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Protocols and applications of cellular metabolomics in safety studies using precision-cut tissue slices and carbon 13
Gabriel Baverel1, Sophie Renault, Hassan Faiz
1Metabolys Inc, Lyon Cedex, France.
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 often remain 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 physiologic substrates of any normal or pathologic 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 cellular metabonomics), 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 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 metabolic pathway effects and predict compound toxicity early in development.
Area of Science:
- Biochemistry
- Toxicology
- Cell Biology
Background:
- Xenobiotics can be toxic by disrupting cellular metabolism, but the exact mechanisms are often unknown.
- Existing methods have limitations in fully characterizing these metabolic interactions.
- There is a need for advanced techniques to study xenobiotic effects on cellular metabolism.
Purpose of the Study:
- To introduce and validate cellular metabolomics as a novel approach for studying xenobiotic effects on cellular metabolism.
- To demonstrate the utility of precision-cut tissue slices in metabolic research.
- To assess the potential of cellular metabolomics in predicting compound toxicity and efficacy.
Main Methods:
- Development of cellular metabolomics, integrating enzymatic assays, carbon-13 Nuclear Magnetic Resonance (NMR) spectroscopy, and mathematical modeling.
- Utilizing metabolically differentiated, precision-cut tissue slices for in vitro incubations (24-48 hours).
- Application of the approach to study insulin's effect on glucose metabolism in rat liver slices and valproate's effect on glutamine metabolism in human renal slices.
Main Results:
- Cellular metabolomics provides a comprehensive view of metabolic pathways and xenobiotic interactions.
- Precision-cut tissue slices maintain metabolic function, enabling short- and long-term incubation studies.
- The method successfully illustrated metabolic pathway modulation by insulin and valproate.
Conclusions:
- Cellular metabolomics is a powerful, complementary approach to other 'omics' technologies, offering dynamic, functional insights.
- It enables early prediction of toxic and beneficial effects of compounds using minimal test material.
- This technique advances the understanding of xenobiotic-induced metabolic alterations and aids in drug development.
