MECHANISMS OF CARCINOGENESIS OF DIBENZO(A,1)PYRENE

虽然与吸烟有关的健康危害是众所周知的， 目前还没有定量的致癌物质， 确定或在某些情况下定性识别。 二苯并[a，l]芘 (DB[a，1]P）的生物活性级分中， 烟草烟雾冷凝物。 我们最近发现这种化合物是一种 极强的致癌物质，比苯并[a]芘（BP）强得多， 这表明它可能是香烟烟雾中的一个重大风险， 和其他环境污染物。 因此，我们计划确定 通过比较DB[a，l]P在大鼠乳腺中的致瘤活性来确定其效力 在大鼠肺中，通过直接应用于 BP是已知的最强的环境多环芳烃， 碳氢化合物（PAH）和7，12-二甲基苯并[a]蒽（DMBA）， 已知最强致癌性PAH。 提供关于机制的证据 DB[a，l]P的致癌作用，我们建议调查1）是否 代谢产物DB[a，l]P 11，12-二氢二醇是一种近似的肿瘤引发剂; 2） DBp[a，l] P是否类似于DMBA或BP激活ras癌基因， 小鼠皮肤、大鼠乳腺和大鼠肺肿瘤的点检测 突变的Ha-ras、Ki-ras或N-ras基因，使用扩增的方法， 聚合酶链反应和直接双脱氧核苷酸DNA 3）DB[a，l]P、DB[a，e]P和BP与 亲核试剂与Mn（OAc）的单电子氧化，以及 DB[a，l]P与DNA的体外结合 辣根过氧化物酶，前列腺素H合成酶，大鼠 微粒体和大鼠肝细胞核的结合水平， 鉴定形成的DNA加合物;和5）DB[a，l]P在 在小鼠皮肤、大鼠乳腺和大鼠肺中， 结合水平和鉴定形成的DNA加合物。 与此 实验方法，我们将评估DB[a，l]P的致癌效力 与DMBA和BP相比，我们还将知道它是否能够激活ras 癌基因类似于DMBA和BP，我们也将知道是否 其激活ras癌基因能力类似于DMBA或BP。 由于我们预期DB[a，l]P的致癌性与 我们认为DB[a，l]P的致瘤性研究将证明， 这种PAH在香烟中对人体健康有重大危害 烟雾和其他环境污染物。 获得的数据 化学、致瘤性、DNA结合研究和癌基因激活 将提供有关致癌机制的重要线索 DB[a，l] P的

Although health hazards associated with cigarette smoking are well-known, the carcinogens that present these hazards have not been quantitatively determined or in some cases qualitatively identified. Dibenzo[a,l]pyrene (DB[a,l]P) has been identified in the biologically active fraction of tobacco smoke condensate. We have recently found this compound to be an extremely potent carcinogen, much stronger than benzo[a]pyrene (BP), suggesting that it may represent a significant risk in cigarette smoke and other environmental pollutants. Therefore, we plan to determine the potency of DB[a,l]P by comparing its tumorigenic activity in rat mammary gland by direct application, and in rat lung by direct application to that of BP, the strongest known environmental polycyclic aromatic hydrocarbon (PAH), and 7,12-dimethylbenz[a]anthracene (DMBA), the strongest known carcinogenic PAH. To provide evidence on the mechanism of carcinogenesis of DB[a,l]P, we propose to investigate 1) whether the metabolite DB[a,l]P 11,12-dihydrodiol is a proximate tumor-initiator; 2) whether DBp[a,l[P activates ras oncogenes similarly to DMBA or BP in mouse skin, rat mammary gland and rat lung tumors by detection of a point mutated Ha-ras, Ki-ras or N-ras gene using amplification by the polymerase chain reaction and direct dideoxyribonucleotide DNA sequencing; 3) the relative reactivity of DB[a,l]P, DB[a,e]P and BP with nucleophiles in one-electron oxidation with Mn(OAc), and in electrochemical oxidation; 4) the binding of DB[a,l]P to DNA in vitro with horseradish peroxidase, prostaglandin H synthase, rat lever microsomes and rat liver nuclei by determining the level of binding and identifying the DNA adducts formed; and 5) the binding of DB[a,l]P in vivo in mouse skin, rat mammary gland and rat lung by determining the level of binding and identifying the DNA adducts formed. With this experimental approach we will assess the carcinogenic potency of DB[a,l]P vs DMBA and BP, and we will also know whether its ability to activate ras oncogenes resembles that of DMBA and BP, and we will also know whether its ability to activate ras oncogenes resembles that of DMBA or BP. Since we expect that the carcinogenicity of DB[a,l]P is similar to that of DMBA, we think our tumorigenicity studies of DB[a,l]P will demonstrate that this PAH represents a significant human health hazard in cigarette smoke and other environmental pollutants. The data obtained from the chemistry, tumorigenicity, DNA-binding studies and oncogene activation will provide significant clues concerning the mechanism of carcinogenesis of DB[a,l]P.