A mathematical modelling approach to assessing the reliability of biomarkers of glutathione metabolism

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dc.contributor.authorGeenen S.
dc.contributor.authordu Preez F.B.
dc.contributor.authorReed M.
dc.contributor.authorFrederik Nijhout H.
dc.contributor.authorGerry Kenna J.
dc.contributor.authorWilson I.D.
dc.contributor.authorWesterhoff H.V.
dc.contributor.authorSnoep J.L.
dc.date.accessioned2011-10-13T16:58:11Z
dc.date.available2011-10-13T16:58:11Z
dc.date.issued2011-10-13
dc.description.abstractOne of the main pathways for the detoxification of reactive metabolites in the liver involves glutathione conjugation. Metabolic profiling studies have shown paradoxical responses in glutathione-related biochemical pathways. One of these is the increase in 5-oxoproline and ophthalmic acid concentrations with increased dosage of paracetamol. Experimental studies have thus far failed to resolve these paradoxes and the robustness of how these proposed biomarkers correlate with liver glutathione levels has been questioned. To better understand how these biomarkers behave in the glutathione system a kinetic model of this pathway was made. By using metabolic control analysis and by simulating biomarker levels under a variety of conditions, we found that 5-oxoproline and ophthalmic acid concentrations may not only depend on the glutathione but also on the methionine status of the cell. We show that neither of the two potential biomarkers are reliable on their own since they need additional information about the methionine status of the system to relate them uniquely to intracellular glutathione concentration. However, when both biomarkers are measured simultaneously a direct inference of the glutathione concentration can be made, irrespective of the methionine concentration in the system. © 2011 Elsevier B.V. All rights reserved.
dc.description.versionArticle in Press
dc.identifier.citationEuropean Journal of Pharmaceutical Sciences
dc.identifier.citationhttp://www.scopus.com/inward/record.url?eid=2-s2.0-80052856050&partnerID=40&md5=ab386ce74c59a80296aeb3f38f07e07b
dc.identifier.issn9280987
dc.identifier.other10.1016/j.ejps.2011.08.017
dc.identifier.urihttp://hdl.handle.net/10019.1/16638
dc.subject5-Oxoproline
dc.subjectGlutathione
dc.subjectMetabolic control analysis
dc.subjectOphthalmic acid
dc.subjectParacetamol
dc.titleA mathematical modelling approach to assessing the reliability of biomarkers of glutathione metabolism
dc.typeArticle in Press
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