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大黄素-8-O-β-D-葡萄糖苷的体内外遗传毒性评价
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| 篇名： | 大黄素-8-O-β-D-葡萄糖苷的体内外遗传毒性评价 |
| TITLE： | |
| 摘要： |
摘 要 目的：评价大黄素-8-O-β-D-葡萄糖苷（EG）的体内外遗传毒性，并比较体外细胞试验及大鼠体内实验评价结果的差异。 方法：采用体外二维（2D）、三维（3D）细胞培养法分别构建2D、3D HepaRG细胞模型，造模成功后，分别将2D、
3D HepaRG细胞分 为空白对照组[0.5％二甲基亚砜（DMSO）]、丝裂霉素C组（阳性对照，0.1 μg/mL）和EG低、中、高剂量组（10、50、200 μg/mL），然后 检测各组HepaRG细胞的微核形成率和尾DNA百分含量。将SD大鼠分为空白对照组（0.5％羧甲基纤维素钠）、甲磺酸乙酯组（阳 性对照，200 mg/kg）和EG低、中、高剂量组（100、300、1 000 mg/kg），每组6只，连续灌胃给药15 d，每天1次；15 d后检测各组大鼠 骨髓嗜多染红细胞、肝细胞的微核形成率及外周血淋巴细胞、肝细胞的尾DNA百分含量、尾距。结果：在体外2D HepaRG细胞模 型中，与空白对照组比较，丝裂霉素 C 组 HepaRG 细胞的微核形成率和尾 DNA 百分含量均显著升高（P＜0.01），EG 各剂量组 HepaRG细胞的微核形成率和尾DNA百分含量差异无统计学意义（P＞0.05）；在3D HepaRG细胞模型中，与空白对照组比较，丝 裂霉素 C 组 HepaRG 细胞的微核形成率和尾 DNA 百分含量均显著升高（P＜0.01 或 P＜0.001），EG 高剂量组 HepaRG 细胞的尾 DNA百分含量显著升高（P＜0.01）。在大鼠体内实验中，与空白对照组比较，甲磺酸乙酯组大鼠骨髓嗜多染红细胞、肝细胞的微 核形成率和外周血淋巴细胞、肝细胞的尾DNA百分含量、尾距均显著升高（P＜0.01），EG高剂量组大鼠外周血淋巴细胞尾DNA
百分含量显著升高（P＜0.01），EG各剂量组大鼠骨髓嗜多染红细胞、肝细胞的微核形成率和肝细胞尾DNA百分含量、尾距差异无 统计学意义（P＞0.05），但随剂量增加有升高趋势。结论：本研究结果提示在2D细胞模型中，EG未导致染色体断裂及DNA损伤， 但3D细胞模型长期给药和体内重复给药结果均显示EG存在一定DNA损伤风险，故3D HepaRG细胞模型的评价结果更接近大 鼠体内实验结果。
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| ABSTRACT： |
ABSTRACT OBJECTIVE：To evaluate the in vitro and in vivo genotoxicity of emodin-8-O-β-D-glucoside（EG），and to compare the difference of in vitro cell test and in vivo test of rats. METHODS：2D and 3D hepatocyte models were established by in vitro two-dimensional（2D）and three-dimensional（3D）cell culture. After modeling，2D and 3D hepatocyte were divided into blank control group（0.5％ DMSO），mitomycin C group（positive control，0.1 μg/mL），EG low-dose，medium-dose and high-dose groups（10，50，200 μg/mL），respectively. The micronucleus ratio and tail DNA％ of HepaRG cells were detected. SD rats were divided into blank control group（0.5％ sodium carboxymethyl cellulose），ethyl methanesulfonate group（positive control，200 mg/kg），EG low-dose，medium-dose and high-dose groups（100，300，1 000 mg/kg），with 6 rats in each group. They were given medicine intragastrically for consecutive 15 d，once a day. 15 days later，the micronucleus formation rate of bone marrow polychromatic erythrocytes and hepatocytes，the tail DNA％ and tail distance of peripheral blood lymphocytes and hepatocytes were measured. RESULTS：In the in vitro 2D HepaRG hepatocyte model，compared with blank control group，the micronucleus formation rate and tail DNA％ of HepaRG cell were increased significantly in mitomycin C group （P＜0.01）. There was no statistical significance in micronucleus formation rate and tail DNA％ of HepaRG cell among EG groups（P＞0.05）. In 3D
HepaRG cell model， compared with blank control group， micronucleus formation rate and tail DNA％ of HepaRG cell
were increased significantly in mitomycin C group （P＜0.01 or P＜0.001）， while tail DNA％ of HepaRG cell was
increased significantly in EG high-dose group（P＜0.01）. In the in vivo test，compared with blank control group，the micronucleus formation rate of bone marrow polychromatic erythrocytes and hepatocytes，the tail DNA％ and tail distance of peripheral blood lymphocytes and hepatocytes were all increased significantly in ethyl methanesulfonate group（P＜0.01）. Tail DNA％ of peripheral blood lymphocytes was increased significantly in EG high-dose group （P＜0.01）. There was no statistical significance in the micronucleus formation rate of bone marrow polychromatic erythrocytes and hepatocytes，the tail DNA％ and tail distance of hepatocytes among EG groups（P＞0.05）；with the increase of dose，there was an increasing trend. CONCLUSIONS：The results of this study suggest that in 2D cell model，EG not lead to chromosome breakage and DNA damage，but the long-term administration and repeated administration in vivo of 3D cell model show that EG has a certain risk of DNA damage，so the evaluation results of 3D HepaRG cell model are more similar to those of rats in vivo.
KEYWORDS Emodin-8-O-β-D-glucoside；Genotoxicity；Two-dimensional culture；Three-dimensional culture；Rat；Micronucleus test
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| 期刊： | 2020年第31卷第1期 |
| 作者： | 文海若，颜玉静，宋 捷，鄂 蕊，马双成，汪 祺 |
| AUTHORS： | WEN Hairuo，YAN Yujing，SONG Jie，AO Rui，MA Shuangcheng，WANG Qi |
| 关键字： | 大黄素-8-O-β-D-葡萄糖苷；遗传毒性；HepaRG细胞；二维培养；三维培养；大鼠；微核试验 |
| KEYWORDS： | Emodin-8-O-β-D-glucoside；Genotoxicity；Two-dimensional culture；Three-dimensional culture；Rat；Micronucleus |
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