Quantitative evaluation of bromodichloromethane metabolism, by recombinant rat and human cytochrome P450s
Quantitative evaluation of bromodichloromethane metabolism, by recombinant rat and human cytochrome P450s
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DOI：
10.1016/s0009-2797(02)00022-4
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发表时间：
2002-05-20
影响因子：
5.1
通讯作者：
Zhao, GY
中科院分区：
文献类型：
--
作者：
Allis, JW;Zhao, GY
我们报告定量估计的参数代谢溴二氯甲烷（BDCM）的重组制剂的肝细胞色素P450（CYP）从大鼠和人类。早期的工作确定CYP 2 E1、CYP 2B 1/2和CYP 1A 2是大鼠肝毒性所必需的活化酶。为了扩展现有的大鼠PBPK模型，包括外推到人类的能力，有必要定量评价这两个物种的主要代谢途径。我们使用上述三种大鼠CYP同工酶以及CYP 2C 11和CYP 3A 1的重组制剂进行了体外实验。已对CYP 2 E1、CYP 1A 2、CYP 2A 6、CYP 2B 6、CYP 2D 6和CYP 3A 4的人重组同工酶进行了类似实验。结果表明，大鼠体内的主要代谢酶是以前鉴定的那些，CYP 2 E1，CYP 2B 1/2和CYP 1A 2。CYP 3A 1也可能具有一定的活性。在人体中，CYP 2 E1、CYP 1A 2和CYP 3A 4显示出显著的活性，CYP 2A 6也可测量地代谢BDCM。在这两个种属中，CYP 2 E1是低K-m同工酶，在两个种属中均发现BDCM的K-m均高于CYP 2 E1。结果似乎与大鼠体内可用数据一致，并与大鼠中BDCM的现有PBPK模型的预测一致。在PBPK模型中包含多种β-淀粉样蛋白同工酶可以提高模型预测BDCM生理分布的能力。评价大鼠和人的代谢参数对于模型扩展到预测对人体的影响至关重要。
We report quantitative estimates of the parameters for metabolism of bromodichloromethane (BDCM) by recombinant preparations of hepatic cytochrome P450s (CYPs) from rat and human. Earlier work identified CYP2E1, CYP2B1/2 and CYP1A2 as activating enzymes necessary for hepatotoxicity in rat. In order to extend an existing PBPK model for rat to include a capability for extrapolation to humans, it is necessary to evaluate quantitatively the principal metabolic pathways in both species. We have conducted in vitro experiments using recombinant preparations of the three rat CYP isoenzymes mentioned above and for CYP2C11 and CYP3A1 as well. Similar experiments have been performed with human recombinant isoenzymes for CYP2E1, CYP1A2, CYP2A6, CYP2B6, CYP2D6 and CYP3A4. Results indicate that the principal metabolizing enzymes in rat are those identified previously, CYP2E1, CYP2B1/2 and CYP1A2. CYP3A1 may also have some activity. In human, CYP2E1, CYP1A2 and CYP3A4 show substantial activity, and CYP2A6 also measurably metabolizes BDCM. In both species, CYP2E1 is the low K-m isoenzyme, with each with a higher K-m for BDCM than CYP2E1, have been identified in both species. The results appear consistent with available in vivo data in rat and with the predictions of the existing PBPK model for BDCM in rat. The inclusion of multiple CYP isoenzymes in the PBPK model may improve the model's ability to predict the physiological distribution of BDCM. Evaluation of the metabolic parameters for rat and human are essential for the model to be extended to predict effects in humans.