Assessment of the Genotoxic Potential of Azidothymidine in the Comet, Micronucleus, and Pig-a Assay
Assessment of the Genotoxic Potential of Azidothymidine in the Comet, Micronucleus, and Pig-a Assay
复制标题
DOI：
10.1093/toxsci/kft148
复制
发表时间：
2013-10-01
影响因子：
3.8
通讯作者：
Zeller, Andreas
中科院分区：
文献类型：
--
作者：
Guerard, Melanie;Koenig, Julie;Zeller, Andreas
选择叠氮胸苷 (Zidovudine, AZT) 作为核苷酸类似物的模型化合物，其基因毒性潜力在体内进行了基因突变、染色体断裂和 DNA 断裂终点的全面评估。雄性 Wistar 大鼠经口灌胃 AZT，剂量水平为 20（对照）、2250、2500 和 21000mg/kg/天，并在第 8 天给予最终单剂量。然后在同一动物中通过肝脏、胃和外周血中的彗星测定以及骨髓和外周血中的微核测试（通过流式细胞术）评估 DNA 损伤。在长达 42 天的无治疗期后，对高剂量动物的外周血进行 Pig-a 基因突变测定。在彗星试验和微核试验中，AZT 在所有评估的组织中造成 DNA 损伤的剂量依赖性显着增加，并且对骨髓和外周血细胞具有高度细胞毒性。这些数据与已发表的结果非常一致。令人惊讶的是，AZT 并没有显着增加 Pig-a 突变细胞的数量。我们推测有两个因素可能导致了这一负面结果：AZT 引起的大缺失占主导地位，以及本研究使用的第一代评分方法的统计功效相对较低。
The genotoxic potential of azidothymidine (Zidovudine, AZT), chosen as a model compound for nucleotide analogs, was comprehensively assessed in vivo for gene mutation, clastogenicity, and DNA breakage endpoints. Male Wistar rats were treated by oral gavage over 7 days with AZT at dose levels of 20 (control), 2250, 2500, and 21000mg/kg/day with a final single dose given on day 8. DNA damage was then evaluated with the comet assay in liver, stomach, and peripheral blood and with the micronucleus test in bone marrow and peripheral blood (by flow cytometry) in the same animals. After a treatment-free period of upto 42 days, the Pig-a gene mutation assay was performed in peripheral blood of the high-dose animals. In the comet assay as well as the micronucleus test, AZT caused a considerable dose-dependent increase in DNA damage in all tissues evaluated and was highly cytotoxic to bone marrow and peripheral blood cells. These data are well in line with published results. Surprisingly, AZT did not significantly increase the number of Pig-a mutant cells. We speculate that two factors likely contributed to this negative result: a predominance of large deletions caused by AZT, and the relatively low statistical power of the first-generation scoring method used for this study.