Drug induced liver injury is a leading cause of human illness and a major cause of drug withdrawals from the market. A systems biology approach has the potential to aid toxicology research since toxicological responses are a consequence of multiple non-linear and interdependent biological responses. Here such an approach is developed.The glutathione pathway is a key hepatic defence mechanism and deactivates reactive metabolites before they have the chance to damage cellular proteins. However, glutathione availability is limited and can vary between individuals. As hepatic glutathione levels cannot be measured directly, two serum-based biomarkers, i.e. 5-oxoproline and ophthalmic acid, have been proposed in literature as a means of tracking glutathione depletion. This thesis aims to test the reliability of the correlation between biomarker concentration and decreasing glutathione concentration.In this study a spiral between experiments, model predictions and falsifications, model improvement, and experimental design is described. Using this approach a kinetic model of the hepatic glutathione pathway and biomarker metabolism was constructed and subsequently expanded by adding physiologically based pharmacokinetic (PBPK) models of paracetamol and the proposed biomarkers. These models have increased the understanding of the glutathione pathway. For example, the model predicted that Glutamyl-Cysteine Synthetase induction should be a highly effective way to increase the robustness of the liver to a paracetamol challenge.In addition, it was possible to qualify with increasing precision, the correlation between biomarkers and hepatic glutathione depletion. 5-Oxoproline and ophthalmic acid provide different information about the status of the glutathione pathway. 5-Oxoproline is correlated with paracetamol-glutathione conjugate formation, but not with extreme toxicity. Ophthalmic acid is a biomarker of a more advanced stage of toxicity, where the cell is unable to protect against glutathione depletion. However, care must be taken when inferring hepatic glutathione concentration. Both models demonstrate that the sensitivity of biomarkers to exposure of paracetamol, depends on the dynamics of exposure as well as on the concentrations of intracellular metabolites, such as methionine.I discuss how the methodology of biomarker assessment could be personalised with regards to individual patients and how systems toxicology could be further developed towards reliable tools for the pharmaceutical industry.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:568641 |
| Date | January 2013 |
| Creators | Geenen, Suzanne Aleida Birgitta |
| Contributors | Westerhoff, Hans |
| Publisher | University of Manchester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://www.research.manchester.ac.uk/portal/en/theses/systems-biology-approach-to-understanding-hepatic-glutathione-metabolism-and-its-biomarkers-of-depletion(760cb481-d46b-494b-8aba-e8759aec025a).html |
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