Transgenic mice and metabolomics for study of hepatic xenobiotic metabolism and toxicity.
Transgenic mice and metabolomics for study of hepatic xenobiotic metabolism and toxicity.
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DOI：
10.1517/17425255.2015.1032245
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发表时间：
2015-06
影响因子：
4.3
通讯作者：
Ma X
中科院分区：
文献类型：
--
作者：
Gonzalez FJ;Fang ZZ;Ma X
外源性生物质代谢和毒性的研究已大大有助于使用转基因小鼠模型和代谢组学。基因敲除小鼠可用于确定负责外源性物质体内代谢的酶，并研究外源性物质诱导毒性的机制。人源化小鼠模型是特别重要的，因为在外源性物质代谢酶和调节这些酶的核受体中存在显著的物种差异。产生了表达细胞色素P450（CYP）和核受体（包括孕烷X受体（PXR））的人源化小鼠，孕烷X受体是异生物质代谢和转运的主要调节因子。通过转基因小鼠模型，代谢组学可以确定许多外源性物质的分子图谱，其灵敏度甚至可以发现次要代谢物。该技术可用于确定外源性生物毒性的机制和寻找毒性的早期生物标志物。代谢组学和基因修饰小鼠模型可用于研究外源性生物质代谢和毒性：1）比较野生型和基因修饰小鼠的代谢组学特征，寻找基因型依赖的内源性代谢物; 2）寻找和阐明外源性生物质衍生的代谢物; 3）发现外源性生物质诱导的毒性诱导的内源性化合物的特异性改变。
The study of xenobiotic metabolism and toxicity has been greatly aided by the use of genetically-modified mouse models and metabolomics. Gene knockout mice can be used to determine the enzymes responsible for the metabolism of xenobiotics in vivo and to examine the mechanisms of xenobiotic-induced toxicity. Humanized mouse models are especially important since there exist marked species differences in the xenobiotic-metabolizing enzymes and the nuclear receptors that regulate these enzymes. Humanized mice expressing cytochromes P450 (CYPs) and nuclear receptors including the pregnane X receptor (PXR), the major regulator of xenobiotic metabolism and transport were produced. With genetically-modified mouse models, metabolomics can determine the molecular map of many xenobiotics with a level of sensitivity that allows the discovery of even minor metabolites. This technology can be used for determining the mechanism of xenobiotic toxicity and to find early biomarkers for toxicity. Metabolomics and genetically-modified mouse models can be used for the study of xenobiotic metabolism and toxicity by: 1) Comparison of the metabolomics profiles between wild-type and genetically-modified mice, and searching for genotype-dependent endogenous metabolites; 2) Searching for and elucidating metabolites derived from xenobiotics; 3) Discovery of specific alteration of endogenous compounds induced by xenobiotics-induced toxicity.