alpha,beta-Unsaturated aldehydes (enals) are not only common environmental pollutants but they are also formed endogenously by metabolism of certain carcinogens and by lipid peroxidation. Enals are easily epoxidized to the epoxy aldehydes. Both enals and the epoxides modify DNA bases by forming the exocyclic adducts. The former yields propano adducts, whereas, the latter forms a variety of structurally unique adducts including etheno adducts. The expoxides are considerably more reactive toward DNA than the parent aldehydes. Consistent with these observations, the epoxide aldehydes are also more mutagenic and tumorigenic. The site-specific mutagenesis studies showed that exocyclic adducts are miscoding lesions. These adducts are detected by immunoassays and 32P-postlabeling in cultured cells and rodents exposed directly or metabolically to acrolein,crotonaldehyde and other related aldehydes. Exocyclic adducts are, therefore, likely to be involved in carcinogenesis. Recent studies showed that the propano and etheno adducts are present, at relatively high levels, in the tissue DNA of untreated rodents and humans. These results suggest that exocyclic adducts are formed from endogenous sources. We hypothesize that 1,N2- propanodeoxyguanosine adducts of acrelein and crotonaldehyde, 1,N2- ethenodeoxyguanosine, and 1,N6-ethenodeoxyadenosine are formed in tissue DNA by endogenous lipid peroxidation. To test this hypothesis we will: 1. study effects of lipid peroxidation on the formation of exocyclic adducts in DNA with hepatic microsomes and cultured hepatocytes; 2. examine effects of in vivo lipid peroxidation on levels and persistence of the exocyclic adducts in the liver DNA of rats; 3. establish specific in vivo epoxidation pathways by studying the formation of the substituted etheno adducts in rat liver DNA; 4. examine the interspecies and age-related differences in adduct levels; 5. examine effects of dietary fat on the formation of adducts in the DNA of rats; 6. study the roles of enal conjugates in DNA adduction and mutagenicity.
Showing the most recent 10 out of 35 publications
