Benzo[a]pyrene at an environmentally relevant dose is slowly absorbed by, and extensively metabolized in, tracheal epithelium

While tobacco smoke has been conclusively identified as a lung carcinogen,there is much debate over which smoke constituent(s) are primarilyresponsible for its carcinogenicity. Previous studies in our laboratorysuggested that highly lipophilic carcinogens are slowly absorbed in thethicker epithelium of the conducting airways, potentially allowing forsubstantial local metabolism. The bioactivation of polycyclic aromatichydrocarbons in airway epithelium may, hence, be important in tobaccosmoke-induced carcinogenesis. In the present study, the hypothesis of slowabsorption and substantial local metabolic activation of highly lipophiliccarcinogen in airway epithelium was tested in dogs. A single dose oftritiated benzo[a]pyrene (BaP) dissolved in a saline/phospholipidsuspension was instilled in the trachea, just anterior to the carina. Atintervals of a few minutes up to 30 min over a 3-h period, blood sampleswere drawn from the azygous vein, which drains the area around the point ofinstillation, and from the systemic circulation. Tissue samples were takenat the end of the experiment. The concentration of BaP with depth into thetracheal mucosa was determined with autoradiography. BaP was slowlyabsorbed into the trachea with a half-time of approximately 73 min, whichis consistent with diffusion-limited passage through the epithelium andlead to local doses in the tracheal epithelium that were more than a1000-fold those of other tissues. The long retention of BaP in theepithelium provided the local metabolizing enzymes with high substratelevels over a long period, resulting in extensive metabolism. At 3 h afterthe exposure, 23% of the BaP-equivalent activity remained in the trachealmucosa. Of this fraction, 13% was parent compound, 28% was organicextractable, 31% was water-soluble, and 28-7% of the instilled dose wasbound to tracheal tissues. These results explain the tendency of highlylipophilic carcinogens, such as BaP, to induce tumors at the site of entryand, furthermore, indicate that the highly lipophilic components of tobaccosmoke and polluted air may be the most important contributors to lungtumors of the conducting airways.