Development of an updated PBPK model for trichloroethylene and metabolites in mice, and its application to discern the role of oxidative metabolism in TCE-induced hepatomegaly
Development of an updated PBPK model for trichloroethylene and metabolites in mice, and its application to discern the role of oxidative metabolism in TCE-induced hepatomegaly
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DOI：
10.1016/j.taap.2009.02.013
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发表时间：
2009-05-01
影响因子：
3.8
通讯作者：
Caldwell, J. C.
中科院分区：
文献类型：
--
作者：
Evans, M. V.;Chiu, W. A.;Caldwell, J. C.
三氯乙烯(TCE)是一种亲脂性溶剂，通过氧化和结合成各种代谢物而迅速被吸收和代谢，这些代谢物对几个内部靶标造成毒性。据报道，啮齿动物在接触三氯乙烯后，肝脏重量增加(肝肿大)发生得很快，在长期接触三氯乙烯后，小鼠也会诱发肝脏肿瘤。使用灌胃和吸入TCE的综合数据集以及接触其两种氧化代谢物(TCA和DCA)的口服数据，结合更新和更准确的生理学药代动力学(PBPK)模型，研究肝脏中TCA的存在是否导致TCE诱导的小鼠肝肿大的问题。更新的PBPK模型被用来帮助辨别代谢物对这一效应的定量贡献。该模型的更新是基于对先前发表的模型的预测进行的详细评估，以及基于小鼠的气体摄取吸入数据的额外初步分析。利用扩展的药代动力学数据库使用贝叶斯方法校准更新后的模型的参数，该数据库包括口服、吸入和静脉注射TCE的研究以及小鼠体内TCE代谢物的研究。从多项研究数据库得出的肝肿大的剂量-反应关系表明，在所研究的剂量范围内，没有观察到TCE和DCA诱导的肝肿大的剂量与反应的比例。使用更新的PBPK模型对TCA的代谢和给药内剂量进行了定量比较。通过TCE暴露模型预测的TCA内剂量(即mg TCA/kg·d)与肝肿大呈线性关系，但这种关系的斜率远大于直接给药的TCA。因此，通过TCE氧化产生的每单位TCA诱导的肝肿大程度大于直接给药的每单位TCA的预期程度，这与TCA单独解释TCE诱导的肝肿大的假设是不一致的。此外，TCE诱导的肝肿大与PBPK模型对总氧化代谢的预测比与TCE在血液中曲线下面积的预测显示出更一致的关系，与氧化代谢物而不是母体化合物诱导的毒性一致。因此，这些结果强烈地表明，除了TCA外，氧化代谢产物在TCE诱导的小鼠肝脏重量变化中是必要的贡献因素。由爱思唯尔公司出版。
Trichloroethylene (TCE) is a lipophilic solvent rapidly absorbed and metabolized via oxidation and conjugation to a variety of metabolites that cause toxicity to several internal targets. Increases in liver weight (hepatomegaly) have been reported to occur quickly in rodents after TCE exposure, with liver tumor induction reported in mice after long-term exposure. An integrated dataset for gavage and inhalation TCE exposure and oral data for exposure to two of its oxidative metabolites (TCA and DCA) was used, in combination with an updated and more accurate physiologically-based pharmacokinetic (PBPK) model, to examine the question as to whether the presence of TCA in the liver is responsible for TCE-induced hepatomegaly in mice. The updated PBPK model was used to help discern the quantitative contribution of metabolites to this effect. The update of the model was based on a detailed evaluation of predictions from previously published models and additional preliminary analyses based on gas uptake inhalation data in mice. The parameters of the updated model were calibrated using Bayesian methods with an expanded pharmacokinetic database consisting of oral, inhalation, and iv studies of TCE administration as well as studies of TCE metabolites in mice. The dose-response relationships for hepatomegaly derived from the multi-study database showed that the proportionality of dose to response for TCE- and DCA-induced hepatomegaly is not observed for administered doses of TCA in the studied range. The updated PBPK model was used to make a quantitative comparison of internal dose of metabolized and administered TCA. While the internal dose of TCA predicted by modeling of TCE exposure (i.e., mg TCA/kg-d) showed a linear relationship with hepatomegaly, the slope of the relationship was much greater than that for directly administered TCA. Thus, the degree of hepatomegaly induced per unit of TCA produced through TCE oxidation is greater than that expected per unit of TCA administered directly, which is inconsistent with the hypothesis that TCA alone accounts for TCE-induced hepatomegaly. In addition, TCE-induced hepatomegaly showed a much more consistent relationship with PBPK model predictions of total oxidative metabolism than with predictions of TCE area-under-the-curve in blood, consistent with toxicity being induced by oxidative metabolites rather than the parent compound. Therefore, these results strongly suggest that oxidative metabolites in addition to TCA are necessary contributors to TCE-induced liver weight changes in mice. Published by Elsevier Inc.