respectively in the liver microsomes of TgCYP3A4/hPXR mice pretreated with rifampicin. In vivo, rifampicin pretreatment resulted in ∼80% decrease in the area under serum amprenavir concentration-time curve in TgCYP3A4/hPXR mice. These results suggest that the TgCYP3A4/hPXR mouse model could serve as a useful tool for studies on CYP3A4 transcription and function in vivo.
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影响因子：
4.9
作者：
Polk, RE;Brophy, DF;Stein, DS
通讯作者：
Stein, DS
影响因子：
5.2
作者：
Ribera, Esteban;Azuaje, Carlos;Pahissa, Albert
通讯作者：
Pahissa, Albert
影响因子：
4.8
作者：
Guo, GL;Lambert, G;Sinal, CJ
通讯作者：
Sinal, CJ
DOI：
10.1124/jpet.105.094367
发表时间：
2006-03-01
影响因子：
3.5
作者：
Cheung, C;Yu, AM;Gonzalez, FJ
通讯作者：
Gonzalez, FJ
影响因子：
2.3
作者：
Crommentuyn, KML;Rosing, H;Beijnen, JH
通讯作者：
Beijnen, JH