CHEMOPREVENTION OF CARCINOGEN-DNA ADDUCTS AND CHRONIC DEGENERATIVE DISEASES

Molecular dosimetry techniques were exploited in order to assess the e fficacy of experimental chemoprevention assays and to evaluate the inv olvement of DNA alterations, not only in cancer but also in other chro nic degenerative diseases. In agreement with other protective effects previously observed in the same animal models, the thiol N-acetylcyste ine (NAC) totally prevented or significantly reduced the formation of carcinogen-DNA adducts in three experimental systems in rats. Thus, as assessed by P-32 postlabeling, supplement of the diet with NAC decrea sed both deoxyguanosine-C-8-aminofluorene adducts (butanol enrichment) and deoxyguanosine-N2-acetylaminofluorene adducts (nuclease P1 enrich ment) formed in rat liver following dietary administration of 2-acetyl aminofluorene for 3 weeks. DNA adducts were detected by synchronous fl uorescence spectrophotometry in rat liver, lung, heart, and testis fol lowing a daily i.t. instillation of benzo(a)pyrene for 3 consecutive d ays. The whole-body exposure of rats to mainstream cigarette smoke for 40 consecutive days resulted in the appearance of DNA adducts in hear t, lung, and aorta, whereas no adduct was detected by synchronous fluo rescence spectrophotometry in liver, brain, and testis. Multiple DNA a dducts in the aorta were also measured by P-32 postlabeling. Administr ation of NAC by gavage inhibited the formation of DNA adducts in all o rgans of rats treated with benzo(a)pyrene or exposed to cigarette smok e. 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 cap acity, DNA repair efficiency, and cell proliferation rate. Whereas inh ibition by NAC of DNA adducts in testis can be correlated with its dem onstrated ability to prevent dominant lethal mutations, we raise the h ypothesis that DNA adducts in lung, heart, and aorta may be pathogenet ically associated with lung cancer, cardiomyopathies, and arterioscler osis, respectively. In order to explore the involvement of molecular a nd biochemical alterations in human arteriosclerosis, we started an ex tensive collaborative project and report here preliminary data showing the presence of DNA adducts in aorta smooth muscle cells obtained fro m arteriosclerotic patients.