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2D3D 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阳性对照0.1 μg/mLEG高剂量组1050200 μg/mL),然后 检测各组HepaRG细胞的微核形成率和尾DNA百分含量SD大鼠分为空白对照组0.5羧甲基纤维素钠)、甲磺酸乙酯组性对照200 mg/kgEG高剂量组1003001 000 mg/kg),每组6连续灌胃给药15 d每天115 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 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);3D HepaRG细胞模型中与空白对照组比较裂霉素 C HepaRG 细胞的微核形成率和尾 DNA 百分含量均显著升高P<0.01 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3D HepaRG细胞模型的评价结果更接近大 鼠体内实验结果
ABSTRACT:

ABSTRACT OBJECTIVETo evaluate the in vitro and in vivo genotoxicity of emodin-8-O-β-D-glucosideEG),and to compare the difference of in vitro cell test and in vivo test of rats. METHODS2D and 3D hepatocyte models were established by in vitro two-dimensional2Dand three-dimensional3Dcell culture. After modeling2D and 3D hepatocyte were divided into blank control group0.5DMSO),mitomycin C grouppositive control0.1 μg/mL),EG low-dosemedium-dose and high-dose groups1050200 μg/mL),respectively. The micronucleus ratio and tail DNAof HepaRG cells were detected. SD rats were divided into blank control group0.5sodium carboxymethyl cellulose),ethyl methanesulfonate grouppositive control200 mg/kg),EG low-dosemedium-dose and high-dose groups1003001 000 mg/kg),with 6 rats in each group. They were given medicine intragastrically for consecutive 15 donce a day. 15 days laterthe micronucleus formation rate of bone marrow polychromatic erythrocytes and hepatocytesthe tail DNAand tail distance of peripheral blood lymphocytes and hepatocytes were measured. RESULTSIn the in vitro 2D HepaRG hepatocyte modelcompared with blank control groupthe micronucleus formation rate and tail DNAof HepaRG cell were increased significantly in mitomycin C group P<0.01. There was no statistical significance in micronucleus formation rate and tail DNAof HepaRG cell among EG groupsP>0.05. In 3D
HepaRG cell modelcompared with blank control groupmicronucleus formation rate and tail DNAof HepaRG cell
were increased significantly in mitomycin C group P<0.01 or P<0.001), while tail DNAof HepaRG cell was
increased significantly in EG high-dose groupP<0.01. In the in vivo testcompared with blank control groupthe micronucleus formation rate of bone marrow polychromatic erythrocytes and hepatocytesthe tail DNAand tail distance of peripheral blood lymphocytes and hepatocytes were all increased significantly in ethyl methanesulfonate groupP<0.01. Tail DNAof 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 hepatocytesthe tail DNAand tail distance of hepatocytes among EG groupsP>0.05);with the increase of dosethere was an increasing trend. CONCLUSIONSThe results of this study suggest that in 2D cell modelEG not lead to chromosome breakage and DNA damagebut the long-term administration and repeated administration in vivo of 3D cell model show that EG has a certain risk of DNA damageso the evaluation results of 3D HepaRG cell model are more similar to those of rats in vivo.
KEYWORDS Emodin-8-O-β-D-glucosideGenotoxicityTwo-dimensional cultureThree-dimensional cultureRatMicronucleus test
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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