DNA adduct formation from tobacco-specific N-nitrosamines
DNA adduct formation from tobacco-specific N-nitrosamines
复制标题
DOI：
10.1016/s0027-5107(99)00014-7
复制
发表时间：
1999-03-08
影响因子：
2.3
通讯作者：
Hecht, SS
中科院分区：
文献类型：
--
作者：
Hecht, SS
烟草特有的N-亚硝胺是烟草生物碱衍生的一类致癌物质。它们可能是吸烟者患肺癌、食道癌、胰腺癌和口腔癌的致病因素。在实验室动物中最具致癌性的烟草特有亚硝胺是4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）、4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁醇（NNAL）和N '-亚硝基去甲烟碱（NNN）。DNA加合物的形成从NNK和NNN已被广泛研究，并在这里进行审查。NNK被细胞色素P450代谢活化，成为甲基化和吡啶氧代丁酸化DNA的中间体。已在啮齿动物中对NNK致癌作用敏感的细胞和组织中检测到所得加合物。甲基化和吡啶氧丁基化途径在NNK的致癌作用中都很重要。NNK还诱导单链断裂并增加经处理动物DNA中8-氧代脱氧鸟苷的水平。与NNK一样，NNAL也是一种强效的肺部致癌物，也被代谢活化为甲基化和吡啶氧代丁基化中间体。NNN吡啶氧代丁酸在其大鼠靶组织、食管和鼻粘膜中使DNA发生作用。在人体组织中检测到甲基和吡啶氧丁基DNA加合物。甲基加合物最有可能部分由吸烟者暴露于NNK导致，但这些加合物也在非吸烟者中检测到。在非吸烟者中检测到的一些甲基加合物可能是由于环境烟草烟雾暴露。这些加合物也有潜在的饮食和内源性来源。人体组织中的吡啶氧丁基DNA加合物主要是由于暴露于烟草特有的N-亚硝胺。在实验室动物中，DNA加合物的形成和烟草特异性N-亚硝胺的致癌性在许多情况下密切相关，并且很可能在人类中也存在类似的关系。(C)1999 Elsevier Science B. V.保留所有权利。
Tobacco-specific N-nitrosamines are a group of carcinogens derived from the tobacco alkaloids. They are likely causative factors for cancers of the lung, esophagus, pancreas, and oral cavity in people who use tobacco products. The most carcinogenic tobacco-specific nitrosamines in laboratory animals are 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL), and N'-nitrosonornicotine (NNN). DNA adduct formation from NNK and NNN has been studied extensively and is reviewed here. NNK is metabolically activated by cytochromes P450 to intermediates which methylate and pyridyloxobutylate DNA. The resulting adducts have been detected in cells and tissues susceptible to NNK carcinogenesis in rodents. The methylation and pyridyloxobutylation pathways are both important in carcinogenesis by NNK. NNK also induces single strand breaks and increases levels of 8-oxodeoxyguanosine in DNA of treated animals. NNAL, which like NNK is a potent pulmonary carcinogen, is also metabolically activated to methylating and pyridyloxobutylating intermediates. NNN pyridyloxobutylates DNA in its rat target tissues, esophagus and nasal mucosa. Methyl and pyridyloxobutyl DNA adducts are detected in human tissues. The methyl adducts most likely result in part from exposure of smokers to NNK, but these adducts are also detected in non-smokers. Some of the methyl adducts detected in non-smokers may be due to environmental tobacco smoke exposure. There are also potential dietary and endogenous sources of these adducts. Pyridyloxobutyl DNA adducts in human tissues result mainly from exposure to tobacco-specific N-nitrosamines. In laboratory animals, DNA adduct formation and carcinogenicity of tobacco-specific N-nitrosamines are closely correlated in many instances, and it is likely that similar relationships will hold in humans. (C) 1999 Elsevier Science B.V. All rights reserved.