Transgenic mice and metabolomics for study of hepatic xenobiotic metabolism and toxicity

• Published in: Expert opinion on drug metabolism & toxicology Vol. 11; no. 6; p. 869
• Main Authors: Gonzalez, Frank J, Fang, Zhong-Ze, Ma, Xiaochao
• Format: Journal Article
• Language: English
• Published: England 01.06.2015
• Subjects: Animals; Humans; Liver - metabolism; Metabolomics - methods; Mice; Mice, Knockout; Mice, Transgenic; Species Specificity; Xenobiotics - metabolism; Xenobiotics - toxicity; metabolomics; genetically modified mice; xenobiotics; UPLC-ESI-QTOFMS; pregnane X receptor; CYP; CYP3A4
• ISSN: 1744-7607
• DOI: 10.1517/17425255.2015.1032245

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.