Gerde P, Muggenburg B A, Stephens T, Lewis J L, Pyon K H, Dahl A R
Lovelace Respiratory Research Institute, Albuquerque, New Mexico 87185, USA.
Cancer Res. 1998 Apr 1;58(7):1417-22.
Lung cancer is largely a site-of-entry disease caused by inhaled carcinogenic agents, especially tobacco smoke. Two major groups of procarcinogens, tobacco-specific nitrosamines and polycyclic aromatic hydrocarbons, are putative agents, but their relative contributions are disputed. An important indicator of relative potency for these compounds is the dose to the target epithelial cells. Although we have reported the dose of polycyclic aromatic hydrocarbons to the canine tracheal epithelium [Gerde et al., Carcinogenesis (Lond.), 18: 1825-1832, 1997; Gerde et al., Carcinogenesis (Lond.), in press, 1998], the purpose of the current study was to characterize the absorption and metabolism of low levels of one tobacco-specific nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in the canine trachea. One hundred ng of tritiated NNK were instilled in the distal trachea of the dog. Blood was repeatedly sampled from the azygous vein and both sides of the systemic circulation from 15 s to 30 min after instillation. Tissues were then removed and analyzed for the tritiated NNK and its metabolites. Autoradiography was used to determine the depth distribution of tritium in the tracheal mucosa. Most NNK appeared rapidly in the blood draining the airway mucosa, but there was also a slow clearance phase. During absorption, NNK was distributed within the entire depth of the mucosa to the tracheal cartilage; however, a portion was conspicuously bound to the mucin component of the mucous lining layer. Reversible binding to mucin may be largely responsible for the slow clearance phase. Despite the rapid absorption of most of the tritium, NNK was nonetheless extensively metabolized in the tracheal mucosa. Systemic metabolism was also rapid: within 18 min of instillation, the NNK parent compound had disappeared from the systemic circulation, and 45 min after instillation, no NNK was found in the trachea or any distal tissue. Although the rapid absorption and distribution of NNK and its metabolites ensured widespread and extensive distal binding in all tissues, first-pass metabolism and activation of NNK in the airway mucosa were sufficiently rapid to cause levels of binding at the site of absorption to be approximately 20-fold those of distal tissues. NNK may thus act as a site-of-entry carcinogen. This observation may be important in estimating the contribution of NNK to lung cancer relative to other carcinogens and for explaining increased incidences of oral cancers in users of snuff and chewing tobacco in which NNK is present in high concentrations.
肺癌很大程度上是一种由吸入致癌物质引起的进入部位疾病，尤其是烟草烟雾。两组主要的前致癌物，即烟草特异性亚硝胺和多环芳烃，被认为是致病因素，但它们的相对作用存在争议。这些化合物相对效力的一个重要指标是到达靶上皮细胞的剂量。尽管我们已经报道了多环芳烃到达犬气管上皮的剂量[格尔德等人，《癌变》（伦敦），18: 1825 - 1832，1997；格尔德等人，《癌变》（伦敦），即将发表，1998]，但本研究的目的是描述低水平的一种烟草特异性亚硝胺，4 -（甲基亚硝氨基）- 1 -（3 -吡啶基）- 1 -丁酮（NNK）在犬气管中的吸收和代谢情况。将100纳克氚标记的NNK注入犬的气管远端。注入后15秒至30分钟内，从奇静脉和体循环两侧反复采集血液样本。然后取出组织，分析其中的氚标记NNK及其代谢产物。利用放射自显影术确定气管黏膜中氚的深度分布。大部分NNK迅速出现在引流气道黏膜的血液中，但也有一个缓慢清除阶段。在吸收过程中，NNK分布于黏膜的整个深度直至气管软骨；然而，有一部分明显与黏液衬里层的黏蛋白成分结合。与黏蛋白的可逆结合可能在很大程度上导致了缓慢清除阶段。尽管大部分氚迅速被吸收，但NNK在气管黏膜中仍被广泛代谢。全身代谢也很快：注入后18分钟内，NNK母体化合物已从体循环中消失，注入后45分钟，在气管或任何远端组织中均未发现NNK。尽管NNK及其代谢产物迅速吸收和分布确保了在所有组织中广泛而深入的远端结合，但气道黏膜中NNK的首过代谢和活化足够迅速，导致吸收部位的结合水平约为远端组织的20倍。因此，NNK可能作为一种进入部位致癌物起作用。这一观察结果对于估计NNK相对于其他致癌物对肺癌的贡献以及解释鼻烟和嚼烟使用者口腔癌发病率增加可能具有重要意义，因为这些产品中NNK浓度很高。
