Dose-response relationship between O6-methylguanine formation in Clara cells and induction of pulmonary neoplasia in the rat by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
Dose-response relationship between O6-methylguanine formation in Clara cells and induction of pulmonary neoplasia in the rat by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone.
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发表时间：
1990-06
期刊：
影响因子：
11.2
通讯作者：
S. Belinsky;J. Foley;C. M. White;M. W. Anderson;R. Maronpot
中科院分区：
文献类型：
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作者：
S. Belinsky;J. Foley;C. M. White;M. W. Anderson;R. Maronpot
用剂量-反应研究方法，研究了烟草特异性亚硝胺4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone(NNK)诱发Fisher 344大鼠肺、肝、鼻肿瘤与O6-甲基鸟嘌呤(O6-MG)形成的关系。NNK浓度为0.03~50 mg/kg，连续给药20wk(3次/wk)，诱发肿瘤。在NNK治疗4wk后，对O6 MG的稳态浓度进行定量，并对靶细胞和组织进行细胞毒性评估。在NNK治疗过程中，肺内未检测到细胞毒性。与巨噬细胞、II型细胞、小细胞和全肺相比，在所有剂量下，Clara细胞中O6 MG的形成最多。在低剂量致癌物作用下，Clara细胞与其他类型的肺细胞之间的加合物浓度差异最为明显。当NNK剂量从50 mg/kg降至1 mg/kg时，烷基化效率指标O6 MG：剂量比增加了29倍。相比之下，在II型细胞和全肺中仅观察到少量的烷基化效率增加。0.1~50 mg/kg剂量组大鼠肺内出现大量肿瘤，发生率从最低剂量组的10%到50 mg/kg组的87%不等。当Clara细胞中O6 MG的浓度与剂量的函数关系与相应的肿瘤发病率作图时，观察到了线性关系。使用第二类细胞或全肺中的DNA加合物浓度没有观察到这种关系。肺肿瘤的发展似乎涉及肺泡增生症的形成，肺泡增生症发展为腺瘤，最后发展为癌。腺瘤以实性为主，而癌以乳头状癌为主。对增生性病变、腺瘤和癌的超微结构检查显示与II型细胞有关的形态结构(如板层小体、管状髓鞘)。因此，这些数据表明，大多数肺肿瘤以II型细胞增殖开始，并进展为增生区内的腺瘤和癌。生化和形态学结果之间缺乏一致性，因此很难推测肺肿瘤的起源细胞。与肺相反，只有在暴露于高剂量NNK后，肝脏和鼻腔才会诱发肿瘤。此外，DNA加合物的形成和细胞毒性似乎都是在这些组织中产生肿瘤的必要条件。
The relationship between the formation of O6-methylguanine (O6MG) and the induction of lung, liver, and nasal tumors in the Fisher 344 rat by the tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) was examined in a dose-response study. Animals were treated for 20 wk (3 times/wk) with concentrations of NNK ranging from 0.03 to 50 mg/kg to induce tumors. Steady-state concentrations of O6MG were quantitated, and cytotoxicity was assessed in target cells and tissues after 4 wk of treatment with NNK. No cytotoxicity was detected in the lung during treatment with NNK. The formation of O6MG was greatest in Clara cells compared with macrophages, type II cells, small cells, and whole lung at all doses examined. The difference in adduct concentration between the Clara cell and other pulmonary cell types was most pronounced with low doses of carcinogen. The O6MG:dose ratio, an index of alkylation efficiency, increased 29-fold as the dose of NNK was decreased from 50 to 1 mg/kg of carcinogen. In contrast, only a small increase in alkylation efficiency was observed in type II cells and whole lung. A significant number of tumors were induced in the lung at doses of 0.1 to 50 mg/kg with incidences ranging from 10% at the lowest dose up to 87% in the group of animals which received 50 mg/kg of NNK. A linear relationship was observed when the concentration of O6MG in Clara cells as a function of dose was plotted against the corresponding tumor incidence. This relationship was not observed using DNA adduct concentrations in type II cells or whole lung. The development of pulmonary tumors appeared to involve the formation of alveolar hyperplasias which progressed to adenomas and finally to carcinomas. The majority of adenomas were solid, whereas carcinomas were mainly papillary. Examination of the ultrastructure of the hyperplasias, adenomas, and carcinomas revealed morphological structures (e.g., lamellar bodies, tubular myelin) which are associated with type II cells. Thus, these data suggest that the majority of neoplasms in the lung begin as type II cell proliferations with progression to adenomas and carcinomas within the areas of hyperplasia. The lack of agreement between biochemical and morphological findings makes it difficult to hypothesize a cell of origin for the pulmonary neoplasms. In contrast to the lung, tumors were induced in the liver and nasal passages only after exposure to high doses of NNK. Moreover, both the formation of DNA adducts and cytotoxicity appear obligatory for the generation of tumors in these tissues.(ABSTRACT TRUNCATED AT 400 WORDS)