It has been hypothesized that high glucose concentrations might contribute to the overall intracellular oxidative stress either by the direct generation of reactive oxygen species (ROS) or by altering the redox balance. Moreover, it has also been suggested that high glucose concentration can increase the susceptibility of DNA to genotoxic effects of xenobiotics. The aim of this approach was to test high glucose concentrations for pro-genotoxicity in human liver cells by setting up an in vitro model for hyperglycaemia. The experimental design included performing of tests on both human HepG2 tumour cells and HepaRG immortalized cells. Increased cell susceptibility to genotoxic xenobiotics was tested by challenging cell cultures with 4-nitroquinoline-N-oxide (4NQO) and evaluating the extent of primary DNA damage by comet assay. Moreover, we evaluated the relationship between glucose concentration and intracellular ROS, as well as the effects of glucose concentration on the induction of Nrf2-dependent genes such as Glutathione S-transferases, Heme‑oxygenase-1, and Glutathione peroxidase-4. To investigate the involvement of ROS in the induced pro-genotoxic activity, parallel experimental sets were set up by considering co-treatment of cells with the model mutagen 4NQO and the antioxidant, glutathione precursor N-acetyl-L-cysteine. High glucose concentrations caused a significant increase in the levels of primary DNA damage, with a pro-genotoxic condition closely related to the concentration of glucose in the culture medium when cells were exposed to 4NQO. High glucose concentrations also stimulated the production of ROS and down-regulated genes involved in contrasting of the effects of oxidative stress. In conclusion, in the presence of high concentrations of glucose, the cells are in unfavourable conditions for the maintenance of genome integrity.

据推测，高葡萄糖浓度可能通过直接产生活性氧 (ROS) 或通过改变氧化还原平衡来促进整体细胞内氧化应激。此外，也有人提出高葡萄糖浓度会增加 DNA 对异生素基因毒性作用的敏感性。这种方法的目的是通过建立高血糖的体外模型来测试高葡萄糖浓度对人肝细胞的促基因毒性。实验设计包括对人 HepG2 肿瘤细胞和 HepaRG 永生化细胞进行测试。通过用 4-硝基喹啉-N挑战细胞培养来测试细胞对基因毒性异生素的敏感性增加-氧化物 (4NQO) 并通过彗星试验评估原始 DNA 损伤的程度。此外，我们评估了葡萄糖浓度与细胞内 ROS 之间的关系，以及葡萄糖浓度对 Nrf2 依赖性基因（如谷胱甘肽S-转移酶、血红素加氧酶-1 和谷胱甘肽过氧化物酶-4）诱导的影响。为了研究 ROS 在诱导的前基因毒性活动中的参与，通过考虑与模型诱变剂 4NQO 和抗氧化剂谷胱甘肽前体N共同处理细胞，建立了平行实验组-乙酰-L-半胱氨酸。高葡萄糖浓度导致原代 DNA 损伤水平显着增加，当细胞暴露于 4NQO 时，前基因毒性条件与培养基中的葡萄糖浓度密切相关。高葡萄糖浓度还刺激了 ROS 的产生，并下调了参与对比氧化应激影响的基因。总之，在高浓度葡萄糖的存在下，细胞处于不利于维持基因组完整性的条件下。