Physiological model for tissue glutathione depletion and increased resynthesis after ethylene dichloride exposure.
Physiological model for tissue glutathione depletion and increased resynthesis after ethylene dichloride exposure.
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发表时间：
1988-05
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通讯作者：
R. W. D'souza;W. R. Francis;M. Andersen
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作者：
R. W. D'souza;W. R. Francis;M. Andersen
二氯乙烷（EDC）通过两种竞争途径代谢，这两种途径都消耗谷胱甘肽（GSH）。EDC经过氧化形成氯乙醛（CAA），氯乙醛（CAA）被GSH解毒，并直接与GSH反应形成2-（s-氯乙基）-GSH。一个生理药代动力学模型开发的EDC扩展到描述组织GSH周转和EDC暴露后的消耗。由于EDC代谢受GSH状态的影响，因此GSH模型对于跟踪GSH浓度随时间的变化是必要的。GSH与EDC和GSH与CAA的反应被定义为二级反应。稳态GSH的形成被建模为零阶和GSH损失为一阶。GSH反弹后，其耗尽的影响是由GSH合成酶反应，这使得时间和GSH浓度依赖性的反馈增加GSH再合成控制。该模型是针对大鼠肝脏GSH开发的，并外推至包括肺。异速生长标度被用来外推模型到其他动物物种。大鼠和小鼠的实验观察结果与模型预测一致。
Ethylene dichloride (EDC) is metabolized by two competing pathways both of which consume glutathione (GSH). EDC undergoes oxidation to form chloroacetaldehyde (CAA) which is detoxified by GSH and also reacts directly with GSH to form 2-(s-chloroethyl)-GSH. A physiological pharmacokinetic model developed for EDC was extended to describe tissue GSH turnover and its depletion after EDC exposures. This GSH model was necessary to keep track of GSH concentrations with time, as EDC metabolism is affected by GSH status. Reactions of GSH with EDC and GSH with CAA were defined as second-order. Steady-state GSH formation was modeled as zero-order and GSH loss as first-order. GSH rebound effects after its depletion were controlled by a GSH synthetase reaction, which allowed time- and GSH concentration-dependent feedback for increased GSH resynthesis. The model was developed for liver GSH in the rat and was extrapolated to include the lung. Allometric scaling was used to extrapolate the model to other animal species. Experimental observations in the rat and mouse were consistent with model predictions.