Hoffmann D, Rivenson A, Chung F L, Hecht S S
Naylor Dana Institute for Disease Prevention, American Health Foundation, Valhalla, New York 10595.
Crit Rev Toxicol. 1991;21(4):305-11. doi: 10.3109/10408449109017917.
Biochemical studies and bioassays support the concept that the increased risk for cancer of the oral cavity in snuff dippers and cancer of the lung, upper aerodigestive tract, and pancreas in smokers is most likely associated with the exposure to tobacco-specific N-nitrosamines. The doses of TSNA required to induce tumors in the oral cavity in rats and tumors in the lungs of rats and hamsters are comparable to the total doses of TSNA to which a long-term snuff dipper, respectively a cigarette smoker, are exposed over 4 decades. The carcinogenic NNN and NNK are metabolized to highly reactive electrophiles which react with nucleophilic centers of DNA and with proteins. The DNA-adducts are known to cause miscoding which can activate K-ras proto-oncogenes. K-ras oncogenes have been detected in adenocarcinomas of the lung of smokers. TSNA also form globin adducts in the blood of laboratory animals as well as of snuff dippers and smokers. Such adducts are currently being evaluated for their significance as biochemical markers of exposure to TSNA. These biomarkers may also serve as indicators for the possible endogenous formation of TSNA in tobacco chewers and smokers. Additional research needs in TSNA carcinogenesis include the development of modified methods for the reduction of TSNA in tobacco and smoke, inhibition of TSNA carcinogenesis by nutrients and micro-nutrients and the testing of chemopreventive agents.
生化研究和生物测定支持这样一种观点，即鼻烟使用者患口腔癌的风险增加，以及吸烟者患肺癌、上呼吸道和消化道癌及胰腺癌的风险增加，很可能与接触烟草特有的N-亚硝胺有关。在大鼠口腔中诱发肿瘤以及在大鼠和仓鼠肺部诱发肿瘤所需的烟草特有的N-亚硝胺剂量，与长期鼻烟使用者或吸烟者在40年中接触的烟草特有的N-亚硝胺总剂量相当。致癌性的N-亚硝基去甲烟碱（NNN）和4-(甲基亚硝胺基)-1-(3-吡啶基)-1-丁酮（NNK）被代谢代谢代谢代谢为高反应性亲电试剂，它们会与DNA的亲核中心以及蛋白质发生反应。已知DNA加合物会导致错配，从而激活K-ras原癌基因。在吸烟者的肺癌腺癌中已检测到K-ras癌基因。烟草特有的N-亚硝胺还会在实验动物以及鼻烟使用者和吸烟者的血液中形成珠蛋白加合物。目前正在评估此类加合物作为接触烟草特有的N-亚硝胺的生化标志物的意义。这些生物标志物还可作为烟草咀嚼者和吸烟者体内烟草特有的N-亚硝胺可能内源性形成的指标。烟草特有的N-亚硝胺致癌作用方面的其他研究需求包括开发减少烟草和烟雾中烟草特有的N-亚硝胺的改良方法、营养素和微量营养素对烟草特有的N-亚硝胺致癌作用的抑制以及化学预防剂的测试。
