Gerde P, Muggenburg B A, Thornton-Manning J R, Lewis J L, Pyon K H, Dahl A R
Lovelace Respiratory Research Institute, Albuquerque, NM 87185, USA.
Carcinogenesis. 1997 Sep;18(9):1825-32. doi: 10.1093/carcin/18.9.1825.
While tobacco smoke has been conclusively identified as a lung carcinogen, there is much debate over which smoke constituent(s) are primarily responsible for its carcinogenicity. Previous studies in our laboratory suggested that highly lipophilic carcinogens are slowly absorbed in the thicker epithelium of the conducting airways, potentially allowing for substantial local metabolism. The bioactivation of polycyclic aromatic hydrocarbons in airway epithelium may, hence, be important in tobacco smoke-induced carcinogenesis. In the present study, the hypothesis of slow absorption and substantial local metabolic activation of highly lipophilic carcinogen in airway epithelium was tested in dogs. A single dose of tritiated benzo[a]pyrene (BaP) dissolved in a saline/phospholipid suspension was instilled in the trachea, just anterior to the carina. At intervals of a few minutes up to 30 min over a 3-h period, blood samples were drawn from the azygous vein, which drains the area around the point of instillation, and from the systemic circulation. Tissue samples were taken at the end of the experiment. The concentration of BaP with depth into the tracheal mucosa was determined with autoradiography. BaP was slowly absorbed into the trachea with a half-time of approximately 73 min, which is consistent with diffusion-limited passage through the epithelium and lead to local doses in the tracheal epithelium that were more than a 1000-fold those of other tissues. The long retention of BaP in the epithelium provided the local metabolizing enzymes with high substrate levels over a long period, resulting in extensive metabolism. At 3 h after the exposure, 23% of the BaP-equivalent activity remained in the tracheal mucosa. Of this fraction, 13% was parent compound, 28% was organic extractable, 31% was water-soluble, and 28-7% of the instilled dose was bound to tracheal tissues. These results explain the tendency of highly lipophilic carcinogens, such as BaP, to induce tumors at the site of entry and, furthermore, indicate that the highly lipophilic components of tobacco smoke and polluted air may be the most important contributors to lung tumors of the conducting airways.
虽然烟草烟雾已被确凿地认定为一种肺部致癌物，但对于哪种烟雾成分是其致癌性的主要原因仍存在诸多争议。我们实验室之前的研究表明，高度亲脂性致癌物在传导气道较厚的上皮细胞中吸收缓慢，这可能使大量的局部代谢成为可能。因此，气道上皮细胞中多环芳烃的生物活化在烟草烟雾诱导的致癌过程中可能很重要。在本研究中，在犬类动物身上测试了高度亲脂性致癌物在气道上皮细胞中缓慢吸收和大量局部代谢活化的假说。将单剂量溶解于盐水/磷脂混悬液中的氚标记苯并[a]芘（BaP）滴注到气管隆突前方的气管中。在3小时内每隔几分钟直至30分钟，从引流滴注部位周围区域的奇静脉以及体循环中采集血样。在实验结束时采集组织样本。通过放射自显影测定BaP在气管黏膜中的浓度随深度的变化。BaP缓慢吸收进入气管，半衰期约为73分钟，这与通过上皮细胞的扩散受限通道一致，并导致气管上皮细胞中的局部剂量比其他组织高出1000多倍。BaP在上皮细胞中的长时间滞留使局部代谢酶在很长一段时间内处于高底物水平，从而导致广泛的代谢。暴露后3小时，23%的BaP等效活性仍保留在气管黏膜中。在这一部分中，13%是母体化合物，28%是可有机萃取的，31%是水溶性的，28 - 7%的滴注剂量与气管组织结合。这些结果解释了高度亲脂性致癌物（如BaP）在进入部位诱发肿瘤的倾向，此外，还表明烟草烟雾和污染空气中的高度亲脂性成分可能是传导气道肺部肿瘤的最重要促成因素。
