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In silico Modeling of Intracellular Diffusion and Reaction of Benzo[a]pyrene Diol Epoxide
KTH, School of Computer Science and Communication (CSC), Numerical Analysis, NA (closed 2012-06-30).
KTH, School of Computer Science and Communication (CSC), Numerical Analysis, NA (closed 2012-06-30).ORCID iD: 0000-0003-4950-6646
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2012 (English)Report (Other academic)
Abstract [en]

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.
Series
TRITA-NA, 2012:3
National Category
Computational Mathematics
Identifiers
URN: urn:nbn:se:kth:diva-93464OAI: oai:DiVA.org:kth-93464DiVA: diva2:516280
Funder
Swedish e‐Science Research Center
Note

QC 20120418

Available from: 2012-04-17 Created: 2012-04-17 Last updated: 2013-04-09Bibliographically approved
In thesis
1. Computational Modeling of Reaction and Diffusion Processes in Mammalian Cell
Open this publication in new window or tab >>Computational Modeling of Reaction and Diffusion Processes in Mammalian Cell
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

PAHs are the reactive toxic chemical compounds which are present as environmental pollutants. These reactive compounds not only diffuse through the membranes of the cell but also partition into the membranes. They react with the DNA of the cell giving rise to toxicity and may cause cancer. To understand the cellular behavior of these foreign compounds, a mathematical model including the reaction-diffusion system and partitioning phenomenon has been developed. In order to reduce the complex structure of the cytoplasm due to the presence of many thin membranes, and to make the model less computationally expensive and numerically treatable, homogenization techniques have been used. The resulting complex system of PDEs generated from the model is implemented in Comsol Multiphysics. The numerical results obtained from the model show a nice agreement with the in vitro cell experimental results. Then the model was reduced to a system of ODEs, a compartment model (CM). The quantitative analysis of the results of the CM shows that it cannot fully capture the features of metabolic system considered in general. Thus the PDE model affords a more realistic representation. In order to see the influence of cell geometry in drug diffusion, the non-spherical axi-symmetric cell geometry is considered, where we showed that the cellular geometry plays an important role in diffusion through the membranes. For further reduction of complexity of the model, another simplified model was developed. In the simplified model, we used PDEs for the extracellular domain, cytoplasm and nucleus, whereas the plasma and nuclear membranes were taken away, and replaced by the membrane flux, using Fick's Law. We further extended the framework of our previously developed model by benchmarking against the results from four different cell lines. Global optimization techniques are used for the parameters describing the diffusion and reaction to fit the measured data. Numerical results were in good agreement with the in vitro results. For the further development of the model, the process of surface bound reactions were added, thus developing a new cell model. The effective equations were derived using iterative homogenization for this model. The numerical results of some of the species were qualitatively verified against the in vitro results found in literature.

Place, publisher, year, edition, pages
Stockholm: KTH Royal Institute of Technology, 2012. xiii, 52 p.
Series
Trita-CSC-A, ISSN 1653-5723 ; 2012:03
National Category
Computational Mathematics
Identifiers
urn:nbn:se:kth:diva-93466 (URN)978-91-7501-315-2 (ISBN)
Public defence
2012-05-15, E2, Lindstedsvägen 3, KTH, Stockholm, 10:00 (English)
Opponent
Supervisors
Note
QC 20120419Available from: 2012-04-19 Created: 2012-04-17 Last updated: 2012-04-19Bibliographically approved

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Hanke, Michael

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