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Understanding 'Global' Systems Biology: Metabonomics and the Continuum of Metabolism

Nature Reviews Drug Discovery volume 2, pages 668–676 (2003)Cite this article

Abstract

To apply genomic knowledge effectively in drug discovery, mechanistic connectivities between genetic variation and disease processes need to be established via systems biology approaches. Humans have hundreds of functionally specialized cell types that interact differentially with environmental factors to influence disease development and to modulate the effects of drugs. Metabonomics can provide a means of modelling these interactions, but the relationships between 'endogenous' metabolic processes (coded in the genome and intrinsic to cellular function) and 'xenobiotic' (foreign compound) metabolism are poorly understood, especially with respect to environmental factors. We present an overview of 'global' mammalian metabolic conversions that should be accounted for in human systems biology models and propose a new probabilistic approach to help understand gene–disease relationships and vexed issues of idiosyncratic drug toxicity.

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Figure 1: Mammalian system–microbial–nutritional–xenobiotic interactions.
Figure 2: Three common examples of sym-xenobiotic metabolism occuring in mammals.
Figure 3: Possible interactions between diet, gut microfloral composition, parasites and gut structure and the influence of drugs.
Figure 4: The dynamic Pachinko model of metabolism.
Figure 5: Visualizing metabolic space and influence vectors.

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Acknowledgements

We thank the BBSRC, EPSRC, The Wellcome Trust and NIH and the COMET consortium for funding this and related work. We also thank Professors John Lindon, Paul Elliot and James Scott, FRS, Drs Elaine Holmes, Paul Carmichael, George Tranter, Mary Bollard, Hector Keun, Olaf Boeckoenert, Tim Ebbels, Henrik Antti and Steve Mitchell (Imperial College), Dr Istvan Peltzer, Dr Yueurg Utzinger and Professor Burt Singer (Princeton University), Professor Jeremy Everett (Pfizer Global Research, UK) and Dr Felicity Nicholson for their helpful comments and discussion on this work and related subjects.

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Authors and Affiliations

  1. Biomedical Sciences Division, Biological Chemistry, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington, London, SW7 2AZ, UK

    Jeremy K. Nicholson

  2. Department of Drug Metabolism and Pharmacokinetics, AstraZeneca, Mereside, Alderley Park, Macclesfield, SK10 4TG, Cheshire, UK

    Ian D. Wilson

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Correspondence to Jeremy K. Nicholson.

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DATABASES

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CYP2E1

FURTHER INFORMATION

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Glossary

ENDOGENOUS METABOLISM

Metabolic conversions under direct host cell genome/proteome control or under mitochondrial control, for example, all major energy-generating pathways and biosynthetic routes.

METABOLOMICS

The measurement of metabolite concentrations and fluxes and secretions in cells and tissues in which there is a direct connection between the genetic activity (gene expression), protein activity (proteome) and the metabolic activity itself.

METABOLOME

The full set of metabolites within, or that can be secreted by, a given cell type of tissue.

METABONOMICS

The quantitative measurement of the multivariate metabolic responses of multicellular systems to pathophysiological stimuli or genetic modification5,6. An approach to understanding global metabolic regulation of organism and its commensal and symbiotic partners.

METABONOME

The sum of the cellular metabolomes in a multi-cellular organism and their interaction components plus the products of facile chemical transformations and extra-genomically generated metabolites.

METABONATE

A compound that is produced by a facile chemical rearrangement or reaction within an organism, that can be excreted or further metabolized.

SYM-ENDOGENOUS

Processes or compounds that are essential to host biological function and which can be metabolized or further utilized by host, but for which there is no biosynthetic capability in the host genome, for example, vitamins and essential amino acids.

SYM-XENOBIOTIC

Metabolites or processes involving co-metabolism by two or more organisms that are commensal or symbiotic (for example, bile acid metabolism). Not necessarily essential to the host, but can influence endogenous or other xenobiotic metabolic processes.

TRANS-XENOBIOTIC

Compounds of extra-genomic or chemical origin but which are metabolically converted to endogenous species or metabolites that can be utilized directly in endogenous processes, for example, ethanol.

XENOBIOTIC

A compound that is foreign to the endogenous process and has no intrinsic biological function but which can have major effects on endogenous pathway control and can be extensively metabolized by complexes of host enzymic systems that have collectively relatively low substrate specificities.

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Nicholson, J., Wilson, I. Understanding 'Global' Systems Biology: Metabonomics and the Continuum of Metabolism. Nat Rev Drug Discov 2, 668–676 (2003). https://doi.org/10.1038/nrd1157

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