TOBACCO-SPECIFIC NITROSAMINE ADDUCTS - STUDIES IN LABORATORY-ANIMALS AND HUMANS
TOBACCO-SPECIFIC NITROSAMINE ADDUCTS - STUDIES IN LABORATORY-ANIMALS AND HUMANS
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DOI：
10.2307/3431458
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发表时间：
1993-03-01
影响因子：
10.4
通讯作者：
PETERSON, LA
中科院分区：
文献类型：
--
作者：
HECHT, SS;CARMELLA, SG;PETERSON, LA
本文报道了烟草特有的致癌亚硝胺4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）和N '-亚硝基去甲烟碱（NNN）的人血红蛋白和DNA加合物的定量。NNK和NNN被认为与使用烟草制品的人的肺癌、食道癌、口腔癌和胰腺癌有关。加合物剂量测定法采用GC-MS定量血红蛋白弱碱水解或DNA酸水解释放的4-羟基-1-（3-吡啶基）-1-丁酮（HPB），作为吡啶氧代丁基化代谢活化途径的生化标志物。大约22%的吸烟者（n = 101）从血红蛋白中释放的HPB水平升高（范围为200-1600 fmole/g Hb）。鼻烟勺中的加合物水平范围为200-1800 fmole/g Hb。非吸烟者的HPB水平通常低于检测限。酸水解的肺和气管的DNA在尸检和分析释放HPB显示水平范围高达50 fmole/mg的DNA在吸烟者中，加合物在非吸烟者中未检测到。这些发现与NNK在大鼠中形成加合物的研究中产生的数据一致。将释放HPB的DNA吡啶氧丁基化途径的生物学意义与A/J小鼠中DNA甲基化途径的生物学意义进行比较。这些研究表明，O 6-甲基鸟嘌呤在肺DNA中的持久性对于NNK的肿瘤发生是至关重要的，并且吡啶基氧代丁基化增强了O 6-甲基鸟嘌呤的持久性和乙酰氧基甲基甲基亚硝胺的肿瘤发生。在大鼠中，甲基化和吡啶氧丁基化在NNK引起的肺肿瘤发生中的相对作用还没有明确定义。虽然DNA甲基化在NNK肿瘤发生中的生物学意义已得到很好的表征，但由于其对烟草产品的特异性，因此应使用吡啶氧丁基化途径的生物化学标记物进行烟草特异性亚硝胺在人体中的剂量测定研究。
This paper describes quantitation of human hemoglobin and DNA adducts of the carcinogenic tobacco-specific nitrosamines 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN). NNK and NNN are believed to be involved in cancers of the lung, esophagus, oral cavity, and pancreas in people who use tobacco products. The adduct dosimetry method employs GC-MS for quantitation of 4-hydroxy-1-(3-pyridyl)-1-butanone (HPB) released by mild base hydrolysis of hemoglobin or acid hydrolysis of DNA as a biochemical marker of the pyridyloxobutylation metabolic activation pathway. Approximately 22% of smokers (n = 101) had elevated levels of HPB released from hemoglobin (range, 200-1600 fmole/g Hb). Adduct levels in snuff dippers ranged from 200-1800 fmole/g Hb. HPB levels in nonsmokers were generally below the detection limit. Acid hydrolysis of lung and tracheal DNA obtained at autopsy and analysis for released HPB revealed levels ranging up to 50 fmole/mg DNA in smokers; the adduct was not detected in nonsmokers. These findings are consistent with data generated in studies of adduct formation by NNK in rats. The biological significance of the HPB-releasing DNA pyridyloxobutylation pathway was compared to that of the DNA methylation pathway in the A/J mouse. These studies demonstrated that the persistence of O6-methylguanine in lung DNA is critical for tumorigenesis by NNK and that pyridyloxobutylation enhances both persistence of O6-methylguanine and tumorigenesis by acetoxymethylmethylnitrosamine. In the rat, the relative roles of methylation and pyridyloxobutylation in lung tumorigenesis by NNK are not as clearly defined. Although the biological significance of DNA methylation in NNK tumorigenesis is well characterized, dosimetry studies of tobacco-specific nitrosamines in humans should be carried out using biochemical markers of the pyridyloxobutylation pathway because of their specificity to tobacco products.