In silico Modeling of Intracellular Diffusion and Reaction of Benzo[a]pyrene Diol Epoxide
2012 (English)Report (Other academic)
Several studies has suggested that glutathione conjugation of polycyclicaromatic hydrocarbons (PAHs) catalyzed by glutathione transferases (GSTs)are important factors in protecting cells against toxicity and DNA damagederived from these compounds. To further characterize the intracellular dynamicsof PAH DEs and the role of GSTs in protection against DNA damage,we recently developed a PDE model using techniques for mathematicalhomogenization (Dreij K et al. PLoS One 6(8), 2011). In this study, wewanted to further develop our model by benchmarking against results fromfour V79 cell lines; control cells and cells overexpressing human GSTs A1-1, M1-1 and P1-1. We used an approach of global optimization of the parametersdescribing the diffusion and reaction of the ultimate carcinogenic PAHmetabolite benzo[a]pyrene diol epoxide to fit measured values from the fourV79 cell lines. Numerical results concerning the formation of glutathioneconjugates and hydrolysis were in good agreement with results from measurementsin V79 cell culture. Cellular results showed significant protectionby GST expression against formation of DNA adducts with more than 10-fold reduced levels compared to control cells. Results from the model usingglobally optimized parameters showed that the model cannot predict theprotective effects of GSTs. Extending the model to also include effects fromprotein interactions and GST localization showed the same discrepancy. Insummary, the results show that we have an incomplete understanding of theintracellular dynamics of the interaction between BPDE and GST that warrantsfurther investigation and development of the model.
Place, publisher, year, edition, pages
KTH Royal Institute of Technology, 2012. , 28 p.
, TRITA-NA, 2012:3
IdentifiersURN: urn:nbn:se:kth:diva-93464OAI: oai:DiVA.org:kth-93464DiVA: diva2:516280
FunderSwedish e‐Science Research Center
QC 201204182012-04-172012-04-172013-04-09Bibliographically approved