BENZO[A]PYRENE AT AN ENVIRONMENTALLY RELEVANT DOSE IS SLOWLY ABSORBEDBY, AND EXTENSIVELY METABOLIZED IN, TRACHEAL EPITHELIUM

While tobacco smoke has been conclusively identified as a lung carcino gen, there is much debate over which smoke constituent(s) are primaril y responsible for its carcinogenicity, Previous studies in our laborat ory suggested that highly lipophilic carcinogens are slowly absorbed i n the thicker epithelium of the conducting airways, potentially allowi ng for substantial local metabolism, The bioactivation of polycyclic a romatic hydrocarbons in airway epithelium may, hence, be important in tobacco smoke-induced carcinogenesis, In the present study, the hypoth esis 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 per iod, blood samples were drawn from the azygous vein, which drains the area around the point of instillation, and from the systemic circulati on, Tissue samples were taken at the end of the experiment, The concen tration 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 trachea l epithelium that were more than a 1000-fold those of other tissues, T he long retention of BaP in the epithelium provided the local metaboli zing enzymes with high substrate levels over a long period, resulting in extensive metabolism, At 3 h after the exposure, 23% of the BaP-equ ivalent activity remained in the tracheal mucosa, Of this fraction, 13 % was parent compound, 28% was organic extractable, 31% was water-solu ble, and 28-7% of the instilled dose was bound to tracheal tissues, Th ese results explain the tendency of highly lipophilic carcinogens, suc h as BaP, to induce tumors at the site of entry and, furthermore, indi cate that the highly lipophilic components of tobacco smoke and pollut ed air may be the most important contributors to lung tumors of the co nducting airways.