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| Content Provider | Royal Society of Chemistry (RSC) |
|---|---|
| Author | Bois, Frederic Y. Wilson, Ian D. Kenna, J. Gerry Yates, James W. T. Westerhoff, Hans V. Geenen, Suzanne |
| Copyright Year | 2013 |
| Abstract | A key role of the antioxidant glutathione is detoxification of chemically reactive electrophilic drug metabolites within the liver. Therefore glutathione depletion can have severe toxic consequences. Ophthalmic acid and 5-oxoproline are metabolites involved in glutathione metabolism, which can be measured readily in the blood and urine and have been proposed as candidate biomarkers of hepatic glutathione content. However, currently it is unclear whether their concentrations in plasma exhibit a robust correlation with hepatic glutathione content. To explore this important question, we have developed a novel approach which combines a physiologically based pharmacokinetic (PBPK) model of metabolism and disposition of paracetamol (acetaminophen) with a previously developed mathematical systems model of hepatic glutathione homeostasis. Paracetamol is metabolised to reactive intermediates which deplete glutathione and cause toxicity when given at high doses. Our model correctly predicted that hepatic glutathione depletion following paracetamol administration resulted in elevated concentrations of 5-oxoproline and ophthalmic acid in blood and of 5-oxoproline in urine. However, we also found from the model that concentrations of both of the compounds were likely to be influenced by prolonged administration of paracetamol and by the concentrations of intracellular metabolites such as methionine. We conclude that care must be taken when extrapolating from concentrations of these biomarkers to hepatic glutathione status. |
| Starting Page | 877 |
| Ending Page | 888 |
| Page Count | 12 |
| File Format | HTM / HTML PDF |
| ISSN | 17579694 |
| Volume Number | 5 |
| Issue Number | 6 |
| Journal | Integrative Biology |
| DOI | 10.1039/c3ib20245c |
| Language | English |
| Publisher | Royal Society of Chemistry |
| Access Restriction | Open |
| Subject Keyword | Antioxidant Glutathione Electrophile Liver Ophthalmic acid Pyroglutamic acid Urine Blood plasma Physiologically based pharmacokinetic modelling Metabolism Paracetamol Homeostasis Acid Methionine |
| Content Type | Text |
| Resource Type | Article |
| Subject | Medicine Biochemistry Biophysics |
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