Gerde P, Muggenburg B A, Scott G G, Lewis J L, Pyon K H, Dahl A R
Lovelace Respiratory Research Institute, Albuquerque, NM 87185, USA.
Carcinogenesis. 1998 Mar;19(3):493-500. doi: 10.1093/carcin/19.3.493.
While inhaled polycyclic aromatic hydrocarbons have long been suspected to induce lung cancer in humans, their dosimetry has not been fully elucidated. A key question is whether the critical exposure occurs during absorption in the lungs, or if toxicants in the systemic circulation contribute significantly to lung cancer risk. In particular, data are needed to determine how the physical properties of inhalants affect local dosimetry in the respiratory tract. Pyrene, a tobacco smoke component, was selected for study because it has physical properties between those of highly lipophilic benzo[a]pyrene and water-soluble nitrosamines. Aliquots of 5 ng of pyrene dissolved in a phospholipid/ saline suspension were instilled as a single-spray bolus in the posterior trachea of the dog just anterior to the carina. For 3 h after instillation, blood was repeatedly sampled from the azygous vein, which drains the mucosa around the point of instillation, and from both sides of the systemic circulation. At 3 h post-instillation, tissue samples were taken. Autoradiography was used to determine the depth distribution of pyrene in the tracheal mucosa. The concentration of pyrene-equivalent radioactivity in the azygous vein peaked 9 min after the instillation. At approximately 30 min after instillation, a rapid early clearance phase shifted into a distinctly slower second clearance phase. Rates of rapid clearance were, however, sufficiently slow to indicate diffusion-limited absorption of pyrene in the trachea. This finding was corroborated by high concentrations of pyrene in the epithelium as determined by autoradiography. High epithelial concentration of pyrene combined with a slow penetration into the circulating blood allowed substantial first-pass metabolic conversion of pyrene in the tracheal mucosa. A total of 13% of the instilled pyrene was retained in the tracheal mucosa 3.2 h after instillation; of this, 29% was parent compound, 52% was organic-extractable metabolites, 14% was water-soluble metabolites and 6% (approximately 1% of the instilled amount) was covalently bound to tracheal tissues. Results support the inference that lipophilic protoxicants, because of slow, diffusion-limited absorption, are more likely than water-soluble protoxicants to be bioactivated in the lining epithelium and, in turn, induce first-pass toxicity at the site of entry. In addition, limitations were identified in the use of systemically distributed biomarkers of PAHs, such as urinary hydroxypyrene levels, as indicators of the biologically effective dose in airway target cells.
长期以来，人们一直怀疑吸入的多环芳烃会诱发人类肺癌，但其剂量测定尚未完全阐明。一个关键问题是，关键暴露是发生在肺部吸收过程中，还是体循环中的毒物对肺癌风险有显著影响。特别是，需要数据来确定吸入剂的物理性质如何影响呼吸道中的局部剂量测定。芘是烟草烟雾的一种成分，被选作研究对象，因为它的物理性质介于高度亲脂性的苯并[a]芘和水溶性亚硝胺之间。将5纳克溶解在磷脂/盐水悬浮液中的芘等分试样作为单次喷雾团注入狗气管隆突前方的后气管。注入后3小时，从引流注入点周围黏膜的奇静脉以及体循环两侧反复采集血液样本。注入后3小时，采集组织样本。利用放射自显影术确定芘在气管黏膜中的深度分布。注入后9分钟，奇静脉中芘等效放射性浓度达到峰值。注入后约30分钟，快速的早期清除阶段转变为明显较慢的第二清除阶段。然而，快速清除率足够慢，表明芘在气管中的吸收受扩散限制。放射自显影术测定上皮细胞中芘的高浓度证实了这一发现。芘在上皮细胞中的高浓度与缓慢渗透到循环血液中的情况相结合，使得芘在气管黏膜中发生了大量的首过代谢转化。注入后3.2小时，共13%的注入芘保留在气管黏膜中；其中，29%为母体化合物，52%为可有机萃取的代谢物，14%为水溶性代谢物，6%（约占注入量的1%）与气管组织共价结合。结果支持了这样的推断：由于吸收缓慢且受扩散限制，亲脂性原毒物比水溶性原毒物更有可能在衬里上皮细胞中被生物活化，进而在进入部位诱发首过毒性。此外，还发现将多环芳烃的全身分布生物标志物（如尿中羟基芘水平）用作气道靶细胞中生物有效剂量的指标存在局限性。
