DNA Binding as a Probe for Metabolic Activation in Various Systems

The metabolic activation of chemical carcinogens has been studied intensively over the last 20 years. Classically, the pathway of activation was recognized by identifying a metabolite that exhibited greater carcinogenic potency than the parent carcinogen (1). For the polycyclic hydrocarbon carcinogens, this approach met with little success. However, theoretical chemists emphasized the K-regions as likely sites for interactions of these hydrocarbons with cellular components (2), and this theorization found a basis in the potent activity of hydrocarbon K-region oxides in various in vitro systems (3). As a result, there was a growing acceptance of these K-region oxides as the active forms of the hydrocarbon carcinogens, despite their very limited carcinogenic activities in in vivo animal test systems (4). The limited carcinogenic activity of these compounds was rationalized by the theory that their chemical reactivity led to their destruction before they reached the appropriate target cells or macromolecules.