Prediction of liver toxicity and mode of action using metabolomics in vitro in HepG2 cells

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2018
Autor:innen
Ramirez, Tzutzuy
Strigun, Alexander
Verlohner, Andreas
Huener, Hans-Albrecht
Peter, Erik
Herold, Michael
Bordag, Natalie
Mellert, Werner
Walk, Tilmann
Spitzer, Michael
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Published
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Archives of toxicology. 2018, 92(2), pp. 893-906. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-017-2079-6
Zusammenfassung

Liver toxicity is a leading systemic toxicity of drugs and chemicals demanding more human-relevant, high throughput, cost effective in vitro solutions. In addition to contributing to animal welfare, in vitro techniques facilitate exploring and understanding the molecular mechanisms underlying toxicity. New 'omics technologies can provide comprehensive information on the toxicological mode of action of compounds, as well as quantitative information about the multi-parametric metabolic response of cellular systems in normal and patho-physiological conditions. Here, we combined mass-spectroscopy metabolomics with an in vitro liver toxicity model. Metabolite profiles of HepG2 cells treated with 35 test substances resulted in 1114 cell supernatants and 3556 intracellular samples analyzed by metabolomics. Control samples showed relative standard deviations of about 10-15%, while the technical replicates were at 5-10%. Importantly, this procedure revealed concentration-response effects and patterns of metabolome changes that are consistent for different liver toxicity mechanisms (liver enzyme induction/inhibition, liver toxicity and peroxisome proliferation). Our findings provide evidence that identifying organ toxicity can be achieved in a robust, reliable, human-relevant system, representing a non-animal alternative for systemic toxicology.

Zusammenfassung in einer weiteren Sprache
Fachgebiet (DDC)
570 Biowissenschaften, Biologie
Schlagwörter
Metabolomics; Liver toxicity; In vitro; HepG2 cells
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ISO 690RAMIREZ, Tzutzuy, Alexander STRIGUN, Andreas VERLOHNER, Hans-Albrecht HUENER, Erik PETER, Michael HEROLD, Natalie BORDAG, Werner MELLERT, Tilmann WALK, Michael SPITZER, Thomas HOFMANN, Thomas HARTUNG, 2018. Prediction of liver toxicity and mode of action using metabolomics in vitro in HepG2 cells. In: Archives of toxicology. 2018, 92(2), pp. 893-906. ISSN 0340-5761. eISSN 1432-0738. Available under: doi: 10.1007/s00204-017-2079-6
BibTex
@article{Ramirez2018Predi-41990,
  year={2018},
  doi={10.1007/s00204-017-2079-6},
  title={Prediction of liver toxicity and mode of action using metabolomics in vitro in HepG2 cells},
  number={2},
  volume={92},
  issn={0340-5761},
  journal={Archives of toxicology},
  pages={893--906},
  author={Ramirez, Tzutzuy and Strigun, Alexander and Verlohner, Andreas and Huener, Hans-Albrecht and Peter, Erik and Herold, Michael and Bordag, Natalie and Mellert, Werner and Walk, Tilmann and Spitzer, Michael and Hofmann, Thomas and Hartung, Thomas}
}
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