Is intercalation a critical factor in the covalent binding of mutagenic and tumorigenic polycyclic aromatic diol epoxides to DNA?

The tumorigenic and mutagenic effects induced by polycyclic aromatic diol epoxides are widely believed to involve the covalent binding of these electrophilic metabolites of polycyclic aromatic hydrocarbons to DNA. Here the relationships between the formation of non-covalent intercalation complexes with DNA, the DNA-catalyzed reaction rates, the formation of tetraols (which constitutes a detoxification pathway) and the level of covalent binding to DNA, are examined critically within the context of available experimental results. When the rates of reaction of the diol epoxide molecules at DNA binding sites dominate over those in the external aqueous solution, the level of covalent binding is independent of the intercalative non-covalent binding (association constant K, M-1) which precedes the covalent binding reaction. However, under conditions in which DNA does not catalyze or enhance the reaction rate of diol epoxide molecules (e.g. at high salt concentrations), or when there are efficient competitive reaction pathways in the solution external to the DNA, the level of covalent binding to DNA is predicted to be directly proportional to K. Since these latter reaction conditions are expected to prevail in a cellular environment, the ability of a given diol epoxide derivative to form intercalative non-covalent complexes with DNA prior to covalent binding should be an important factor in determining the biological activities of these compounds. The experimental conditions which are suitable for testing the relationships between non-covalent intercalative complex formation and covalent binding to DNA in vitro are described.