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, cell turnover and gene expression in tissues and cells that are susceptible or resistant to carcinogen-induced neoplasia. We are concerned with the effects of dose of carcinogen on DNA adduct formation and repair, cytotoxicity and cell replication. Studies with 4-(N-Methyl-N-Nitrosamino)1-(3-Pyridyl)-1-Butanone (NNK), a major nitrosamine found in tobacco smoke and products, demonstrate that extrapolation from high to low doses for the estimation of carcinogenic risk are often significantly enhanced by data on DNA adduct formed for the specific chemical in question. Moreover, data from the target organ may be insufficient for accurate risk assessment. For example, the Clara cell, although accounting for only 1% of the pulmonary cells in the lung of rat, was found to possess a 30-fold higher level of 06- methylguanine adduct than lung tissue. The Clara cell is the purported progenitor cell for NNK-induced pulmonary neoplasia.
