George E, Burlinson B, Gatehouse D
Genetic and Reproductive Toxicology Department, Glaxo Group Research, Ltd, Ware, Herts, UK.
Carcinogenesis. 1989 Dec;10(12):2329-34. doi: 10.1093/carcin/10.12.2329.
2-Nitropropane (2-NP) is a rat liver carcinogen, whilst the 1-isomer is non-carcinogenic in rodents. Although DNA repair tests in the rat liver discriminated clearly between the carcinogenic and the non-carcinogenic isomer, uniformly negative results have been published for the mouse bone marrow micronucleus test (BMMN test) with both isomers. Therefore, the latter assay did not discriminate between the carcinogenic and the non-carcinogenic isomer. To investigate whether this is due to endpoint specificity or organospecificity of 2-NP, studies were carried out in the rat in which micronucleus induction (bone marrow and liver) and unscheduled DNA synthesis (UDS) induction (liver) were measured after oral treatment with either nitropropane isomer. 2-NP induced UDS in the liver whilst the 1-isomer was negative, thus confirming the published studies. In the BMMN test, occasional small increases in the incidence of micronuclei were found for both compounds, but results were interpreted as negative after considering the control background data and the lack of reproducibility. By contrast, the liver micronucleus test revealed a clastogenic effect of 2-NP in the liver. This indicates that 2-NP induces chromosome aberrations as well as DNA repair in vivo, but it seems to act organospecifically. For 1-NP a slightly increased incidence of micronuclei was found in the liver, which was accompanied by a markedly increased mitotic index. It therefore remains questionable as to whether this increased micronucleus frequency for 1-NP is an indicator of a clastogenic effect, or whether it is caused by an increased cell proliferation induced by 1-NP. Consequently, it is too early to conclude whether the liver micronucleus assay is able to discriminate between the carcinogenic and non-carcinogenic isomer. However, the results provide further evidence that bone marrow assays are insufficient for the detection of all genotoxic carcinogens in vivo. This indicates the need for analysing a second tissue, particularly when negative bone marrow results have been obtained with in vitro genotoxins.
2-硝基丙烷（2-NP）是一种大鼠肝脏致癌物，而其1-异构体在啮齿动物中无致癌性。尽管大鼠肝脏中的DNA修复试验能够清晰地区分致癌异构体和非致癌异构体，但两种异构体的小鼠骨髓微核试验（BMMN试验）均公布了一致的阴性结果。因此，后一种试验无法区分致癌异构体和非致癌异构体。为了研究这是由于2-NP的终点特异性还是器官特异性所致，在大鼠中进行了研究，在口服任一硝基丙烷异构体后，测量微核诱导（骨髓和肝脏）和非程序性DNA合成（UDS）诱导（肝脏）情况。2-NP可诱导肝脏中的UDS，而1-异构体为阴性，从而证实了已发表的研究结果。在BMMN试验中，两种化合物均偶尔出现微核发生率的小幅增加，但在考虑对照背景数据和缺乏可重复性后，结果被解释为阴性。相比之下，肝脏微核试验显示2-NP对肝脏有断裂效应。这表明2-NP在体内可诱导染色体畸变以及DNA修复，但它似乎具有器官特异性作用。对于1-NP，在肝脏中发现微核发生率略有增加，同时有丝分裂指数显著升高。因此，1-NP微核频率的增加是断裂效应的指标，还是由1-NP诱导的细胞增殖增加所致，仍存在疑问。因此，现在就得出肝脏微核试验能否区分致癌异构体和非致癌异构体的结论还为时过早。然而，这些结果进一步证明，骨髓试验不足以检测体内所有的遗传毒性致癌物。这表明需要分析第二个组织，特别是当体外遗传毒素的骨髓结果为阴性时。
