Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Horikoshi 717, Fukuroi-shi, Shizuoka-ken 437-0065 Japan.
Medicinal Safety Research Laboratories, Daiichi Sankyo Co., Ltd., Horikoshi 717, Fukuroi-shi, Shizuoka-ken 437-0065 Japan.
Mutat Res. 2012 Aug 30;747(1):98-103. doi: 10.1016/j.mrgentox.2012.04.007. Epub 2012 Apr 23.
The liver micronucleus test is an important method to detect pro-mutagens such as active metabolites not reaching bone marrow due to their short lifespan. We have already reported that dosing of the test compound after partial hepatectomy (PH) is essential to detect genotoxicity of numerical chromosome aberration inducers in mice [Mutat. Res. 632 (2007) 89-98]. In naive animals, the proportion of binucleated cells in rats is less than half of that in mice, which suggests a species difference in the response to chromosome aberration inducers. In the present study, we investigated the responses to structural and numerical chromosome aberration inducers in the rat liver micronucleus test. Two structural chromosome aberretion inducers (diethylnitrosamine and 1,2-dimethylhydrazine) and two numerical chromosome aberration inducers (colchicine and carbendazim) were used in the present study. PH was performed a day before or after the dosing of the test compound in 8-week old male F344 rats and hepatocytes were isolated 4 days after the PH. As a result, diethylnitrosamine and 1,2-dimethylhydrazine, structural chromosome aberration inducers, exhibited significant increase in the incidence of micronucleated hepatocyte (MNH) when given either before and after PH. Colchicine and carbendazim, numerical chromosome aberration inducers, did not result in any toxicologically significant increase in MNH frequency when given before PH, while they exhibited MNH induction when given after PH. It is confirmed that dosing after PH is essential in order to detect genotoxicity of numerical chromosome aberration inducers in rats as well as in mice. Regarding the species difference, a different temporal response to colchicine was identified. Colchicine increased the incidence of MNH 4 days after PH in rats, although such induction in mice was observed 8-10 days after PH.
肝微核试验是一种重要的方法，用于检测由于其短寿命而未到达骨髓的活性代谢物等前诱变剂。我们已经报道过，在部分肝切除（PH）后给药测试化合物对于检测小鼠中数值染色体畸变诱导剂的遗传毒性至关重要[Mutat. Res. 632 (2007) 89-98]。在未处理的动物中，大鼠双核细胞的比例不到小鼠的一半，这表明在对染色体畸变诱导剂的反应中存在种属差异。在本研究中，我们研究了大鼠肝微核试验中结构和数值染色体畸变诱导剂的反应。使用了两种结构染色体畸变诱导剂（二乙基亚硝胺和 1,2-二甲基肼）和两种数值染色体畸变诱导剂（秋水仙碱和多菌灵）。在 8 周龄雄性 F344 大鼠中，在给药前一天或 PH 后一天进行 PH，并在 PH 后 4 天分离肝细胞。结果，结构染色体畸变诱导剂二乙基亚硝胺和 1,2-二甲基肼，无论是在 PH 前还是 PH 后给药，均显著增加微核肝细胞（MNH）的发生率。数值染色体畸变诱导剂秋水仙碱和多菌灵，在 PH 前给药时，未导致 MNH 频率出现任何毒理学显著增加，而在 PH 后给药时，则表现出 MNH 诱导作用。证实了 PH 后给药对于检测大鼠以及小鼠中数值染色体畸变诱导剂的遗传毒性是必要的。关于种属差异，鉴定出对秋水仙碱的不同时间反应。秋水仙碱在大鼠 PH 后 4 天增加了 MNH 的发生率，尽管在小鼠中观察到这种诱导作用发生在 PH 后 8-10 天。
