Effects of drugs in subtoxic concentrations on the metabolic fluxes in human hepatoma cell line Hep G2

Jens Niklas, Fozia Noor*, Elmar Heinzle

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

44 Citations (Scopus)


Commonly used cytotoxicity assays assess the toxicity of a compound by measuring certain parameters which directly or indirectly correlate to the viability of the cells. However, the effects of a given compound at concentrations considerably below EC50 values are usually not evaluated. These subtoxic effects are difficult to identify but may eventually cause severe and costly long term problems such as idiosyncratic hepatotoxicity. We determined the toxicity of three hepatotoxic compounds, namely amiodarone, diclofenac and tacrine on the human hepatoma cell line Hep G2 using an online kinetic respiration assay and analysed the effects of subtoxic concentrations of these drugs on the cellular metabolism by using metabolic flux analysis. Several changes in the metabolism could be detected upon exposure to subtoxic concentrations of the test compounds. Upon exposure to diclofenac and tacrine an increase in the TCA-cycle activity was observed which could be a signature of an uncoupling of the oxidative phosphorylation. The results indicate that metabolic flux analysis could serve as an invaluable novel tool for the investigation of the effects of drugs. The described methodology enables tracking the toxicity of compounds dynamically using the respiration assay in a range of concentrations and the metabolic flux analysis permits interesting insights into the changes in the central metabolism of the cell upon exposure to drugs.

Original languageEnglish
Pages (from-to)327-336
Number of pages10
JournalToxicology and Applied Pharmacology
Issue number3
Publication statusPublished - 1 Nov 2009
Externally publishedYes


  • HepG2 cells
  • In-vitro assays
  • Metabolic flux analysis
  • Preclinical drug development
  • Respiration
  • Subtoxic effects
  • Toxicity screening


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