Unsubstituted hydroxamic acids (ArCONHOH orRCONHOH) are mutagenic for bacteria and mammalian cells and, therefore, are potential carcinogens. It is generally believed that the binding of chemicals to DNA is an early step in many of the processes of mutagenesis and carcinogenesis. For one class of known mutagens and carcinogens, i.e., arylhydroxamic acid, (ArNOHCOR), which is structurally different from the N-unsubstituted hydroxamic acid, (ArCONHOH), the activation pathways leading to DNA adduct formation and carcinogenesis have been well studied. In contrast, very little is known about the reaction of unsubstituted hydroxamic acids with macromolecules under biological and chemical conditions. In this proposal, 2-naphthohydroxamic acid will be used as a model compound, because it is one of the most mutagenic hydroxamic acids of this class. The appropriately labeled 2-napthohydroxamic acid and its derivatives wil be used to explore the reaction pathways responsible for their metabolic activation to yield adducts with DNA of bacteria and cell free systems. One potential of this compound to elicit a genotoxic response in animals will also be tested by determining the extent and types of adduct formation of this compound with the macromolecules of rat liver and kidney in vivo. The carcinogenicity of 2-naphthohydroxamic acid will be tested with newborn CD rats by S.C. injections, thus establishing the carcinogenic or non-carcinogenic nature of this model compound. The results obtained from this project will provide the basis for future studies of mechanisms of activation and carcinogenicity of these hydroxamic acids.
