Izzotti A, D'Agostini F, Bagnasco M, Scatolini L, Rovida A, Balansky R M, Cesarone C F, De Flora S
Institute of Hygiene and Preventive Medicine, University of Genoa, Italy.
Cancer Res. 1994 Apr 1;54(7 Suppl):1994s-1998s.
Molecular dosimetry techniques were exploited in order to assess the efficacy of experimental chemoprevention assays and to evaluate the involvement of DNA alterations, not only in cancer but also in other chronic degenerative diseases. In agreement with other protective effects previously observed in the same animal models, the thiol N-acetylcysteine (NAC) totally prevented or significantly reduced the formation of carcinogen-DNA adducts in three experimental systems in rats. Thus, as assessed by 32P postlabeling, supplement of the diet with NAC decreased both deoxyguanosine-C8-aminofluorene adducts (butanol enrichment) and deoxyguanosine-N2-acetylaminofluorene adducts (nuclease P1 enrichment) formed in rat liver following dietary administration of 2-acetylaminofluorene for 3 weeks. DNA adducts were detected by synchronous fluorescence spectrophotometry in rat liver, lung, heart, and testis following a daily i.t. instillation of benzo(a)pyrene for 3 consecutive days. The whole-body exposure of rats to mainstream cigarette smoke for 40 consecutive days resulted in the appearance of DNA adducts in heart, lung, and aorta, whereas no adduct was detected by synchronous fluorescence spectrophotometry in liver, brain, and testis. Multiple DNA adducts in the aorta were also measured by 32P postlabeling. Administration of NAC by gavage inhibited the formation of DNA adducts in all organs of rats treated with benzo(a)pyrene or exposed to cigarette smoke. It is of interest that a single chemopreventive agent can display a broad-spectrum protective ability. The selective localization of DNA adducts in different organs depends on pharmacokinetics, metabolic capacity, DNA repair efficiency, and cell proliferation rate. Whereas inhibition by NAC of DNA adducts in testis can be correlated with its demonstrated ability to prevent dominant lethal mutations, we raise the hypothesis that DNA adducts in lung, heart, and aorta may be pathogenetically associated with lung cancer, cardiomyopathies, and arteriosclerosis, respectively. In order to explore the involvement of molecular and biochemical alterations in human arteriosclerosis, we started an extensive collaborative project and report here preliminary data showing the presence of DNA adducts in aorta smooth muscle cells obtained from arteriosclerotic patients.
分子剂量测定技术被用于评估实验性化学预防试验的效果，并评估DNA改变的参与情况，不仅在癌症中，而且在其他慢性退行性疾病中。与先前在相同动物模型中观察到的其他保护作用一致，硫醇N-乙酰半胱氨酸（NAC）在大鼠的三个实验系统中完全预防或显著减少了致癌物-DNA加合物的形成。因此，通过32P后标记评估，在饮食中补充NAC可降低大鼠肝脏中在给予2-乙酰氨基芴3周后形成的脱氧鸟苷-C8-氨基芴加合物（丁醇富集）和脱氧鸟苷-N2-乙酰氨基芴加合物（核酸酶P1富集）。连续3天每日经气管内滴注苯并(a)芘后，通过同步荧光分光光度法在大鼠肝脏、肺、心脏和睾丸中检测到DNA加合物。大鼠连续40天全身暴露于主流香烟烟雾中导致心脏、肺和主动脉中出现DNA加合物，而通过同步荧光分光光度法在肝脏、大脑和睾丸中未检测到加合物。主动脉中的多种DNA加合物也通过32P后标记进行了测量。通过灌胃给予NAC可抑制用苯并(a)芘处理或暴露于香烟烟雾的大鼠所有器官中DNA加合物的形成。有趣的是，单一的化学预防剂可以表现出广谱的保护能力。DNA加合物在不同器官中的选择性定位取决于药代动力学、代谢能力、DNA修复效率和细胞增殖率。虽然NAC对睾丸中DNA加合物的抑制作用可能与其预防显性致死突变的已证实能力相关，但我们提出假说，即肺、心脏和主动脉中的DNA加合物可能分别与肺癌、心肌病和动脉硬化的发病机制相关。为了探索分子和生化改变在人类动脉硬化中的参与情况，我们启动了一个广泛的合作项目，并在此报告初步数据，显示从动脉硬化患者获得的主动脉平滑肌细胞中存在DNA加合物。
