A mathematical modeling approach to assessing the reliabilty of biomarkers of glutathione metabolism.

S. Geenen, F.B. du Preez, M. Reed, H.F. Nijhout, J.G. Kenna, I.D. Wilson, H.V. Westerhoff, J.L. Snoep

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

One 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.
Original languageEnglish
Pages (from-to)233-243
Number of pages11
JournalEuropean Journal of Pharmaceutical Sciences
Volume46
Issue number4
Early online date24 Aug 2011
DOIs
Publication statusPublished - 16 Jul 2012

Bibliographical note

Part of special issue: Modelling for Pharmaceutical Sciences

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