  In a recent paper, Wilmes et al. demonstrated a qualitative integration of
omics data streams to gain a mechanistic understanding of cyclosporine A
toxicity. One of their major conclusions was that cyclosporine A strongly
activates the nuclear factor (erythroid-derived 2)-like 2 pathway (Nrf2) in
renal proximal tubular epithelial cells exposed in vitro. We pursue here the
analysis of those data with a quantitative integration of omics data with a
differential equation model of the Nrf2 pathway. That was done in two steps:
(i) Modeling the in vitro pharmacokinetics of cyclosporine A (exchange between
cells, culture medium and vial walls) with a minimal distribution model. (ii)
Modeling the time course of omics markers in response to cyclosporine A
exposure at the cell level with a coupled PK-systems biology model. Posterior
statistical distributions of the parameter values were obtained by Markov chain
Monte Carlo sampling. Data were well simulated, and the known in vitro toxic
effect EC50 was well matched by model predictions. The integration of in vitro
pharmacokinetics and systems biology modeling gives us a quantitative insight
into mechanisms of cyclosporine A oxidative-stress induction, and a way to
predict such a stress for a variety of exposure conditions.
