{"title":"肝细胞内源性过氧化氢代谢的计算模型,GSH 在其中发挥关键作用","authors":"L.M. Bilinsky","doi":"10.1016/j.comtox.2024.100299","DOIUrl":null,"url":null,"abstract":"<div><p>This paper presents an ordinary differential equation (ODE) model of endogenous H<sub>2</sub>O<sub>2</sub> <!-->metabolism in hepatocytes that is unique, at the time of writing, in its ability to accurately compute intracellular H<sub>2</sub>O<sub>2</sub> <!-->concentration during incidents of oxidative stress and in its usefulness for constructing PBPK/PD models for ROS-generating xenobiotics. Versions of the model are presented for rat hepatocytes <em>in vitro</em> and mouse liver <em>in vivo</em>. A generic method is given for using the model to create PBPK/PD models which predict intracellular H<sub>2</sub>O<sub>2</sub> <!-->concentration and oxidative-stress-induced hepatocyte death; these are identifiable from <em>in vitro</em> data sets reporting cell mortality following xenobiotic exposure at various levels. The procedure is demonstrated for the trivalent arsenical dimethylarsinous acid (DMA<sup><em>III</em></sup>), which is produced in liver as part of the arsenic elimination pathway. This is the first model of H<sub>2</sub>O<sub>2</sub> <!-->metabolism in hepatocytes to feature values for the endogenous rates of H<sub>2</sub>O<sub>2</sub> <!-->production by mitochondria and other organelles which are inferred from the physiology literature, and to feature a detailed, realistic treatment of GSH metabolism; the latter is achieved by incorporating a minimal version of Reed and coworkers’ pioneering model of GSH metabolism in liver. Model simulations indicate that critical GSH depletion is the immediate trigger for intracellular H<sub>2</sub>O<sub>2</sub> <!-->rising to concentrations associated with apoptosis (<span><math><mrow><mo>></mo><mn>1</mn><mi>μ</mi><mi>M</mi></mrow></math></span>), that this may only occur hours after the xenobiotic concentration peaks (“delay effect”), that when critical GSH depletion does occur, H<sub>2</sub>O<sub>2</sub> <!-->concentration rises rapidly in a sequence of two boundary layers, characterized by the kinetics of glutathione peroxidase (first boundary layer) and catalase (second boundary layer), and that intracellular H<sub>2</sub>O<sub>2</sub> <!-->concentration <span><math><mrow><mo>></mo><mn>1</mn><mi>μ</mi><mi>M</mi></mrow></math></span> implies critical GSH depletion. There has been speculation that ROS levels in the range associated with apoptosis simply indicate, rather than cause, an apoptotic milieu. Model simulations are consistent with this view. In a result of interest to the wider physiology community, the delay effect is shown to provide a GSH-based mechanism by which cells can distinguish transient elevations in H<sub>2</sub>O<sub>2</sub> <!-->concentration, of use in intracellular signaling, from persistent ones indicative of either pathology or the presence of toxins, the second state of affairs eventually triggering apoptosis.</p></div>","PeriodicalId":37651,"journal":{"name":"Computational Toxicology","volume":null,"pages":null},"PeriodicalIF":3.1000,"publicationDate":"2024-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A computational model of endogenous hydrogen peroxide metabolism in hepatocytes, featuring a critical role for GSH\",\"authors\":\"L.M. Bilinsky\",\"doi\":\"10.1016/j.comtox.2024.100299\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>This paper presents an ordinary differential equation (ODE) model of endogenous H<sub>2</sub>O<sub>2</sub> <!-->metabolism in hepatocytes that is unique, at the time of writing, in its ability to accurately compute intracellular H<sub>2</sub>O<sub>2</sub> <!-->concentration during incidents of oxidative stress and in its usefulness for constructing PBPK/PD models for ROS-generating xenobiotics. Versions of the model are presented for rat hepatocytes <em>in vitro</em> and mouse liver <em>in vivo</em>. A generic method is given for using the model to create PBPK/PD models which predict intracellular H<sub>2</sub>O<sub>2</sub> <!-->concentration and oxidative-stress-induced hepatocyte death; these are identifiable from <em>in vitro</em> data sets reporting cell mortality following xenobiotic exposure at various levels. The procedure is demonstrated for the trivalent arsenical dimethylarsinous acid (DMA<sup><em>III</em></sup>), which is produced in liver as part of the arsenic elimination pathway. This is the first model of H<sub>2</sub>O<sub>2</sub> <!-->metabolism in hepatocytes to feature values for the endogenous rates of H<sub>2</sub>O<sub>2</sub> <!-->production by mitochondria and other organelles which are inferred from the physiology literature, and to feature a detailed, realistic treatment of GSH metabolism; the latter is achieved by incorporating a minimal version of Reed and coworkers’ pioneering model of GSH metabolism in liver. Model simulations indicate that critical GSH depletion is the immediate trigger for intracellular H<sub>2</sub>O<sub>2</sub> <!-->rising to concentrations associated with apoptosis (<span><math><mrow><mo>></mo><mn>1</mn><mi>μ</mi><mi>M</mi></mrow></math></span>), that this may only occur hours after the xenobiotic concentration peaks (“delay effect”), that when critical GSH depletion does occur, H<sub>2</sub>O<sub>2</sub> <!-->concentration rises rapidly in a sequence of two boundary layers, characterized by the kinetics of glutathione peroxidase (first boundary layer) and catalase (second boundary layer), and that intracellular H<sub>2</sub>O<sub>2</sub> <!-->concentration <span><math><mrow><mo>></mo><mn>1</mn><mi>μ</mi><mi>M</mi></mrow></math></span> implies critical GSH depletion. There has been speculation that ROS levels in the range associated with apoptosis simply indicate, rather than cause, an apoptotic milieu. Model simulations are consistent with this view. In a result of interest to the wider physiology community, the delay effect is shown to provide a GSH-based mechanism by which cells can distinguish transient elevations in H<sub>2</sub>O<sub>2</sub> <!-->concentration, of use in intracellular signaling, from persistent ones indicative of either pathology or the presence of toxins, the second state of affairs eventually triggering apoptosis.</p></div>\",\"PeriodicalId\":37651,\"journal\":{\"name\":\"Computational Toxicology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.1000,\"publicationDate\":\"2024-01-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Computational Toxicology\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S246811132400001X\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"TOXICOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Computational Toxicology","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S246811132400001X","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"TOXICOLOGY","Score":null,"Total":0}
A computational model of endogenous hydrogen peroxide metabolism in hepatocytes, featuring a critical role for GSH
This paper presents an ordinary differential equation (ODE) model of endogenous H2O2 metabolism in hepatocytes that is unique, at the time of writing, in its ability to accurately compute intracellular H2O2 concentration during incidents of oxidative stress and in its usefulness for constructing PBPK/PD models for ROS-generating xenobiotics. Versions of the model are presented for rat hepatocytes in vitro and mouse liver in vivo. A generic method is given for using the model to create PBPK/PD models which predict intracellular H2O2 concentration and oxidative-stress-induced hepatocyte death; these are identifiable from in vitro data sets reporting cell mortality following xenobiotic exposure at various levels. The procedure is demonstrated for the trivalent arsenical dimethylarsinous acid (DMAIII), which is produced in liver as part of the arsenic elimination pathway. This is the first model of H2O2 metabolism in hepatocytes to feature values for the endogenous rates of H2O2 production by mitochondria and other organelles which are inferred from the physiology literature, and to feature a detailed, realistic treatment of GSH metabolism; the latter is achieved by incorporating a minimal version of Reed and coworkers’ pioneering model of GSH metabolism in liver. Model simulations indicate that critical GSH depletion is the immediate trigger for intracellular H2O2 rising to concentrations associated with apoptosis (), that this may only occur hours after the xenobiotic concentration peaks (“delay effect”), that when critical GSH depletion does occur, H2O2 concentration rises rapidly in a sequence of two boundary layers, characterized by the kinetics of glutathione peroxidase (first boundary layer) and catalase (second boundary layer), and that intracellular H2O2 concentration implies critical GSH depletion. There has been speculation that ROS levels in the range associated with apoptosis simply indicate, rather than cause, an apoptotic milieu. Model simulations are consistent with this view. In a result of interest to the wider physiology community, the delay effect is shown to provide a GSH-based mechanism by which cells can distinguish transient elevations in H2O2 concentration, of use in intracellular signaling, from persistent ones indicative of either pathology or the presence of toxins, the second state of affairs eventually triggering apoptosis.
期刊介绍:
Computational Toxicology is an international journal publishing computational approaches that assist in the toxicological evaluation of new and existing chemical substances assisting in their safety assessment. -All effects relating to human health and environmental toxicity and fate -Prediction of toxicity, metabolism, fate and physico-chemical properties -The development of models from read-across, (Q)SARs, PBPK, QIVIVE, Multi-Scale Models -Big Data in toxicology: integration, management, analysis -Implementation of models through AOPs, IATA, TTC -Regulatory acceptance of models: evaluation, verification and validation -From metals, to small organic molecules to nanoparticles -Pharmaceuticals, pesticides, foods, cosmetics, fine chemicals -Bringing together the views of industry, regulators, academia, NGOs