title: Integration of pharmacokinetic and NRF2 system biology models to describe reactive oxygen species production and subsequent glutathione depletion in liver microfluidic biochips after flutamide exposure.
abstract: We present a systems biology analysis of rat primary hepatocytes response after exposure to 10 μM and 100 μM flutamide in liver microfluidic biochips. We coupled an in vitro pharmacokinetic (PK) model of flutamide to a system biology model of its reactive oxygen species (ROS) production and scavenging by the Nrf2 regulated glutathione production. The PK model was calibrated using data on flutamide kinetics, hydroxyflutamide and glutathione conjugates formation in microfluidic conditions. The parameters of Nrf2-related gene activities and the subsequent glutathione depletion were calibrated using microarray data from our microfluidic experiments and literature information. Following a 10 μM flutamide exposure, the model predicted a recovery time to baseline levels of glutathione (GSH) and ROS in agreement with our experimental observations. At 100 μM, the model predicted that metabolism saturation led to an important accumulation of flutamide in cells, a high ROS production and complete GSH depletion. The high levels of ROS predicted were consistent with the necrotic switch observed by transcriptomics, and the high cell mortality we had experimentally observed. The model predicted a transition between recoverable GSH depletion and deep GSH depletion at about 12.5 μM of flutamide (single perfusion exposure). Our work shows that in vitro biochip experiments can provide supporting information for complex in silico modeling including data from extra cellular and intra cellular levels. We believe that this approach can be an efficient strategy for a global integrated methodology in predictive toxicology.
authors.affiliation: CNRS UMR 7338, Laboratoire de Biomécanique et Bioingénierie, Université de Technologie de Compiègne, France. Electronic address: eric.leclerc@utc.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Leclerc
authors.affiliation: CNRS UMR 7338, Laboratoire de Biomécanique et Bioingénierie, Université de Technologie de Compiègne, France; Chair of Mathematical Modeling for Systems Toxicology, Université de Technologie de Compiègne, Centre de Recherche de Royallieu, 60205 Compiègne Cedex, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Hamon
authors.affiliation: CNRS UMR 7338, Laboratoire de Biomécanique et Bioingénierie, Université de Technologie de Compiègne, France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Legendre
authors.affiliation: Chair of Mathematical Modeling for Systems Toxicology, Université de Technologie de Compiègne, Centre de Recherche de Royallieu, 60205 Compiègne Cedex, France; INERIS/DRC/VIVA/METO, Verneuil en Halatte, France.
authors.forename: Frederic Y
authors.initials: FY
authors.lastname: Bois
mesh_terms: D000726:Androgen Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D019149:Bioreactors; D002478:Cells, Cultured; D005485:Flutamide / Q000493:pharmacokinetics / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D044085:Microfluidics; D008954:Models, Biological; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism*; D049490:Systems Biology
chemical_list: D000726:Androgen Antagonists; D051267:NF-E2-Related Factor 2; C495637:Nfe2l2 protein, rat; D017382:Reactive Oxygen Species; D005485:Flutamide; D005978:Glutathione
keywords: Flutamide; Hepatocytes; Microfluidic biochips; Nrf2 systems biology modeling; Pharmacokinetic modeling