Benzo[a]pyrene at an environmentally relevant dose is slowly absorbed by, and extensively metabolized in, tracheal epithelium
Benzo[a]pyrene at an environmentally relevant dose is slowly absorbed by, and extensively metabolized in, tracheal epithelium
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DOI：
10.1093/carcin/18.9.1825
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发表时间：
1997-09-01
期刊：
影响因子：
4.7
通讯作者：
Dahl, AR
中科院分区：
文献类型：
--
作者：
Gerde, P;Muggenburg, BA;Dahl, AR
虽然烟草烟雾已被最终确定为肺致癌物，但对于哪种烟雾成分主要负责其致癌性存在许多争论。我们实验室的先前研究表明，高度亲脂性致癌物在传导气道的较厚上皮中缓慢吸收，可能允许大量局部代谢。因此，在本研究中，在狗的气道上皮中对高度亲脂性致癌物的缓慢吸收和大量局部代谢活化的假设进行了测试。将溶解在盐水/磷脂悬浮液中的单剂量氚化苯并[a]芘（BaP）滴注到气管隆突前，在3小时的时间内，以几分钟至30分钟的间隔，从奇静脉（其排出滴注点周围的区域）和体循环抽取血液样品。在实验结束时采集组织样品，用放射自显影法测定BaP进入气管粘膜的浓度，BaP进入气管的半衰期约为73 min，这与通过上皮的扩散受限通道一致，并导致气管上皮中的局部剂量超过其他组织的1000倍，BaP在气管粘膜中的长期滞留使局部代谢酶在较长时间内保持较高的底物水平，导致广泛的代谢。暴露后3 h，23%的BaP当量活性留在气管粘膜中，其中13%为母体化合物。28%是有机可提取物，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趋势，此外，研究表明，烟草烟雾和污染空气中的高度亲脂性成分可能是导致传导气道肺肿瘤的最重要因素。
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 similar to 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.