Snouber, et al.. Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: Application to acetaminophen injury. Toxicology and Applied Pharmacology, Elsevier, 2012, 259 (3) ABSTRACTWe -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 profiles collected 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.
We used the recently introduced "metabolomics-on-a-chip" approach to test secondary drug toxicity in bioartificial organs. Bioartificial organs cultivated in microfluidic culture conditions provide a beneficial environment, in which the cellular cytoprotective mechanisms are enhanced, compared with Petri dish culture conditions. We investigated the metabolic response of HepG2/C3a cells exposed to flutamide, an anticancer prodrug, and hydroxyflutamide (HF), its active metabolite, in a microfluidic biochip. The cellular response was analyzed by (1)H nuclear magnetic resonance spectroscopy to identify cell-specific molecule-response markers. The metabolic response to flutamide results in a disruption of glucose homeostasis and in mitochondrial dysfunctions. This flutamide-specific metabolic response was illustrated by a reduction of the extracellular glucose and fructose consumptions and a general reduction of the tricarboxylic acid cycle activity leading to the reduction of the consumption of several amino acids. We also found a higher production of 3-hydroxybutyrate and lactate, and the reduction of the albumin production compared with controls. The toxic metabolic signature associated with the active metabolite HF was illustrated by a high-energy demand and an increase in several amino acid metabolism. Finally, for both molecules, the hepatotoxicity was correlated to the glutathione (GSH) metabolism illustrated by the levels of the 2-hydroxybutyrate and pyroglutamate productions and the increase of the glutamate and glycine productions. Thus, the entire set of results contributed to extract specific mechanistic toxic signatures and their relation to hepatotoxicity, which appeared consistent with literature reports. As new finding of HepG2/C3a cells hepatotoxicity, we propose a metabolic network with a related list of metabolite variations to describe the GSH depletion when followed by a cell death for the HepG2/C3a cells cultivated in our polydimethylsiloxane microfluidic biochips. Our findings illustrate the potential of metabolomics-on-a-chip as an in vitro alternative method for predictive toxicology.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.