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Protocols and Applications of Cellular Metabolomics in Safety Studies Using Precision-Cut Tissue Slices and Carbon 13
Gabriel Baverel1, Maha El Hage2, Guy Martin2
1Metabolys Inc., 181 Avenue Jean Jaurès, Lyon, 69007, France. baverel@metabolys.com.
Abstract:
Numerous xenobiotics are toxic to human and animal cells by interacting with their metabolism, but the precise metabolic step affected and the biochemical mechanism behind such a toxicity remain often unknown. In an attempt to reduce the ignorance in this field, we have developed a new approach called cellular metabolomics. This approach, developed in vitro, provides a panoramic view not only of the pathways involved in the metabolism of physiological substrates of any normal or pathological human or animal cell but also of the beneficial and adverse effects of xenobiotics on these metabolic pathways. Unlike many cell lines, precision-cut tissue slices, for which there is a renewed interest, remain metabolically differentiated for at least 24-48 h and allow to study the effect of xenobiotics during short-term and long-term incubations. Cellular metabolomics (or metabolic flux analysis), which combines enzymatic and carbon 13 NMR measurements with mathematical modeling of metabolic pathways, is illustrated in this brief chapter for studying the effect of insulin on glucose metabolism in rat liver precision-cut slices and of valproate on glutamine metabolism in human renal cortical precision-cut slices. The use of very small amounts of test compounds allows to predict their toxic effect and eventually their beneficial effects very early in the research and development processes. Cellular metabolomics is complementary to other omics approaches, but, unlike them, provides functional, mechanistic, and dynamic pieces of information by measuring enzymatic fluxes.
Insights
Cellular metabolomics offers a new way to understand how xenobiotics affect cell metabolism. This approach uses precision-cut tissue slices to reveal toxic and beneficial effects early in research.
Area of Science:
- Biochemistry
- Toxicology
- Cell Biology
Background:
- Xenobiotics can be toxic by disrupting cellular metabolism, but the exact mechanisms are often unknown.
- Understanding these metabolic interactions is crucial for assessing compound safety and efficacy.
- Existing methods may not fully capture the dynamic metabolic effects of xenobiotics in differentiated cells.
Purpose of the Study:
- To introduce and illustrate cellular metabolomics as a novel approach for studying xenobiotic effects on cellular metabolism.
- To provide a comprehensive view of metabolic pathways and xenobiotic interactions in vitro.
- To enable early prediction of toxic and beneficial effects of compounds during research and development.
Main Methods:
- Utilizing precision-cut tissue slices, which maintain metabolic differentiation for 24-48 hours.
- Combining enzymatic measurements and carbon-13 Nuclear Magnetic Resonance (NMR) analysis.
- Applying mathematical modeling for metabolic pathway analysis (metabolic flux analysis).
Main Results:
- Demonstrated the application of cellular metabolomics in studying insulin's effect on glucose metabolism in rat liver slices.
- Showcased its use in analyzing valproate's impact on glutamine metabolism in human renal slices.
- Highlighted the ability to predict compound effects using minimal test compound amounts.
Conclusions:
- Cellular metabolomics provides functional, mechanistic, and dynamic insights into cellular metabolism.
- It is a valuable tool complementary to other omics approaches.
- Enables early-stage assessment of xenobiotic effects, aiding drug discovery and toxicology.
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