Carcinogen binding to DNA

A key initiating event in the induction of neoplasia by a chemical carcinogen is believed to be the covalent reaction of the carcinogen with the DNA of the target cell. Most carcinogens are not biologically active as such, but require metabolic conversion to a chemically reactive form (ultimate carcinogen). Chemical carcinogens undergo an extremely complex set of metabolic reactions, leading for the most part to inactive detoxification products as well as reactive electrophilic species. Direct structural identification of the carcinogen-DNA adduct will (1) immediately confirm that the chemical is acting as a potential carcinogen under a given set of circumstances; and (2) directly identify those critical metabolic pathways which are involved in the metabolism of the chemical to a carcinogenic form rather than an inactive detoxification product. The direct structural identification of carcinogen-DNA adducts represents a formidable analytical challenge, since only picomolar quantities can be isolated. The advent of newer ionization techniques, such as field desorption and mass spectrometric-based separation techniques capable of handling mixtures, are proving to be essential for the characterization of such structures. Examples of nucleic acid-carcinogen adduct structure characterizations that have led to fundamental insights into the mechanisms of chemical carcinogenesis will be discussed, and future trends in mass spectrometry that have a direct bearing on these difficult problems will be pointed out.