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

Abstract

Introduction: The study of xenobiotic metabolism and toxicity has been greatly aided by the use of genetically modified mouse models and metabolomics.

Areas covered: 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.

Expert opinion: 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.

Keywords:

• CYP
• CYP3A4
• genetically modified mice
• metabolomics
• pregnane X receptor
• UPLC-ESI-QTOFMS
• xenobiotics

Declaration of interest

The authors were supported in part by the National Cancer Institute Intramural Research Program, National Institute of Diabetes and Digestive and Kidney Diseases [DK090305] and the National Institute of Allergy and Infectious Diseases [AI095425]. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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