Use of human-derived liver cell lines for the detection of environmental and dietary genotoxicants;: current state of knowledge
Use of human-derived liver cell lines for the detection of environmental and dietary genotoxicants;: current state of knowledge
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DOI：
10.1016/j.tox.2004.02.008
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发表时间：
2004-05-20
期刊：
影响因子：
4.5
通讯作者：
Majer, BJ
中科院分区：
文献类型：
--
作者：
Knasmüller, S;Mersch-Sundermann, V;Majer, BJ
本文概述了在过去5年中对人肝细胞系HepG2进行的遗传毒性试验的结果。它是1998年早期综述（由Knasmuller等人撰写）的更新。此外，还讨论了一些有关在遗传毒理学中使用人源性肝细胞系的出版物。它们涉及到新终点的建立、新细胞系的发展以及可能出现的陷阱和问题。在过去的几年里，HepG2细胞已经被用于测试各种各样的化合物。最有趣的观察结果是，细胞对多环芳烃高度敏感，并且在许多致癌性真菌毒素中可以看到遗传毒性作用，而在其他体外试验中结果为阴性。致癌金属如砷和镉也会产生阳性结果，而亚硝胺只会产生轻微或阴性结果。对后一种致癌物的低敏感性可能是由于缺乏细胞色素P4502E1，而细胞色素P4502E1可以催化它们的激活。此外，对一些结构不同的合成农药以及生物活性植物成分（“天然农药”）进行了测试，发现其中一些具有遗传毒性。在大多数实验中，微核的形成被用作终点；然而，单细胞凝胶电泳法的应用也越来越广泛。已经构建了几种HepG2的转染细胞系，它们表达的I期酶（如CYP1A1、CYP1A2、CYP2E1等）水平增加；此外，表达人谷胱甘肽- s转移酶的细胞系也变得可用。这些新的克隆可能对研究特定类别的基因毒物和机制研究特别有用。除了HepG2细胞外，还分离出了许多其他人类来源的肝细胞系，但迄今为止还没有遗传毒性实验的数据，只有Hep3B细胞与HepG2细胞进行了比较，发现其总体上敏感度较低。对不同来源的HepG2克隆的研究表明，细胞对基因毒物的敏感性不同；培养基效应和培养时间也可能影响遗传毒性研究的结果。总的来说，结果支持HepG2细胞是基因毒性测试的合适工具的假设。2004爱思唯尔爱尔兰有限公司版权所有。
This article gives an overview of the results of genotoxicity tests, which have been conducted within the last 5 years with the human liver cell line HepG2. It is an update of an earlier review from 1998 (by Knasmuller et al.). In addition, a number of publications are discussed which are relevant for the use of human derived liver cell lines in genetic toxicology. They concern the establishment of new endpoints, the development of new cell lines and possible pitfalls and problems. HepG2 cells have been used to test a wide variety of compounds over the last years. The most interesting observations are that the cells are highly sensitive toward polycyclic aromatic hydrocarbons and that genotoxic effects are seen with a number of carcinogenic mycotoxins, that give negative results in other in vitro assays. Carcinogenic metals such as As and Cd caused positive results as well, whereas only marginal or negative results were seen with nitrosamines. The low sensitivity toward these latter carcinogens is probably due to a lack of cytochrome P4502E1 which catalyses their activation. Also, a number of structurally different synthetic pesticides as well as bioactive plant constituents ("natural pesticides") have been tested and with some of them genotoxic effects were found. In most experiments, the formation of micronuclei was used as an endpoint; however also the single cell gel electrophoresis assay is increasingly used. Several transfectant lines of HepG2 have been constructed which express increased levels of phase I enzymes (such as CYP1A1, CYP1A2, CYP2E1 etc.); furthermore, cell lines became available which express human glutathione-S-transferases. These new clones might be particularly useful for the investigation of specific classes of genotoxicants and also for mechanistic studies. Apart from HepG2 cells, a number of other human derived liver cell lines have been isolated, but so far no data from genotoxicity experiments are available, except for Hep3B cells, which were compared with HepG2 and found to be less sensitive in general. Studies with HepG2 clones of a different origin indicate that the cells differ in regard to their sensitivity toward genotoxicants; also medium effects and the cultivation time might affect the outcome of genotoxicity studies. Overall, the results support the assumption that HepG2 cells are a suitable tool for genotoxicity testing. (C) 2004 Elsevier Ireland Ltd. All rights reserved.