Smoking-related O4-ethylthymidine formation in human lung tissue and comparisons with bulky DNA adducts
Smoking-related O4-ethylthymidine formation in human lung tissue and comparisons with bulky DNA adducts
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DOI：
10.1093/mutage/ger011
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发表时间：
2011-07-01
期刊：
影响因子：
2.7
通讯作者：
Nair, Jagadeesan
中科院分区：
文献类型：
--
作者：
Anna, Livia;Kovacs, Katalin;Nair, Jagadeesan
烟草烟雾中含有许多烷化剂，可以与 DNA 反应产生 O-4-乙基胸苷 (O-4-etT) 和几种其他类型的促突变碱基修饰。我们的目的是 (i) 确认试点研究的结果（Godschalk, R.、Nair, J.、Schooten, F. J.、Risch, A.、Drings, P.、Kayser, K.、Dienemann, H. 和 Bartsch, H. (2002) 肿瘤邻近人肺组织中多种 DNA 加合物类型的比较：吸烟的影响。致癌作用, 23, 2081-2086）上 吸烟者肺部 O-4-etT 的形成； (ii) 探索 O-4-etT 水平与吸烟状况之间的关联，以及 (iii) 研究 O-4-etT 水平与大体积（多环芳烃衍生）DNA 加合物之间是否存在相关性。存档的 DNA 样本来源于 64 名接受肺切除术的匈牙利肺癌患者的组织学正常的周围肺组织。 O-4-etT 通过免疫富集 P-32 标记后高效液相色谱法测定。通过富含核酸酶 P1 加合物的 P-32 标记后测定大体积 DNA 加合物的水平。 O-4-etT 水平范围为 0.01 至 3.91 加合物/10(8) 胸苷。在手术前吸烟或手术前最多 1 年戒烟的受试者组合中，O-4-etT 的平均水平比长期戒烟者 (LES) 和从不吸烟者 (NS) 的总和高 1.7 倍 (P = 0.01.5)，大体积 DNA 加合物的平均水平高 2.2 倍 (P < 0.0001)。我们发现两种 DNA 加合物类型的个体水平之间没有显着相关性。 O-4-etT 形成与吸烟剂量之间未检测到剂量反应。在三分之一的 LES 中，O-4-etT 水平高于 NS 中加合物平均水平的 2.0 倍，表明其高度持久性。我们的结果证实了人肺 DNA 中与吸烟相关的 O-4-etT 形成，应将其作为生物标志物进行探索。它在靶组织中的长期存在暗示了这种潜在的错误编码病变在与吸烟相关的癌症中的作用。
Tobacco smoke contains many alkylating agents that can react with DNA to produce O-4-ethylthymidine (O-4-etT) and several other types of promutagenic base modifications. Our aims were (i) to confirm results of a pilot study (Godschalk, R., Nair, J., Schooten, F. J., Risch, A., Drings, P., Kayser, K., Dienemann, H. and Bartsch, H. (2002) Comparison of multiple DNA adduct types in tumor adjacent human lung tissue: effect of cigarette smoking. Carcinogenesis, 23, 2081-2086) on the formation of O-4-etT in smokers' lung; (ii) to explore associations between levels of O-4-etT and smoking status and (iii) to investigate whether a correlation exists between levels of O-4-etT and bulky (polycyclic aromatic hydrocarbons-derived) DNA adducts. Archived DNA samples originated from histologically normal peripheral lung tissues of 64 Hungarian lung cancer patients, who underwent lung resection. O-4-etT was determined by an immunoenriched P-32-postlabelling-high-performance liquid chromatography method. Levels of bulky DNA adducts were determined by the nuclease P1 adduct-enriched P-32-postlabelling. O-4-etT levels ranged from 0.01 to 3.91 adducts/10(8) thymidines. In the combined group of subjects who smoked until surgery or gave up smoking at most 1 year before it, the mean level of O-4-etT was 1.7-fold (P = 0.01.5) and of bulky DNA adducts 2.2-fold (P < 0.0001) higher than in long-term ex-smokers (LES) and never-smokers (NS) combined. We found no significant correlation between the individual levels of the two DNA adduct types. No dose-response was detected between O-4-etT formation and smoking dose. In one-third of LES, O-4-etT levels were above the 2.0-fold mean level of adducts found in NS, indicating its high persistence. Our results confirm the smoking-related formation of O-4-etT in human lung DNA that should be explored as biomarker. Its long persistence in target tissue implicates a role of this potentially miscoding lesion in tobacco smoking-associated cancers.