摘要
目的:评价尿素的遗传毒性风险。方法:Ames试验:采用TA98、TA100、TA1535、TA1537和WP2 uvr A共5种菌株(有和无S9代谢活化)开展,尿素处理剂量为5000、1667、556和185μg/皿,所有样本置37℃培养48 h后进行菌落计数;染色体畸变试验:CHL细胞分别与尿素作用6 h(有和无S9代谢活化)和24 h(无S9代谢活化),尿素处理浓度范围为0.16~2.50 mg/mL;细胞经秋水仙素处理后,收获并制片。每组观察100个中期分裂相细胞中含结构畸变和/或数目畸变的细胞数;小鼠骨髓微核试验:单次经口灌胃给予ICR小鼠10000、5000和2500 mg/kg尿素,并在给药24 h和48 h后取材。计数2000个嗜多染红细胞中含微核细胞率。结果:尿素处理组各菌回复突变菌落数与阴性对照组比较均未见明显增加;尿素导致的结构畸变率和数目畸变率与阴性对照组比较均无显著性差异(P>0.05);给予尿素后24 h,各剂量组平均含微核嗜多染红细胞率与阴性对照组比较无显著性差异(P>0.05),给予尿素后48 h,10000mg/kg剂量组动物平均含微核嗜多染红细胞率与阴性对照组比较无显著性差异(P>0.05)。结论:尿素浓度为5000μg/皿及以下时无诱导细菌碱基突变作用,在无明显细胞毒性作用浓度条件下无诱导哺乳动物细胞染色体结构畸变作用,剂量为10000 mg/kg及以下时无诱导小鼠骨髓细胞染色体损伤作用。故尿素的整体遗传毒性评价结果为阴性。
Objective:To evaluate the genotoxicity risk of urea.Methods:Ames test:a total of five strains were used,which are TA98,TA100,TA1535,TA1537 and WP2 uvr A,respectively(with and without S9 metabolic activation),and urea at doses of 5000,1667,556,and 185μg/plate was adopted.All samples were incubated at 37℃for 48 h before colony counting.Chromosome aberration test:CHL cells were treated with urea for 6 h(with and without S9 metabolic activation)and 24 h(without S9 metabolic activation),respectively,and urea at concentrations of 0.16-2.50 mg/mL was applied.The cells were treated with colchicine before harvesting and slide preparation.The number of cells with structural and/or numerical aberrations in 100 metaphase cells in each group was observed.Mouse bone marrow micronucleus test:ICR mice were dosed with 10000 mg/kg,5000 mg/kg and 2500 mg/kg urea by oral intragastric administration for once,and the samples were collected at 24 h and 48 h post-administration.The micronucleus rate in 2000 polychromatic erythrocytes was counted.Results:Compared with the negative control group,no significant increase in the number of revertants in groups treated with urea was observed.Compared with the negative control group(P>0.05),there was no significant difference in the rate of structural aberration and numerical aberration caused by urea.At 24 h post-administration of urea,there was no significant difference in the average micronucleated polychromatic erythrocyte rate between each dose group and negative control group(P>0.05).At 48 h post-admnistration of urea,there was no significant difference in the average micronucleated polychromatic erythrocyte rate between 10000 mg/kg group and negative control group(P>0.05).Conclusion:The urea at doses of 5000μg/plate and below could not induce bacterial base mutation,the urea at concentrations without obvious cytotoxicity could not induce chromosome aberration in mammalian cells,and the urea at doses of 10000 mg/kg and below could not induce chromosome damage in mouse bone marrow cells.Thus,the overall genotoxicity evaluation result of urea is negative.
作者
宋捷
鄂蕊
杨颖
耿兴超
胡燕平
文海若
Song Jie;Ao Rui;Yang Ying;Geng Xingchao;Hu Yanping;Wen Hairuo(National Center for Safety Evaluation of Drugs,National Institutes for Food and Drug Control,Key Laboratory of Beijing for Nonclinical Safety Evaluation Research of Drugs,Beijing 100176,China)
出处
《中国药事》
CAS
2021年第9期1016-1023,共8页
Chinese Pharmaceutical Affairs
基金
国家“重大新药创制”科技重大专项(编号2018ZX09201017-001)。
