Manchester Centre for Integrative Systems Biology, Manchester Interdisciplinary Biocentre, University of Manchester, Manchester, UK.
Integr Biol (Camb). 2013 Jun;5(6):877-88. doi: 10.1039/c3ib20245c.
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.
抗氧化剂谷胱甘肽的一个主要作用是在肝脏内解毒化学性质活跃的亲电子药物代谢物。因此，谷胱甘肽耗竭可能会产生严重的毒性后果。眼科酸和 5-氧脯氨酸是参与谷胱甘肽代谢的代谢物，它们可以在血液和尿液中轻易测量，并被提议作为肝谷胱甘肽含量的候选生物标志物。然而，目前尚不清楚它们在血浆中的浓度是否与肝谷胱甘肽含量具有很强的相关性。为了探讨这个重要问题，我们开发了一种新方法，该方法结合了对乙酰氨基酚（扑热息痛）代谢和处置的基于生理学的药代动力学（PBPK）模型以及先前开发的肝谷胱甘肽动态平衡的数学系统模型。扑热息痛代谢为活性中间体，当大剂量给予时会耗尽谷胱甘肽并导致毒性。我们的模型正确地预测，扑热息痛给药后肝谷胱甘肽耗竭会导致血液中 5-氧脯氨酸和眼科酸以及尿液中 5-氧脯氨酸的浓度升高。然而，我们还从模型中发现，这两种化合物的浓度可能受到扑热息痛的长期给药以及细胞内代谢物（如蛋氨酸）浓度的影响。我们的结论是，在将这些生物标志物的浓度推断为肝谷胱甘肽状态时，必须谨慎。
