Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: Application to acetaminophen injury

Jean-Matthieu Prot (1) , Andrei Bunescu (2) , Bénédicte Elena-Herrmann (2) , Caroline Aninat (3) , Leila Choucha Snouber (1) , Laurent Griscom (4) , Florence Razan (4) , Frédéric Y. Bois (5) , Cécile Legallais (1) , Céline Brochot (5) , Anne Corlu (3) , Marc-Emmanuel Dumas (6, 7) , Eric Leclerc (1)

1 BMBI - Biomécanique et Bioingénierie
2 ISA - Centre de RMN à très hauts champs
3 Foie, métabolismes et cancer
4 SATIE - Systèmes et Applications des Technologies de l'Information et de l'Energie
5 INERIS - Institut National de l'Environnement Industriel et des Risques
6 ISA - Institut des Sciences Analytiques
7 Department of Biomolecular Medicine

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.

Keywords: Microfluidic biochip; PDMS; liver tissue engineering; predictive toxicology; acetaminophen; transcriptomic; proteomic; metabolomic; biomarkers identification; SPRAGUE-DAWLEY RATS; DRUG-METABOLISM; TOXICITY; METABONOMICS; MICE; TOOL; HEPATOTOXICITY; NEPHROTOXICITY; PERSPECTIVES; HEPATOCYTES

Domains: Analytical chemistry

Jean-Matthieu Prot, Andrei Bunescu, Bénédicte Elena-Herrmann, Caroline Aninat, Leila Choucha Snouber, et al.. Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: Application to acetaminophen injury. Toxicology and Applied Pharmacology, 2012, 259 (3), pp.270-280. ⟨10.1016/j.taap.2011.12.017⟩. ⟨hal-00699551⟩