Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury.
We have analyzed transcriptomic, proteomic and metabolomic profiles of hepatoma cells cultivated inside a microfluidic biochip with or without acetaminophen (APAP). Without APAP, the results show an adaptive cellular response to the microfluidic environment, leading to the induction of anti-oxidative stress and cytoprotective pathways. In presence of APAP, calcium homeostasis perturbation, lipid peroxidation and cell death are observed. These effects can be attributed to APAP metabolism into its highly reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI). That toxicity pathway was confirmed by the detection of GSH-APAP, the large production of 2-hydroxybutyrate and 3-hydroxybutyrate, and methionine, cystine, and histidine consumption in the treated biochips. Those metabolites have been reported as specific biomarkers of hepatotoxicity and glutathione depletion in the literature. In addition, the integration of the metabolomic, transcriptomic and proteomic collected profiles allowed a more complete reconstruction of the APAP injury pathways. To our knowledge, this work is the first example of a global integration of microfluidic biochip data in toxicity assessment. Our results demonstrate the potential of that new approach to predictive toxicology.
CNRS UMR 6600, Laboratoire de Biomécanique et Bio ingénierie, Université de Technologie de Compiègne, Centre de Recherche de Royallieu, BP20529, F-60205, France.
Jean-Matthieu
JM
Prot
Andrei
A
Bunescu
Bénédicte
B
Elena-Herrmann
Caroline
C
Aninat
Leila Choucha
LC
Snouber
Laurent
L
Griscom
Florence
F
Razan
Frederic Y
FY
Bois
Cécile
C
Legallais
Céline
C
Brochot
Anne
A
Corlu
Marc Emmanuel
ME
Dumas
Eric
E
Leclerc
D000082:Acetaminophen / Q000378:metabolism / Q000633:toxicity*; D018712:Analgesics, Non-Narcotic / Q000378:metabolism / Q000633:toxicity*; D016227:Benzoquinones / Q000378:metabolism / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D019610:Cytoprotection; D020869:Gene Expression Profiling / Q000379:methods; D056945:Hep G2 Cells; D006801:Humans; D007097:Imines / Q000378:metabolism / Q000633:toxicity*; D055432:Metabolomics / Q000379:methods; D046210:Microfluidic Analytical Techniques / Q000379:methods*; D018384:Oxidative Stress; D040901:Proteomics / Q000379:methods
D018712:Analgesics, Non-Narcotic; D016227:Benzoquinones; D007097:Imines; D000082:Acetaminophen; C028473:N-acetyl-4-benzoquinoneimine