Journal
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 46, Issue 4, Pages 233-243Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ejps.2011.08.017
Keywords
Glutathione; Ophthalmic acid; 5-Oxoproline; Paracetamol; Metabolic control analysis
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Funding
- Biotechnology and Biological Sciences Research Council [BBC0082191, BBD0190791, BBG53 02251, BBF0035521, BB/C008219/1, BBF0035361, BBF0035281] Funding Source: Medline
- Biotechnology and Biological Sciences Research Council [BB/C008219/1] Funding Source: researchfish
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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. (C) 2011 Elsevier By. All rights reserved.
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