Formation of cyclic nucleic acid adducts from some simple alpha, beta-unsaturated carbonyl compounds and cyclic...

To determine the structures of the DNA adducts of two cyclic nitrosamines, N-nitrosopyrrolidine and N-nitrosomorpholine, the model compounds, alpha-acetoxy-N-nitrosopyrrolidine, 4-(carbethoxynitrosamino)butanal and 2-(carbethoxynitrosamino)ethoxyacetaldehyde, were allowed to react with deoxyguanosine in the presence of porcine liver esterase or base. These model compounds are stable precursors of intermediates formed upon metabolic alpha-hydroxylation of N-nitrosopyrrolidine and N-nitrosomorpholine. The major adducts formed in these reactions were isolated and characterized, on the basis of ultraviolet absorption, mass spectrometry, proton nuclear magnetic resonance and chromatographic properties, as structurally unique 1,N2-cyclic deoxyguanosine adducts. Reaction of crotonaldehyde and glyoxal with deoxyguanosine at 37 degrees C, pH 7, also led to the formation of 1,N2-cyclic deoxyguanosine adducts identical to those formed from the model compounds for alpha-hydroxylation of N-nitrosopyrrolidine and N-nitrosomorpholine, respectively. The 1,N2-cyclic deoxyguanosine adducts were also formed in DNA, upon incubation with N-nitrosopyrrolidine and rat liver microsomes. Acrolein, the simplest alpha, beta-unsaturated carbonyl compound, reacted readily with deoxyguanosine to form three major adducts. These adducts were characterized as cyclic 1,N2-propanodeoxyguanosine adducts resulting from Michael addition of acrolein to the 1- and N2-positions of deoxyguanosine followed by ring closure. One of these adducts, as well as the corresponding crotonaldehyde adduct, was formed in calf thymus DNA upon reaction with acrolein or crotonaldehyde under physiological conditions. The level of modification of DNA by acrolein was considerably higher than that by either crotonaldehyde or N-nitrosopyrrolidine.