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Metabolomics

, Volume 8, Issue 3, pp 433–443 | Cite as

A high-throughput metabolomics method to predict high concentration cytotoxicity of drugs from low concentration profiles

  • Stéphanie Heux
  • Thomas J. Fuchs
  • Joachim Buhmann
  • Nicola Zamboni
  • Uwe Sauer
Original Article

Abstract

A major source of drug attrition in pharmacological development is drug toxicity, which eventually manifests itself in detrimental physiological effects. These effects can be assessed in large sample cohorts, but generating rich sets of output variables that are necessary to predict toxicity from lower drug dosages is problematic. Currently the throughput of methods that enable multi-parametric cellular readouts over many drugs and large ranges of concentrations is limited. Since metabolism is at the core of drug toxicity, we develop here a high-throughput intracellular metabolomics platform for relative measurement of 50–100 targeted metabolites by flow injection-tandem mass spectrometry. Specifically we focused on central metabolism of the yeast Saccharomyces cerevisiae because potential cytotoxic effects of drugs can be expected to affect this ubiquitous core network. By machine learning based on intracellular metabolite responses to 41 drugs that were administered at seven concentrations over three orders of magnitude, we demonstrate prediction of cytotoxicity in yeast from intracellular metabolome patterns obtained at much lower drug concentrations that exert no physiological toxicity. Furthermore, the 13C-determined intracellular response of metabolic fluxes to drug treatment demonstrates the functional performance of the network to be rather robust, until growth was compromised. Thus we provide evidence that phenotypic robustness to drug challenges is achieved by a flexible make-up of the metabolome.

Keywords

Yeast metabolism Drug enzyme interaction Off-target drug effects Metabolomics Method Machine-learning 

Notes

Acknowledgments

S.H. gratefully acknowledges funding by Marie Curie Intra-European Fellowships (F6P-2005).

Supplementary material

11306_2011_386_MOESM1_ESM.doc (1.7 mb)
Supplementary material 1 (DOC 1787 kb)

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Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Stéphanie Heux
    • 1
    • 3
  • Thomas J. Fuchs
    • 2
    • 3
  • Joachim Buhmann
    • 2
    • 3
  • Nicola Zamboni
    • 1
    • 3
  • Uwe Sauer
    • 1
    • 3
  1. 1.Institute of Molecular Systems BiologyETH ZurichZurichSwitzerland
  2. 2.Department of Computer ScienceETH ZurichZurichSwitzerland
  3. 3.Competence Center for Systems Physiology and Metabolic DiseasesZurichSwitzerland

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