Gonzalez Frank J, Fang Zhong-Ze, Ma Xiaochao
National Institutes of Health, National Cancer Institute, Center for Cancer Research, Laboratory of Metabolism , Bethesda, MD 20892 , USA +1 301 496 9067 ; +1 301 496 8419 ;
Expert Opin Drug Metab Toxicol. 2015 Jun;11(6):869-81. doi: 10.1517/17425255.2015.1032245. Epub 2015 Apr 2.
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 because there exist marked species differences in the xenobiotic-metabolizing enzymes and the nuclear receptors that regulate these enzymes. Humanized mice expressing CYPs and nuclear receptors including the pregnane X receptor, the major regulator of xenobiotic metabolism and transport were produced. With genetically modified mouse models, metabolomics can determine the metabolic 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: i) comparison of the metabolomics profiles between wild-type and genetically modified mice, and searching for genotype-dependent endogenous metabolites; ii) searching for and elucidating metabolites derived from xenobiotics; and iii) discovery of specific alterations of endogenous compounds induced by xenobiotics-induced toxicity.
基因改造小鼠模型和代谢组学的应用极大地推动了对外源物质代谢和毒性的研究。
基因敲除小鼠可用于确定体内负责外源物质代谢的酶，并研究外源物质诱导毒性的机制。人源化小鼠模型尤为重要，因为在外源物质代谢酶和调节这些酶的核受体方面存在显著的物种差异。已培育出表达细胞色素P450（CYPs）和核受体（包括孕烷X受体，外源物质代谢和转运的主要调节因子）的人源化小鼠。利用基因改造小鼠模型，代谢组学能够以一定的灵敏度确定许多外源物质的代谢图谱，甚至可以发现微量代谢物。这项技术可用于确定外源物质毒性的机制，并寻找毒性的早期生物标志物。
代谢组学和基因改造小鼠模型可通过以下方式用于外源物质代谢和毒性研究：i）比较野生型和基因改造小鼠的代谢组学谱，寻找基因型依赖性内源性代谢物；ii）寻找并阐明外源物质衍生的代谢物；iii）发现外源物质诱导毒性引起的内源性化合物的特定变化。
