A semi-mechanistic integrated toxicokinetic-toxicodynamic (TK/TD) model for arsenic(III) in hepatocytes.
BACKGROUND
A systems engineering approach is presented for describing the kinetics and dynamics that are elicited upon arsenic exposure of human hepatocytes. The mathematical model proposed here tracks the cellular reaction network of inorganic and organic arsenic compounds present in the hepatocyte and analyzes the production of toxicologically potent by-products and the signaling they induce in hepatocytes.


RESULTS
The present modeling effort integrates for the first time a cellular-level semi-mechanistic toxicokinetic (TK) model of arsenic in human hepatocytes with a cellular-level toxicodynamic (TD) model describing the arsenic-induced reactive oxygen species (ROS) burst, the antioxidant response, and the oxidative DNA damage repair process. The antioxidant response mechanism is described based on the Keap1-independent Nuclear Factor-erythroid 2-related factor 2 (Nrf2) signaling cascade and accounts for the upregulation of detoxifying enzymes. The ROS-induced DNA damage is simulated by coupling the TK/TD formulation with a model describing the multistep pathway of oxidative DNA repair. The predictions of the model are assessed against experimental data of arsenite-induced genotoxic damage to human hepatocytes; thereby capturing in silico the mode of the experimental dose-response curve.


CONCLUSIONS
The integrated cellular-level TK/TD model presented here provides significant insight into the underlying regulatory mechanism of Nrf2-regulated antioxidant response due to arsenic exposure. While computational simulations are in a fair good agreement with relevant experimental data, further analysis of the system unravels the role of a dynamic interplay among the feedback loops of the system in controlling the ROS upregulation and DNA damage response. This TK/TD framework that uses arsenic as an example can be further extended to other toxic or pharmaceutical agents.
Environmental and Occupational Health Sciences Institute (EOHSI) A Joint Institute of UMDNJ-Robert Wood Johnson Medical School and Rutgers University, 170 Frelinghuysen Road, Piscataway, NJ 08854, USA. spyros@jhu.edu
Spyros K
SK
Stamatelos
Ioannis P
IP
Androulakis
Ah-Ng Tony
AN
Kong
Panos G
PG
Georgopoulos
D001151:Arsenic / Q000493:pharmacokinetics* / Q000633:toxicity*; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D025461:Feedback, Physiological / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D008780:Methyltransferases / Q000378:metabolism; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors
D016328:NF-kappa B; D017382:Reactive Oxygen Species; D008780:Methyltransferases; C505756:AS3MT protein, human; D005721:Glutamate-Cysteine Ligase; D001151:Arsenic