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An Adaption of Human-Induced Hepatocytes to In Vitro Genetic Toxicity Tests.
Mutagenesis ( IF 2.7 ) Pub Date : 2019-05-29 , DOI: 10.1093/mutage/gey041
Weiying Liu 1 , Jing Xi 1 , Yiyi Cao 1 , Xinyue You 1 , Ruixue Chen 1 , Xinyu Zhang 1 , Li Han 2 , Guoyu Pan 2 , Yang Luan 1
Affiliation  

Metabolic activation is essential in standard in vitro genotoxicity test systems. At present, there is a lack of suitable cell models that can express the major characteristics of liver function for predicting substance toxicity in humans. Human-induced hepatocytes (hiHeps), which have been generated from fibroblasts by lentiviral expression of liver transcription factors, can express hepatic gene programs and can be expanded in vitro and display functional characteristics of mature hepatocytes, including cytochrome P450 enzyme activity and biliary drug clearance. Our purpose was to investigate whether hiHeps could be used as a more suitable model for genotoxicity evaluation of chemicals. Therefore, a direct mutagen, methylmethanesulfonate (MMS), and five promutagens [2-nitrofluorene (2-NF), benzo[a]pyrene (B[a]P), aflatoxin B1, cyclophosphamide and N-nitrosodiethylamine] were tested by the cytokinesis-block micronucleus test and the comet assay. Results from genotoxicity tests showed that the micronucleus frequencies were significantly increased by all of the six clastogens tested. Moreover, MMS, 2-NF and B[a]P induced significant increases in the % Tail DNA in the comet assay. In conclusion, our findings from the preliminary study demonstrated that hiHeps could detect the genotoxicity of indirect carcinogens, suggesting their potential to be applied as an effective tool for in vitro genotoxicity assessments.

中文翻译:

人类诱导的肝细胞适应体外遗传毒性测试。

在标准的体外遗传毒性测试系统中,代谢激活至关重要。目前,缺乏可以表达肝功能主要特征以预测人类物质毒性的合适细胞模型。人诱导的肝细胞(hiHeps)是通过肝转录因子的慢病毒表达从成纤维细胞产生的,可以表达肝基因程序,可以在体外扩增并显示成熟肝细胞的功能特征,包括细胞色素P450酶活性和胆道药物清除率。我们的目的是调查hiHeps是否可以用作更合适的化学物质遗传毒性评估模型。因此,直接诱变剂是甲磺酸甲酯(MMS)和五个突变体[2-硝基芴(2-NF),苯并[a] py(B [a] P),黄曲霉毒素B1,通过胞质分裂阻滞微核试验和彗星试验检测了环磷酰胺和N-亚硝基二乙胺]。遗传毒性测试的结果表明,所有测试的六种胶束原均显着提高了微核频率。此外,在彗星试验中,MMS,2-NF和B [a] P诱导了%Tail DNA的显着增加。总而言之,我们从初步研究中获得的结果表明,hiHeps可以检测间接致癌物的遗传毒性,表明其潜力可作为体外遗传毒性评估的有效工具。2-NF和B [a] P在彗星试验中诱导%Tail DNA的显着增加。总而言之,我们从初步研究中获得的结果表明,hiHeps可以检测间接致癌物的遗传毒性,表明其潜力可作为体外遗传毒性评估的有效工具。2-NF和B [a] P在彗星试验中诱导%Tail DNA的显着增加。总而言之,我们从初步研究中获得的结果表明,hiHeps可以检测间接致癌物的遗传毒性,表明其潜力可作为体外遗传毒性评估的有效工具。
更新日期:2019-11-01
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