Different Hepatic Concentrations of Bromobenzene, 1,2-Dibromobenzene, and 1,4-Dibromobenzene in Humanized-Liver Mice Predicted Using Simplified Physiologically Based Pharmacokinetic Models as Putative Markers of Toxicological Potential
Different Hepatic Concentrations of Bromobenzene, 1,2-Dibromobenzene, and 1,4-Dibromobenzene in Humanized-Liver Mice Predicted Using Simplified Physiologically Based Pharmacokinetic Models as Putative Markers of Toxicological Potential
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使用简化的基于生理学的药代动力学模型作为毒理学潜力的假定标志物预测人源化肝小鼠中溴苯、1,2-二溴苯和 1,4-二溴苯的不同肝脏浓度
DOI：
10.1021/acs.chemrestox.0c00387
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发表时间：
2020
影响因子：
4.1
通讯作者：
Yamazaki Hiroshi
中科院分区：
文献类型：
--
作者：
Miura Tomonori;Shimizu Makiko;Uehara Shotaro;Yoshizawa Manae;Nakano Ayane;Yanagi Mayu;Kamiya Yusuke;Murayama Norie;Suemizu Hiroshi;Yamazaki Hiroshi
溴苯是一种工业溶剂，主要对肝脏有毒性。本研究采用简化的生理药代动力学(PBPK)模型预测了人肝小鼠单次口服溴苯及其相关化合物1，2-二溴苯和1，4-二溴苯后的血药浓度。简化的PBPK模型的输出值与大鼠、对照小鼠和人源化肝脏小鼠的血底物浓度的实测值是一致的，合适的输入参数值来自于电子预测和文献，或者通过对测量的血浆底物浓度的拟合来估计。人源化小鼠口服150-250 mg/kg剂量后2 h的单次测定的溴苯和1，4-二溴苯的肝脏浓度，部分证实了预测的人源化肝脏虚拟给药后的时间依赖性浓度。此外，口服溴苯、1，2-二溴苯和1，4-二溴苯后，在人源化肝小鼠血浆中检测到泄漏的人白蛋白mRNA，这是人类肝脏损伤程度的标志。这些结果表明，在使用简化的PBPK模型的虚拟口服剂量后，用剂量学方法确定人源化肝脏小鼠肝脏毒物溴苯、1，2-二溴苯和1，4-二溴苯的组织和/或血液暴露是有用的。利用简化的PBPK模型和人源化小鼠的血浆数据，有可能预测和评估溴苯及其相关化合物对人源化肝小鼠和人类的肝脏毒性。
Bromobenzene is an industrial solvent that elicits toxicity predominantly in the liver. In this study, the hepatic concentrations of bromobenzene and its related compounds 1,2-dibromobenzene and 1,4-dibromobenzene in humanized-liver mice were predicted after single oral administrations by simplified physiologically based pharmacokinetic (PBPK) models that had been set up on experimental plasma concentrations after single oral doses of 100 mg/kg to rats and 100–250 mg/kg to control mice and humanized-liver mice. The output values by simplified PBPK models were consistent with measured blood substrate concentrations in rats, control mice, and humanized-liver mice with suitable input parameter values derived from in silico prediction and the literature or estimated by fitting the measured plasma substrate concentrations. The predicted time-dependent hepatic concentrations after virtual administrations in humanized-liver mice were partly confirmed with single measured hepatic concentrations of bromobenzene and 1,4-dibromobenzene 2 h after oral doses of 150–250 mg/kg to humanized-liver mice. Moreover, leaked human albumin mRNA, a marker of the extent of human hepatic injuries, in humanized-liver mouse plasma was detected after oral administration of bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene. These results suggest that dosimetry approaches for determining tissue and/or blood exposures of hepatic toxicants bromobenzene, 1,2-dibromobenzene, and 1,4-dibromobenzene in humanized-liver mice were useful after virtual oral doses using simplified PBPK models. Using simplified PBPK models and plasma data from humanized-liver mice has potential to predict and evaluate the hepatic toxicity of bromobenzenes and related compounds in humanized-liver mice and in humans.