Dissociation of malondialdehyde mutagenicity in Salmonella typhimurium from its ability to induce interstrand DNA cross-links.

Malondialdehyde (MDA), an in vivo metabolite of lipid peroxidation and prostaglandin biosynthesis, is mutagenic in Salmonella typhimurium. It is a reactive electrophile that can form interstrand cross-links in DNA. To explore the possibility that MDA-induced interstrand cross-links are the pre-mutagenic lesion, we have quantitated the ability of highly purified preparations of MDA to form interstrand cross-links when reacted with linear plasmid DNA. At physiological temperature and pH, MDA did not form DNA cross-links as determined by DNA denaturation followed by agarose gel electrophoresis. DNA cross-links were formed, however, when incubations with MDA were carried out at either pH 4.2 or temperatures exceeding 60 degrees. alpha-Methylmalondialdehyde (CH3MDA) was found to cross-link DNA more efficiently than MDA, but was not mutagenic in any tester strain of Salmonella. MDA polymers, formed by acid incubation of MDA, also were capable of inducing cross-links. However, an inverse relationship was observed between mutagenicity and extent of polymerization. The pattern of mutagenic response for MDA in different strains of Salmonella was compared with mitomycin C, an established mutagenic cross-linking agent. Error-prone repair and a UvrB+ phenotype, which are needed for the induction of mutations by mitomycin C, were not required for MDA mutagenesis. These findings, taken together, dissociate the mutagenicity of MDA from its ability to form interstrand cross-links with DNA.