Department of Toxicogenomics, Maastricht University, Universiteitssingel 50, 6229 ER Maastricht, The Netherlands.
Toxicol In Vitro. 2013 Oct;27(7):2031-40. doi: 10.1016/j.tiv.2013.07.010. Epub 2013 Jul 31.
Efforts are put into developing toxicogenomics-based toxicity testing methods using in vitro human cell models for improving human risk assessment/replacing animal models. Human in vitro liver models include HepG2, HepaRG and primary human hepatocytes (PHH). Studies on comparability/applicability of these cell types mainly focus on assessing baseline biotransformation capacities/cytochrome P450-inducibility, but compound-induced gene expression profiles are at least as important. Therefore, we compared baseline and aflatoxin B1- and benzo(α)pyrene-induced gene expression profiles in HepG2, HepaRG and PHH (11-13 donors). At baseline, all liver models differ from each other with respect to whole genome gene expression levels. PHH show profound inter-individual differences, and are most similar to HepaRG. After compound exposure, induced gene expression profiles are more similar between cell models, especially for benzo(α)pyrene. Pathways involved in compound metabolism are induced in all 3 models, while others are more pronounced in a specific cell model. Examples are transcriptomic modifications of carbohydrate-related genes (HepaRG) and of receptor-related genes (PHH) after benzo(α)pyrene exposure, and of cell cycle-related genes (HepG2) after aflatoxin B1 exposure. PHH gene expression responses are the most heterogeneous. In conclusion, at base line level PHH are more similar to HepaRG than to HepG2, but for toxicogenomics applications both cell lines perform equally well in comparison to PHH.
目前，人们正致力于开发基于毒理基因组学的体外人类细胞模型毒性检测方法，以改进人类风险评估/替代动物模型。体外人类肝脏模型包括 HepG2、HepaRG 和原代人肝细胞（PHH）。这些细胞类型的可比性/适用性研究主要集中在评估基线生物转化能力/细胞色素 P450 诱导能力上，但化合物诱导的基因表达谱至少同样重要。因此，我们比较了 HepG2、HepaRG 和 PHH（11-13 个供体）在基线水平以及黄曲霉毒素 B1 和苯并（α）芘诱导下的基因表达谱。在基线水平，所有的肝脏模型在全基因组基因表达水平上彼此不同。PHH 个体间差异很大，与 HepaRG 最相似。在化合物暴露后，细胞模型之间的诱导基因表达谱更为相似，尤其是苯并（α）芘。所有 3 种模型均诱导参与化合物代谢的途径，而其他途径在特定细胞模型中更为明显。例如，苯并（α）芘暴露后碳水化合物相关基因（HepaRG）和受体相关基因（PHH）的转录组修饰，以及黄曲霉毒素 B1 暴露后细胞周期相关基因（HepG2）的转录组修饰。PHH 的基因表达反应最具异质性。总之，在基线水平，PHH 与 HepaRG 比与 HepG2 更相似，但在毒理基因组学应用方面，与 PHH 相比，这两种细胞系的表现同样出色。
