Effects of DNA structure on oxopropenylation by the endogenous mutagens malondialdehyde and base propenal.

Malondialdehyde (MDA) and nucleobase propenals can transfer oxopropenyl groups to guanine residues of DNA to yield pyrimodopurinone (M(1)G) adducts. The DNA structural requirements for reaction with alpha,beta-unsaturated aldehydes were explored. We found that single-stranded DNA is more sensitive to oxopropenylation than double-stranded DNA, and supercoiled plasmid DNA is more sensitive than linearized plasmid DNA. Increasing ionic strength inhibits oxopropenylation, especially by adenine propenal. The intercalating agents ethidium bromide and 9-aminoacridine enhanced oxopropenylation by severalfold. In contrast, actinomycin D, which both intercalates and binds in the minor groove, inhibited oxopropenylation. The anthracycline drugs daunorubicin and doxorubicin enhanced oxopropenylation by MDA up to 3-fold and by adenine propenal up to 7-fold in a concentration-dependent manner. The minor groove binders netropsin and distamycin inhibited oxopropenylation, but methyl green, a major groove binder, had little effect. These data suggest that steric access to the target nucleophile located in the minor groove of DNA is critical for adduct formation by the endogenous mutagens MDA and base propenals.