Interspecies differences in acetaminophen sensitivity of human, rat, and mouse primary hepatocytes
Interspecies differences in acetaminophen sensitivity of human, rat, and mouse primary hepatocytes
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DOI：
10.1016/j.tiv.2008.02.001
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发表时间：
2008-06-01
影响因子：
3.2
通讯作者：
Vereczkey, Laszlo
中科院分区：
文献类型：
--
作者：
Jemnitz, Katalin;Veres, Zsuzsa;Vereczkey, Laszlo
大多数研究对乙酰氨基酚（APAP）诱导的肝毒性的实验都是以小鼠作为模型物种进行的，正是因为其高度敏感性。虽然在小鼠中很容易引发毒性反应，但这些结果与人类的相关性值得怀疑。在这项研究中，用不断增加浓度的APAP处理人、大鼠和小鼠的原代肝细胞，并通过MTT细胞毒性试验测定细胞活力。在接种后24小时开始用APAP处理24小时后，在细胞活力方面获得了明显的种间差异（在小鼠、大鼠和人肝细胞培养中，EC50分别为3.8 mM、7.6 mM和28.2 mM）。培养时间越长，所有被研究物种的肝细胞抵抗力就越高。在大鼠肝细胞培养中，当在接种后24、48和72小时开始APAP处理时，EC50值分别为6.0 mM、12.5 mM和18.8 mM。尽管N -乙酰苯醌亚胺是APAP的一种次要代谢产物，在每个所研究的物种中，在高APAP浓度下主要由CYP2E1形成，被认为会引发毒性过程，但在不同物种的CYP2E1活性和肝细胞敏感性之间未发现相关性。我们得出结论，APAP过量引起的毒性在很大程度上取决于所应用的动物模型。（c）2008爱思唯尔有限公司。保留所有权利。
Most of the experiments studying acetaminophen (APAP) induced hepatotoxicity were performed using moue as model specie, right because its high sensitivity. While the toxic responses can be called forth easily in mice, the human relevancy of these results is questionable. In this study human, rat, and mouse primary hepatocytes were treated with increasing concentrations of APAP, and cell viability was measured by MTT cytotoxicity assay. Pronounced interspecies differences were obtained in cell viability following 24 h of APAP treatment starting at 24 h after seeding (EC50: 3.8 mM, 7.6 mM, and 28.2 mM, in mouse, rat, and human hepatocyte culture, respectively). The longer time of culturing highly increased the resistance of hepatocytes of all species investigated. In rat hepatocyte culture EC50 values were 6.0 mM, 12.5 mM, and 18.8 mM, when starting APAP treatment after 24, 48, and 72 h of seeding. Although N-acetylbenzoquinoneimine, a minor metabolite of APAP, which is mainly formed by CYP2E1 at high APAP concentration in every species studied, is thought to initiate the toxic processes, no correlation was found between CYP2E1 activities and hepatocyte sensitivity of different species. We conclude that the toxicity induced by APAP overdose highly depends on the animal model applied. (c) 2008 Elsevier Ltd. All rights reserved.