Interindividual variability in DNA damage response (DDR) dynamics may evoke differences in susceptibility to cancer. However, pathway dynamics are often studied in cell lines as alternative to primary cells, disregarding variability. To compare DDR dynamics in the cell line HepG2 with primary human hepatocytes (PHHs), we developed a HepG2-based computational model that describes the dynamics of DDR regulator p53 and targets MDM2, p21 and BTG2. We used this model to generate simulations of virtual PHHs and compared the results to those for PHH donor samples. Correlations between baseline p53 and p21 or BTG2 mRNA expression in the absence and presence of DNA damage for HepG2-derived virtual samples matched the moderately positive correlations observed for 50 PHH donor samples, but not the negative correlations between p53 and its inhibitor MDM2. Model parameter manipulation that affected p53 or MDM2 dynamics was not sufficient to accurately explain the negative correlation between these genes. Thus, extrapolation from HepG2 to PHH can be done for some DDR elements, yet our analysis also reveals a knowledge gap within p53 pathway regulation, which makes such extrapolation inaccurate for the regulator MDM2. This illustrates the relevance of studying pathway dynamics in addition to gene expression comparisons to allow reliable translation of cellular responses from cell lines to primary cells. Overall, with our approach we show that dynamical modeling can be used to improve our understanding of the sources of interindividual variability of pathway dynamics.

In high dosages, acetaminophen (APAP) can cause severe liver damage, but susceptibility to liver failure varies across individuals and is influenced by factors such as health status. Because APAP-induced liver injury and recovery is regulated by an intricate system of intra- and extracellular molecular signaling, we here aim to quantify the importance of specific modules in determining the outcome after an APAP insult and of potential targets for therapies that mitigate adversity. For this purpose, we integrated hepatocellular acetaminophen metabolism, DNA damage response induction and cell fate into a multiscale mechanistic liver lobule model which involves various cell types, such as hepatocytes, residential Kupffer cells and macrophages. Our model simulations show that zonal differences in metabolism and detoxification efficiency are essential determinants of necrotic damage. Moreover, the extent of senescence, which is regulated by intracellular processes and triggered by extracellular signaling, influences the potential to recover. In silico therapies at early and late time points after APAP insult indicated that prevention of necrotic damage is most beneficial for recovery, whereas interference with regulation of senescence promotes regeneration in a less pronounced way.