There is compelling evidence that many mutagens and carcinogens are able to react with cellular DNA either directly or following metabolic formation of reactive products. If DNA replication proceeds on such a modified template before altered bases or nucleotides are removed by enzymic repair processes, the mutations can be genetically fixed. Thus, the extent of carcinogen-induced promutagenic DNA damage and the capacity of cells to repair such damage represent critical events in the initiation of carcinogenesis. We are studying the in vivo formation and repair of carcinogen metabolite-DNA adducts in tissues and cells that are susceptible or resistant to carcinogen-induced neoplasia. We are concerned with the effects of dose of carcinogen on the amounts and types of adducts formed and on the subsequent repair of these adducts. Our studies on the in vivo formation and repair of benzo(a)-pyrene (BP) metabolite-DNA adducts in a variety of tissues and cell types emphasize the possibility that long-term exposure to low levels of BP could result in the accumulation of BP-DNA adducts in cells which have slow turnover rates. Even if environmental exposure to BP (and other polycyclic aromatic hydrocarbons) is too small to induce neoplasia, the persistence of BP-DNA adducts may produce aberrations in transcripts of genetic information in various cell types and lead to other toxic effects. Studies with 4-(N-Methyl-N-Nitrosamino)-1-(3-Pyridyl)-1-Butanone (NNK), a major nitrosamine formed in tobacco smoke, have demonstrated that site specificity for tissue alkylation and carcinogenesis by NNK are identical. High concentrations of O6MG in the lung and nasal cavity may be important factors in the induction of respiratory tumors whereas accumulation of O4MdT may be involved in the induction of hepatocellular carcinoma by NNK. DNA repair was examined in isolated lymphocytes after treatment of rats in vivo with various carcinogens. The in vitro lymphocyte system in conjunction with specific inhibitors of DNA repair may be a valuable approach to detect low levels of in vivo carcinogen-induced DNA damage and to study the mechanism of excision repair.
