INDIRECT MUTAGENESIS BY OXIDATIVE DNA-DAMAGE - FORMATION OF THE PYRIMIDOPURINONE ADDUCT OF DEOXYGUANOSINE BY BASE PROPENAL

Oxidation of endogenous macromolecules can generate electrophiles capa ble of forming mutagenic adducts in DNA, The lipid peroxidation produc t malondialdehyde, for example, reacts with DNA to form M(1)G, the mut agenic pyrimidopurinone adduct of deoxyguanosine, In addition to free radical attack of lipids, DNA is also continuously subjected to oxidat ive damage. Among the products of oxidative DNA damage are base propen als, We hypothesized that these structural analogs of malondialdehyde would react with DNA to form M(1)G. Consistent with this hypothesis, w e detected a dose-dependent increase in M(1)G in DNA treated with cali cheamicin and bleomycin, oxidizing agents known to produce base propen al, The hypothesis was proven when we determined that 9-(3-oxoprop-1-e nyl)adenine gives rise to the M(1)G adduct with greater efficiency tha n malondialdehyde itself. The reactivity of base propenals to form M(1 )G and their presence in the target DNA suggest that base propenals de rived from oxidative DNA damage may contribute to the mutagenic burden of a cell.