In silico Modeling of Intracellular Diffusion and Reaction of Benzo[a]pyrene Diol Epoxide

Several studies has suggested that glutathione conjugation of polycyclic aromatic hydrocarbons (PAHs) catalyzed by glutathione transferases (GSTs) are important factors in protecting cells against toxicity and DNA damage derived from these compounds. To further characterize the intracellular dynamics of PAH DEs and the role of GSTs in protection against DNA damage, we recently developed a PDE model using techniques for mathematical homogenization (Dreij K et al. PLoS One 6(8), 2011). In this study, we wanted to further develop our model by benchmarking against results from four V79 cell lines; control cells and cells overexpressing human GSTs A11, M1-1 and P1-1. We used an approach of global optimization of the parameters describing the diffusion and reaction of the ultimate carcinogenic PAH metabolite benzo[a]pyrene diol epoxide to fit measured values from the four V79 cell lines. Numerical results concerning the formation of glutathione conjugates and hydrolysis were in good agreement with results from measurements in V79 cell culture. Cellular results showed significant protection by GST expression against formation of DNA adducts with more than 10fold reduced levels compared to control cells. Results from the model using globally optimized parameters showed that the model cannot predict the protective effects of GSTs. Extending the model to also include effects from protein interactions and GST localization showed the same discrepancy. In summary, the results show that we have an incomplete understanding of the intracellular dynamics of the interaction between BPDE and GST that warrants further investigation and development of the model.