Metabonomics in Toxicology: A Review

Robertson, Donald G.

doi:10.1093/toxsci/kfi102

Cited by 486 publications

(349 citation statements)

References 121 publications

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“…In humans, metabolomics has been used mainly in studies focusing on diagnosis of disease [9,11,15,25,32,39,40,56,58], mode of drug/toxin action [4,31,36,42,47], and characterisation of novel foods [10,48]. However, several recent commentary articles have suggested that metabolomics will have great value for nutritional studies [12, 16-20, 38, 62, 65] and thus it is timely to exploit this technology platform to assess dietary exposure.…”

Section: Metabolomics Approaches Applied To Measurement Of Dietary Exmentioning

confidence: 99%

Measurement of dietary exposure: a challenging problem which may be overcome thanks to metabolomics?

et al. 2009

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The diet is an important environmental exposure, and its measurement is an essential component of much health-related research. However, conventional tools for measuring dietary exposure have significant limitations being subject to an unknown degree of misreporting and dependent upon food composition tables to allow estimation of intakes of energy, nutrients and non-nutrient food constituents. In addition, such tools may be inappropriate for use with certain groups of people. As an alternative approach, the recent techniques of metabolite profiling or fingerprinting, which allows simultaneous monitoring of multiple and dynamic components of biological fluids, may provide metabolic signals indicative of food intake. Samples can be analysed through numerous analytical platforms, followed by multivariate data analysis. In humans, metabolomics has been applied successfully in pharmacology, toxicology and medical screening, but nutritional metabolomics is still in its infancy. Biomarkers of a small number of specific foods and nutrients have been developed successfully but less targeted and more high-throughput methods, that do not need prior knowledge of which signals might be discriminatory, and which may allow a more global characterisation of dietary intake, remain to be tested. A proof a principle project (the MEDE Study) is currently underway in our laboratories to test the hypothesis that high-throughput, non-targeted metabolite fingerprinting using flow injection electrospray mass spectrometry can be applied to human biofluids (blood and urine) to characterise dietary exposure in humans.

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Section: Metabolomics Approaches Applied To Measurement Of Dietary Exmentioning

confidence: 99%

Measurement of dietary exposure: a challenging problem which may be overcome thanks to metabolomics?

et al. 2009

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“…Although it is early days, it is gratifying that the kinds of molecule being observed do correlate with what is to be expected consequently, e.g. upon nephrotoxicity or hepatotoxicity [93].…”

Section: Toxicity Analysesmentioning

confidence: 99%

Systems biology, metabolic modelling and metabolomics in drug discovery and development

Kell

2006

Drug Discovery Today

266

163

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Unlike signalling pathways, metabolic networks are subject to strict stoichiometric constraints. Metabolomics amplifies changes in the proteome, and represents more closely the phenotype of an organism. Recent advances enable the production (and computer-readable encoding as SBML) of metabolic network models reconstructed from genome sequences, as well as experimental measurements of much of the metabolome. There is increasing convergence between the number of human metabolites estimated via genomics ( 3000) and the number measured experimentally. It is thus both timely, and now possible, to bring these two approaches together as an integrated (if distributed) whole to help understand the genesis of metabolic biomarkers, the progress of disease, and the modes of action, efficacy, off-target effects and toxicity of pharmaceutical drugs. Systems biology and metabolic modelling in the 21st CenturyAlthough there are many individual definitions, most commentators (including this one [1,2]) take it that systems biology involves an iterative interplay between more or less high-throughput and high-content 'wet' experiments, technology development, theory and computational modelling, and that it is the involvement of computational modelling, in particular, in the process that sets systems biology apart from the more traditional and more reductionist molecular biology. Metabolomics illustrates this amply. There is also the view that the perceived decrease in the effectiveness of the target-based drug discovery process [3][4][5], including the still-high levels of attrition [6], means that we must move towards understanding organisms at something more akin to a whole-system level [7][8][9][10][11].The question then arises as to what part of a system one might first beneficially model? Although there has, unsurprisingly, been considerable interest in modelling the major signalling pathways (e.g. Refs [12,13]), there are several reasons why it is timely to turn our attention to the level of small molecule metabolism, which is the focus of this review. Metabolism is more discriminatingIt has long been known, and proven through the formalism of metabolic control analysis [7,10,[14][15][16], that whereas small changes in the concentrations of enzymes (and the transcripts that encode them) have only small effects on the fluxes through metabolic pathways, they have substantial effects on the concentrations of metabolic intermediates. Because the metabolome (nominally the concentrations of 'all' the metabolites measured in a system of interest [17]) is downstream of the proteome, it is thereby 'amplified' both in theory [18] and in practice [19,20] and represents a more sensitive level of organisation than do the macromolecular 'omes for understanding a complex biological system, and the changes in it that might be occasioned by disease or pharmaceutical intervention [21,22]. Metabolic reconstruction is now mature and timelyAn attractive feature for the purposes of modelling is that metabolism, in contrast to signalling pathways, ...

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“…Until recently, most of the work in metabolomics was focused primarily on clinical or pharmaceutical applications such as drug discovery, drug assessment, clinical toxicology, clinical chemistry, cancer research, or food science and nutrition. [21][22][23][24] Within the past few years, metabolomics has also emerged as a field of increasing interest in the context of doping control. If metabolomics only became possible as a result of recent technological breakthroughs in small molecule separation and identification, the complete workflow includes several steps with as many associated skills from the very initial design of the animal experiment to the practical implementation of the tool through sample preparation, sample fingerprinting, data treatment, and analysis and biomarkers structural elucidation.…”

Section: Introductionmentioning

confidence: 99%

Metabolomics in food analysis: application to the control of forbidden substances

Dervilly

Courant

Chéreau

et al. 2012

Drug Testing and Analysis

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Metabolomics is a science of interest in food analysis to describe and predict properties of food products and processes. It includes the development of analytical methods with the ultimate goal being the identification of so-called 'quality markers', (i.e. sets of metabolites that correlate with, for example, quality, safety, taste, or fragrance of foodstuffs). In turn, these metabolites are influenced by factors as genetic differences of the raw food ingredients (such as animal breed or crop species differences), growth conditions (such as climate, irrigation strategy, or feeding) or production conditions (such as temperature, acidity, or pressure). In cases where the routine-based measurement of a food property faces some limitations such as the lack of knowledge regarding the target compounds to monitor, monitoring based on a limited set of crucial biomarkers is a good alternative, which is of great interest for food safety purposes regarding growth promoting practices. Such an approach may be more efficient than using a classic approach based on a limited set of known metabolites of anabolic compounds. In this context, screening strategies allowing detection of the physiological response resulting from anabolic compound administration are promising approaches to detect their misuse. The global metabolomics workflow implemented for such studies is presented and illustrated through various examples of biological matrices profiling (tissue, blood, urine) and for different classes of anabolic compounds (steroids, b-agonists and somatotropin).

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Metabonomics in Toxicology: A Review

Cited by 486 publications

References 121 publications

Measurement of dietary exposure: a challenging problem which may be overcome thanks to metabolomics?

Measurement of dietary exposure: a challenging problem which may be overcome thanks to metabolomics?

Systems biology, metabolic modelling and metabolomics in drug discovery and development

Metabolomics in food analysis: application to the control of forbidden substances

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