Belinsky S A, Devereux T R, Anderson M W
Laboratory of Molecular Toxicology, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709.
Mutat Res. 1990 Nov-Dec;233(1-2):105-16. doi: 10.1016/0027-5107(90)90155-w.
The relationships between DNA methylation and repair induced by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to the activation of proto-oncogenes and the induction of pulmonary neoplasia by this carcinogen is described. The formation of the O6-methylguanine (O6MG) adduct following metabolic activation of NNK appears to be a major factor in the induction of lung tumors in both rats and mice and in the activation of the K-ras oncogene in lung tumors from A/J mouse. The potent carcinogenicity of NNK in the rat lung correlated strongly with cell specificity for formation and persistence of the O6MG adduct in the Clara cells. This conclusion was supported by studies with nitrosodimethylamine (NDMA), a weak carcinogen in the rodent lung. Treatment with NDMA was not associated with any pulmonary cell specificity for DNA methylation. The high affinity for activation of NNK compared to NDMA was ascribed to a difference in cytochrome P-450 isozymes involved in the activation of these two nitrosamines. In the A/J mouse, the induction of pulmonary tumorigenesis involved direct genotoxic activation of the K-ras proto-oncogene as a result of the base mispairing produced by formation of the O6MG adduct. In contrast, the induction of pulmonary tumors in the rat by NNK does not appear to involve the ras pathway. It is apparent that different molecular mechanisms are involved in the development of pulmonary tumors by NNK in the mouse and rat. The studies described in this paper illustrate the utility of performing dose-response experiments and the quantitation of DNA methylation and repair in not only target tissues but also target cell types. The fundamental knowledge gained from unraveling the mechanism of carcinogenesis by NNK could lead ultimately to the identification of factors important in the development of human lung cancer.
本文描述了烟草特异性亚硝胺4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮(NNK)诱导的DNA甲基化和修复与原癌基因激活以及该致癌物诱导肺肿瘤之间的关系。NNK代谢激活后形成的O6-甲基鸟嘌呤(O6MG)加合物似乎是诱导大鼠和小鼠肺肿瘤以及激活A/J小鼠肺肿瘤中K-ras癌基因的主要因素。NNK在大鼠肺中的强致癌性与克拉拉细胞中O6MG加合物形成和持续存在的细胞特异性密切相关。用亚硝基二甲胺(NDMA)进行的研究支持了这一结论，NDMA是啮齿动物肺中的一种弱致癌物。用NDMA处理与DNA甲基化的任何肺细胞特异性无关。与NDMA相比，NNK对激活的高亲和力归因于参与这两种亚硝胺激活的细胞色素P-450同工酶的差异。在A/J小鼠中，肺肿瘤发生的诱导涉及K-ras原癌基因的直接基因毒性激活，这是由O6MG加合物形成产生的碱基错配导致的。相比之下，NNK诱导大鼠肺肿瘤似乎不涉及ras途径。显然，NNK在小鼠和大鼠中诱导肺肿瘤的发展涉及不同的分子机制。本文所述的研究说明了进行剂量反应实验以及不仅在靶组织而且在靶细胞类型中定量DNA甲基化和修复的实用性。从揭示NNK致癌机制中获得的基础知识最终可能导致识别在人类肺癌发展中重要的因素。
