Ashby J, Lefevre P A
ICI Central Toxicology, Macclesfield, Cheshire, Great Britain.
Mutat Res. 1989 Apr;225(4):143-7. doi: 10.1016/0165-7992(89)90111-5.
Alkylation of DNA is generally accepted as the primary event in the carcinogenicity of nitrosamines. However, the cyclic nitrosamine N-nitrosomorpholine (NMOR), a potent rat hepatocarcinogen, has been reported as binding at very low levels to the liver DNA of treated rats. This led us to investigate the activity of NMOR in two in vivo rat-liver genotoxicity assays--for the induction of unscheduled DNA synthesis (UDS) and the production of micronucleated hepatocytes in the liver micronucleus assay (LMN). Rats treated with oral doses of NMOR (10-200 mg/kg) gave a positive liver UDS response either 2.5 h or 12 h after dosing. Similarly, treatment with oral doses of NMOR (10 or 100 mg/kg) followed by mitogenic stimulation with 4-acetylaminofluorene (4AAF) resulted in high incidences of micronucleated hepatocytes in the LMN assay. These data confirm that the genotoxicity reported for NMOR in vitro can be reproduced in vivo and that NMOR interacts with liver DNA of treated rats. Earlier reports of only very weak binding of radiolabelled NMOR to rat liver DNA in vivo are discussed within the context of these data.
DNA烷基化通常被认为是亚硝胺致癌性的主要事件。然而，环状亚硝胺N-亚硝基吗啉（NMOR）是一种强效的大鼠肝癌致癌物，有报道称其与经处理大鼠的肝脏DNA结合水平非常低。这促使我们在两项体内大鼠肝脏遗传毒性试验中研究NMOR的活性，即非程序性DNA合成（UDS）诱导试验和肝脏微核试验（LMN）中微核化肝细胞的产生试验。经口服给予NMOR（10 - 200 mg/kg）的大鼠在给药后2.5小时或12小时出现阳性肝脏UDS反应。同样，经口服给予NMOR（10或100 mg/kg）后再用4-乙酰氨基芴（4AAF）进行促有丝分裂刺激，在LMN试验中导致微核化肝细胞的高发生率。这些数据证实，NMOR在体外报道的遗传毒性在体内可以重现，并且NMOR与经处理大鼠的肝脏DNA相互作用。在这些数据的背景下讨论了早期关于放射性标记的NMOR在体内与大鼠肝脏DNA仅有非常弱结合的报道。
