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Role of expression of prostaglandin synthases 1 and 2 and leukotriene C4 synthase in aspirin-intolerant asthma: a theoretical study

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Abstract

Altered expressions of the key enzymes in arachidonic acid (AA) metabolism, prostaglandin synthase 1 and 2 and cysteinyl leukotriene C4 synthase, are of importance in understanding aspirin-induced asthma. We propose a mathematical model of AA metabolism and its interaction with non-steroidal anti-inflammatory drugs (NSAIDs). Model simulations depict the impact of modified expressions of the above enzymes on the time dependent synthesis of cysteinyl leukotrienes and anti-inflammatory prostaglandins before and during NSAID exposure in different model states describing healthy humans as well as aspirin-tolerant and -intolerant asthmatics. The results are compared and evaluated with experimental data taken from the literature. Our results identify the decreased expression of prostaglandin H synthase 1 and increased expression of leukotriene C4 synthase as the key elements in AA metabolism that contribute to increased leukotriene C4 and decreased anti-inflammatory prostaglandins after NSAID dosing in aspirin-intolerant patients. On the other hand, the decreased expression of prostaglandin H synthase 2 implies permanently increased leukotriene C4 and lowers the sensitivity to increased drug doses. The model is used for identification of susceptible patient populations for aspirin and ibuprofen, and for identification of critical aspirin doses that might induce bronchoconstriction.

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Acknowledgements

The authors acknowledge financial support from the state budget by the Slovenian Research Agency (Program No. P1-0055).

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Authors and Affiliations

  1. Faculty of Natural Sciences and Mathematics, Faculty of Medicine, Faculty of Health Sciences, University of Maribor, Slomškov trg 15, 2000, Maribor, Slovenia

    A. Dobovišek, A. Fajmut & M. Brumen

  2. Institute Jožef Stefan, Jamova cesta 39, 1000, Ljubljana, Slovenia

    M. Brumen

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  1. A. Dobovišek
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  2. A. Fajmut
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  3. M. Brumen
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Correspondence to A. Dobovišek.

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Dobovišek, A., Fajmut, A. & Brumen, M. Role of expression of prostaglandin synthases 1 and 2 and leukotriene C4 synthase in aspirin-intolerant asthma: a theoretical study. J Pharmacokinet Pharmacodyn 38, 261–278 (2011). https://doi.org/10.1007/s10928-011-9192-6

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  • DOI: https://doi.org/10.1007/s10928-011-9192-6

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