Abstract
Biological organisms are constantly exposed to an immense repertoire of molecules that cover environmental or food-derived molecules and drugs, triggering a continuous flow of stimuli-dependent adaptations. The diversity of these chemicals as well as their concentrations contribute to the multiplicity of induced effects, including activation, stimulation, or inhibition of physiological processes and toxicity. Metabolism, as the foremost phenotype and manifestation of life, has proven to be immensely sensitive and highly adaptive to chemical stimuli. Therefore, studying the effect of endo- or xenobiotics over cellular metabolism delivers valuable knowledge to apprehend potential cellular activity of individual molecules and evaluate their acute or chronic benefits and toxicity. The development of modern metabolomics technologies such as mass spectrometry or nuclear magnetic resonance spectroscopy now offers unprecedented solutions for the rapid and efficient determination of metabolic profiles of cells and more complex biological systems. Combined with the availability of well-established cell culture techniques, these analytical methods appear perfectly suited to determine the biological activity and estimate the positive and negative effects of chemicals in a variety of cell types and models, even at hardly detectable concentrations. Metabolic phenotypes can be estimated from studying intracellular metabolites at homeostasis in vivo, while in vitro cell cultures provide additional access to metabolites exchanged with growth media. This article discusses analytical solutions available for metabolic phenotyping of cell culture metabolism as well as the general metabolomics workflow suitable for testing the biological activity of molecular compounds. We emphasize how metabolic profiling of cell supernatants and intracellular extracts can deliver valuable and complementary insights for evaluating the effects of xenobiotics on cellular metabolism. We note that the concepts and methods discussed primarily for xenobiotics exposure are widely applicable to drug testing in general, including endobiotics that cover active metabolites, nutrients, peptides and proteins, cytokines, hormones, vitamins, etc.
Highlights
At the organism or single-cell levels, biological entities are constantly affected by their environment i.e., the multiple chemical and physical stimuli inducing modulation and adaptation of physiological processes that define the “exposome” [1,2]
We summarize current achievements in cell culture metabolome analyses, with particular focus on analytical techniques, especially opportunities given by nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) and their contribution to metabolic profiling of biological samples, indicating the significance of cell models for the analysis xenobiotics-induced biological effects
Metabolomics has immensely progressed over the last decade, with developments of analytical methods and computational solutions, to offer numerous applications in systems biology for medical research, disease diagnostic, or personalized medicine
Summary
At the organism or single-cell levels, biological entities are constantly affected by their environment i.e., the multiple chemical and physical stimuli inducing modulation and adaptation of physiological processes that define the “exposome” [1,2]. Chemical and signaling processes controlled by low molecular weight compounds, either natural endogenous metabolites or xenobiotics, can be characterized by metabolomic approaches. Metabolites are defined as small compounds of less than 1.5 kDa that belong to a variety of molecular classes such as lipids, carbohydrates, amino acids, nucleotides, or organic acids, which constitute substrates, intermediates, and products of metabolic pathways [3]. Metabolomics plays a key role in this translational omics cascade [6,7], and strives to address the chemical complexity of our environment. Post-drug metabolomic profiles have become a valuable and important predictor of drug effectiveness and possible side effects
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