Structure-activity relationships for halobenzene induced cytotoxicity in rat and human hepatoctyes
Structure-activity relationships for halobenzene induced cytotoxicity in rat and human hepatoctyes
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DOI：
10.1016/j.cbi.2006.12.004
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发表时间：
2007-02-20
影响因子：
5.1
通讯作者：
O'Brien, Peter J.
中科院分区：
文献类型：
--
作者：
Chan, Katie;Jensen, Neil S.;O'Brien, Peter J.
卤代苯是一种普遍存在的环境污染物，对啮齿动物和人类都有肝毒性。采用定量构效关系（QSAR）和加速细胞毒性机制筛选（ACMS）技术，研究了对大鼠和人肝细胞中邻苯二酚肝毒性的分子机制。通过将ACMS测定的苯巴比妥（PB）诱导的大鼠肝细胞中12种卤代苯同系物的LC50与体内报道的苯巴比妥诱导的雄性SD大鼠肝毒性相关联，重新评估了分离肝细胞预测体内外源毒性的有效性。高相关性（r(2) = 0.90）证实了肝细胞作为体外毒性试验的“金标准”的应用。衍生qsar以确定在pb诱导的大鼠、正常大鼠和人肝细胞中控制哈苯毒性的物理化学变量。我们发现，在正常大鼠和正常人肝细胞中的毒性与疏水性（log P）、氧化性（E-HOMO，最高分子轨道能量）和根据卤素取代基排列的不对称电荷分布（偶极矩，mu）密切相关。这表明，卤代苯与细胞色素P450的氧化相互作用是毒性的代谢激活途径，并且在两种物种中相似。在铅诱导的大鼠肝细胞中，QSAR衍生发生了变化，其中卤苯毒性与log P和偶极矩密切相关，但与E-HOMO无关。QSAR的变化表明，当CYP2B/3A水平升高时，氧化不再是细胞毒性机制中的限速步骤，证实了CYP450氧化在正常条件下是代谢激活步骤。2006爱思唯尔爱尔兰有限公司版权所有。
Halobenzenes are ubiquitous environmental contaminants, which are hepatotoxic in both rodents and humans. The molecular mechanism of hatobenzene hepatotoxicity was investigated using Quantitative structure-activity relationships (QSAR) and accelerated cytotoxicity mechanism screening (ACMS) techniques in rat and human hepatocytes. The usefulness of isolated hepatocytes for prediciting in vivo xenobiotic toxicity was reassessed by correlating the LC50 of 12 halobenzene congeners in phenobarbital (PB) induced rat hepatocytes in vitro determined by ACMS to the hepatotoxicities reported in vivo in PB-induced male Sprague-Dawely (SD) rats. A high correlation (r(2) = 0.90) confirmed the application of hepatocytes as a "gold standard" for toxicity testing in vitro. QSARs were derived to determine the physico-chemcial variables that govern hatobenzene toxicity in PB-induced rat, normal rat and human hepatocytes. We found that toxicity in normal rat and normal human hepatocytes both strongly correlate with hydrophobicity (log P), ease of oxidation (E-HOMO, energy of the highest molecular orbital) and on the asymmetric charge distribution according to arrangement of halogen substituents (dipole moment, mu). This suggests that halobenzene interaction with cytochrome P450 for oxidation is the metabolic activating path for toxicity and is similar in both species. In PB-induced rat hepatocytes the QSAR derivation is changed, where halobenzene toxicity strongly correlates to log P and dipole moment, but not E-HOMO. The changed QSAR suggests that oxidation is no longer the rate-limiting step in the cytotoxic mechanism when CYP2B/3A levels are increased, confirming CYP450 oxidation as the metabolic activating step under normal conditions. (c) 2006 Elsevier Ireland Ltd. All rights reserved.