Van Benthem J, Feron V J, Leeman W R, Wilmer J W, Vermeulen E, den Engelse L, Scherer E
Division of Molecular Carcinogenesis, The Netherlands Cancer Institute (Antoni van Leeuwenhoekhuis), Amsterdam.
Carcinogenesis. 1994 Sep;15(9):2023-9. doi: 10.1093/carcin/15.9.2023.
The present paper reports about an immunocytochemical inventory of the cell types involved in the metabolic activation of the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) to a DNA methylating metabolite. The formation and distribution of the methylated DNA bases O6-methylguanine (O6-meGua) and 7-methylguanine (7-MeGua) were studied in respiratory tissues, oesophagus, liver, kidneys, pancreas, small intestine, colon and prostate of rat, mouse and hamster 6 h after treatment with a single dose of 30 mg NNK/kg. The tissue- and cell-specific distribution of O6-meGua- and 7-meGua-specific nuclear staining showed the same patterns and were remarkably similar in rat, mouse and hamster in spite of the diverging spectra of NNK-induced tumours in these species. In nasal tissue, a target for NNK-induced tumourigenesis in rat and hamster, but not in mouse, adduct-specific nuclear staining was observed in all three species in sustentacular cells, Bowman glands, respiratory epithelial cells and serous glands. Both methylated DNA bases were also observed in basal cells of the olfactory epithelium of rat and (occasionally) hamster, but not in those of the mouse. In the trachea, a target for NNK-induced tumourigenesis in hamster only, substantial adduct-specific nuclear staining was found in basal epithelial and glandular cells of the hamster; in the same cells of rat and mouse only a weak nuclear staining was found. In the lung, a common target for NNK-induced tumourigenesis, the formation of O6-meGua and 7-meGua was restricted predominantly to bronchial and proximal bronchiolar epithelium. Nuclear staining in the rat was occasionally found in alveolar cells and was also observed in hepatocytes. In the three species investigated, O6-meGua- and 7-MeGua-specific nuclear staining was found in target and non-target tissues. Apparently, and in analogy with results obtained in other studies, the species-specific organotropy for tumour formation of NNK is not exclusively determined by DNA methylation. Expanding methylation data with literature data on factors considered to be involved in tumour formation, namely proliferation, toxicity and DNA repair among others, still did not lead to a satisfactory explanation for the species-specific organotropy observed. Additional factors (yet to be identified), need to be taken into account in order to explain (and predict) tumourigenic effects induced by monofunctional methylating agents.
本文报道了一项免疫细胞化学研究，该研究涉及烟草特异性亚硝胺4-(甲基亚硝氨基)-1-(3-吡啶基)-1-丁酮（NNK）代谢活化为DNA甲基化代谢物过程中所涉及的细胞类型。在用单剂量30mg NNK/kg处理大鼠、小鼠和仓鼠6小时后，研究了甲基化DNA碱基O6-甲基鸟嘌呤（O6-meGua）和7-甲基鸟嘌呤（7-MeGua）在呼吸组织、食管、肝脏、肾脏、胰腺、小肠、结肠和前列腺中的形成和分布。O6-meGua和7-MeGua特异性核染色的组织和细胞特异性分布呈现相同模式，尽管这些物种中NNK诱导的肿瘤谱不同，但在大鼠、小鼠和仓鼠中却非常相似。在鼻腔组织中，大鼠和仓鼠中NNK诱导肿瘤发生的靶器官，但小鼠中不是，在所有三个物种的支持细胞、鲍曼腺、呼吸上皮细胞和浆液腺中均观察到加合物特异性核染色。在大鼠和（偶尔）仓鼠的嗅上皮基底细胞中也观察到了这两种甲基化DNA碱基，但在小鼠中未观察到。在气管中，仅仓鼠是NNK诱导肿瘤发生的靶器官，在仓鼠的基底上皮细胞和腺细胞中发现了大量加合物特异性核染色；在大鼠和小鼠的相同细胞中仅发现了微弱的核染色。在肺中，NNK诱导肿瘤发生的常见靶器官，O6-meGua和7-MeGua的形成主要局限于支气管和近端细支气管上皮。在大鼠中，偶尔在肺泡细胞中发现核染色，在肝细胞中也观察到。在所研究的三个物种中，在靶组织和非靶组织中均发现了O6-meGua和7-MeGua特异性核染色。显然，与其他研究结果类似，NNK肿瘤形成的物种特异性器官嗜性并非完全由DNA甲基化决定。将甲基化数据与关于被认为参与肿瘤形成的因素（即增殖、毒性和DNA修复等）的文献数据相结合，仍然无法对观察到的物种特异性器官嗜性给出令人满意的解释。为了解释（并预测）单功能甲基化剂诱导的致癌作用，需要考虑其他因素（尚未确定）。
