Reactivity and mutagenicity of endogenous DNA oxopropenylating agents: Base propenals, malondialdehyde, and N-epsilon-oxopropenyllysine

Malondialdehyde (MDA), a mutagenic product of lipid peroxidation, reacts wi th DNA to form the premutagenic lesion, pyrimido[1,2-alpha] purin-10(3H)-on e (M(1)G). M(1)G is present in normal human tissues, but the contribution o f other endogenously produced MDA analogues is poorly understood. Oxidation of the DNA backbone can cause strand breaks and release base propenals, an d MDA condensation with proteins yields N-epsilon-oxopropenyllysine. Here w e compare the M(1)G-forming ability and Salmonella typhimurium mutagenicity of MDA with adenine, thymine, and cytosine propenals and N-alpha-acetyl-N- epsilon-oxopropenyllysine methyl ester. Base propenals are 30-150 times mor e potent than MDA in M1G formation and are 30-60 times more mutagenic than MDA. In addition, the Fe-bleomycin complex, which generates base propenals, induced M1G, but gamma -radiation, which generates mostly MDA, did not. M( 1)G formation by MDA and base propenals was concentration-dependent, time-d ependent, and enhanced by acidic conditions. N-alpha-Acetyl-N-epsilon-oxopr openyllysine methyl ester was less reactive and less mutagenic than MDA. Th ese differences in potency are consistent with differences in leaving group ability. This work supports a role for other MDA analogues, especially bas e propenals, in the formation of endogenous M(1)G adducts.