<i>In silico</i> cytotoxicity curves reveal impact of drug’s toxicity profile and protein level on survival.

<p>Time course simulations were run for up to 48 hours from steady states belonging to different parameter sets and extracellular drug concentrations ([X_e], set at t₀ = 0 h) as described in Methods. The minimal <i>Fitness</i> values reached in simulations were plotted against [X_e] (colored circles; connected by interpolation curves—see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115533#pone.0115533.s011" target="_blank">S1 Text</a>). Critical concentrations of X’_c and X”_c are constant on all panels with values 1 μM and 100 μM, respectively. Critical concentration of X_c ([X_c,crit]) is indicated on the panels. <b>a</b> Impact of the toxicity of the unmetabolized form of the drug ([X_c,crit]) on <i>in silico</i> cytotoxicity. <i>In silico</i> cytotoxicity curves were plotted for [X_c,crit] values from 0.05 nM to 5 μM. The EC₅₀ value is indicated for [X_c,crit] = 0.5 nM. <b>b</b> Impact of transporter and oxidase levels on <i>in silico</i> cytotoxicity when X_c is more toxic than X’_c ([X_c,crit] = 0.05 nM). <b>c</b> Impact of transporter and oxidase levels on <i>in silico</i> cytotoxicity when X_c is less toxic than X’_c ([X_c,crit] = 5 μM). In panels <b>b</b> and <b>c</b><i>in silico</i> cytotoxicity curves were calculated after setting the transcription rates of ABC₀ or CYP 0.2 or 5 times of its original value (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0115533#pone.0115533.s007" target="_blank">S3 Table</a>) to model lower or higher expression levels.