CYP3A4 and pregnane X receptor humanized mice
CYP3A4 and pregnane X receptor humanized mice
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DOI：
10.1002/jbt.20173
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发表时间：
2007-01-01
影响因子：
3.6
通讯作者：
Gonzalez, Frank J.
中科院分区：
文献类型：
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作者：
Gonzalez, Frank J.
P450的表达和活性存在显著的物种差异。为了建立能够更准确地预测人类药物和致癌物代谢的小鼠模型，正在使用细菌人工染色体(BAC)和P1噬菌体人工染色体(PAC)基因组克隆来制备P450-和异种受体人源化小鼠。在某些情况下，携带人类基因的转基因小鼠与空白小鼠杂交，产生完全人类-1A2 CY，P化的小鼠。表达人细胞色素P1A1和细胞色素P450 A7基因的小鼠分别是第3基因的细胞色素P450 2E1、细胞色素P2136和细胞色素P3A4。对CYP3A4人源化(HCYP3A4)小鼠的研究揭示了该P450的生理功能及其在体内药物代谢中的作用的新信息。在这一小鼠品系中，研究发现，在某些情况下，CYP3A4会改变血清雌激素水平，导致乳汁分泌不足，乳房发育不全导致幼鼠存活率降低。这只hCYP3A4小鼠证实了肠道细胞色素P3A4在口服药物的药代动力学中的重要性。HhCYP3A4小鼠也被用来建立潜在的性别差异的CYP3A4表达的机制(成年女性和成年男性)，这可以解释药物代谢和反应的性别差异。孕烷X受体(PXR)也通过其靶基因包括CYP3A4参与药物代谢的诱导。由于人类和小鼠在配基特异性上存在物种差异，因此产生了一种PXR人源化小鼠(HPXR)，它对人PXR激活剂如利福平有反应，但对啮齿动物激活剂孕酮-16M-碳腈没有反应。
Marked species differences exist in P450 expression and activities. In order to produce mouse models that can be used to more accurately predict human drug and carcinogen metabolism, P450- and xenobiotic receptor humanized mice are being prepared using bacterial artificial chromosomes (BAC) and P1 phage artificial chromosomes (PAC) genomic clones. In some cases, transgenic mice carrying the human genes are bred with null-mice to produce fully human- 1A2 CY, Pized mice. Mice expressing human CYP1A1, d CYP A7 were gen3 CYP2E1, CYP2136, CYP3A4, an erated and characterized. Studies with the CYP3A4humanized (hCYP3A4) mouse line revealed new information on the physiological function of this P450 and its role in drug metabolism in vivo. With this mouse line, CYP3A4, under certain circumstances, was found to alter the serum levels of estrogen resulting in deficient lactation and low pup survival as a result of underdeveloped mammary glands. This hCYP3A4 mouse established the importance of intestinal CYP3A4 in the pharmacokinetics of orally administered drugs. The h hCYP3A4 mice were also used to establish the mechanisms of potential gender differences in CYP3A4 expression (adult female > adult male) that could account or human gender differences in drug metabolism and response. The pregnane X receptor (PXR) is also involved in induction of drug metabolism through its target genes including CYP3A4. Since species differences exist in ligand specificity between human and mice, a PXR-humanized mouse (hPXR) was produced that responds to human PXR activators such as rifampicin but does not respond to the rodent activator pregnenalone 16m-carbonitrile.