Induction of DNA strand breaks by reduced nitroimidazoles. Implications for DNA base damage

Radiation-reduced 2-nitroimidazoles (misonidazole, RSU-1137, Ro.03-8799 and Ro.03-8800) incubated in air with plasmid DNA (pH 7.0, 310K) induce DNA strand breakage, as revealed following subsequent heat or alkali treatment. Only RSU-1137 resulted in the binding of a [2-14C] fragment and significant yields of heat-labile strand breaks (greater than 20% loss of type-I DNA after 48 hr incubation). RSU-1137 was shown to be greater than 6 times more effective than misonidazole at producing alkali-labile breaks. In fact, the efficiency of alkali-induced strand break production is in the order: misonidazole less than Ro.03-8799 approximately Ro.03-8800 less than RSU-1137. Reaction of these reduced 2-nitroimidazoles with 2'-deoxyguanosine (dG) also results in the formation of a common glyoxal-dG product, with its yield and rate of production being dependent upon the 2-nitroimidazole used. It has been demonstrated that these variations are influenced by the N-1 side-chain of the 2-nitroimidazole. Product yields are approximately 5-6 times greater with misonidazole than with RSU-1137. From the evidence presented, it is apparent that formation of glyoxal (or a glyoxal-like product) is not responsible for the DNA strand breakage seen. It is inferred that these breaks are induced by a nitro-reduction product(s) which remains unidentified.