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Effects of drugs in subtoxic concentrations on the metabolic fluxes in human hepatoma cell line Hep G2.
Niklas, Jens; Noor, Fozia; Heinzle, Elmar
2009In Toxicology and Applied Pharmacology, 240 (3), p. 327-36
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Keywords :
Amiodarone/pharmacology; Carcinoma, Hepatocellular/metabolism/pathology; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Citric Acid Cycle; Diclofenac/pharmacology; Dimethyl Sulfoxide/pharmacology; Humans; Liver Neoplasms/metabolism/pathology; Oxidative Phosphorylation; Oxygen/metabolism; Pharmaceutical Preparations; Tacrine/pharmacology
Abstract :
[en] 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 EC(50) 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Niklas, Jens
Noor, Fozia ;  Saarland University > Biochemical Engineering
Heinzle, Elmar
External co-authors :
yes
Language :
English
Title :
Effects of drugs in subtoxic concentrations on the metabolic fluxes in human hepatoma cell line Hep G2.
Publication date :
2009
Journal title :
Toxicology and Applied Pharmacology
ISSN :
1096-0333
Publisher :
Elsevier, Atlanta, United States - New York
Volume :
240
Issue :
3
Pages :
327-36
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 13 September 2017

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