Cited by 164Drug-Induced Hepatotoxicity and ProtectionMetabolomics and Mass Spectrometry StudiesAnimal testing and alternatives

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

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Ramirez, Tzutzuy, Strigun, Alexander, Verlohner, Andreas, Huener, Hans-Albrecht, Peter, Erik, Herold, Michael, Bordag, Natalie, Mellert, Werner, Walk, Tilmann, Spitzer, Michael, Jiang, Xiaoqi, Sperber, Saskia, Hofmann, Thomas, Hartung, Thomas, Kamp, Hennicke, van Ravenzwaay, Ben·2018·Archives of Toxicology

DOI 10.1007/s00204-017-2079-6PMC PMC5818600

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Abstract

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.

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Authors: Ramirez, T., Strigun, A., Verlohner, A., Huener, H.-A., Peter, E., Herold, M., Bordag, N., Mellert, W., Walk, T., Spitzer, M., Jiang, X., Sperber, S., Hofmann, T., Hartung, T., Kamp, H., & van Ravenzwaay, B.
Affiliations: BASF (Germany) (DE)
Corresponding author: Hofmann, Thomas
ORCID: Verlohner, Andreas
Huener, Hans-Albrecht
Herold, Michael
Bordag, Natalie
Walk, Tilmann
Jiang, Xiaoqi
Sperber, Saskia
Hofmann, Thomas
Kamp, Hennicke
Venue: Archives of Toxicology
Publisher: Springer Science and Business Media LLC
Published: 2017-09-30
Volume: 92
Issue: 2
Pages: 893-906
ISSN: 0340-5761 (ISSN-L)
1432-0738
DOI: 10.1007/s00204-017-2079-6
PMC: PMC5818600
OpenAlex: W2759884959
Cited by: 164
References: 39
Citations by year: 2026: 14 · 2025: 13 · 2024: 14 · 2023: 26 · 2022: 25 · 2021: 25 · 2020: 23 · 2019: 13 · 2018: 10 · 2017: 1
FWCI: 13.67
Type: journal article
Language: en
Open access: hybrid
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0 (unspecified)
Locations: Archives of Toxicology (publishedVersion, cc-by)
Europe PMC (PubMed Central) (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
KOPS (University of Konstanz) (submittedVersion, cc-by)
Topics: Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
Keywords: hepatotoxicity, metabolomics, HepG2 cells, in vitro toxicity models, mechanism of action, non-animal alternatives, liver enzyme induction, liver enzyme inhibition, peroxisome proliferation, concentration-dependent effects, intracellular metabolites, mass spectrometry metabolomics
MeSH terms: Animal Testing Alternatives, Enzyme Induction, Humans, Liver, Toxicity Tests, Metabolomics, Metabolome, Hep G2 Cells

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

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