Endogenous formation and significance of 1,N-2-propanodeoxyguanosine adducts

The detection of 1,N-2-propanodeoxyguanosine adducts in the DNA of rodent a nd human tissues as endogenous lesions has raised important questions regar ding the source of their formation and their roles in carcinogenesis. Both in vitro and in vivo studies have generated substantial evidence which supp orts the involvement of short- and long-chain enals derived from oxidized p olyunsaturated fatty acids (PUFAs) in their formation. These studies show t hat: (1) the cyclic propane adducts are common products from reactions of e nals with DNA bases; (2) they are formed specifically from linoleic acid (L A; omega-6) and docosahexaenoic acid (omega-3) under in vitro stimulated li pid peroxidation conditions; (3) the levels of propane adducts are dramatic ally increased in rat liver DNA upon depletion of glutathione; (4) the addu ct levels are increased in the liver DNA of the CCl4-treated rats and the m utant strain of Long Evans rats which are genetically predisposed to increa sed lipid peroxidation; and (5) adduct levels are significantly higher in o lder rats than in newborn rats. These studies collectively demonstrate that tissue Lipid peroxidation is a main endogenous pathway leading to propane adduction in DNA. The possible contribution from environmental sources, how ever, cannot be completely excluded. The mutagenicity of enals and the muta tions observed in site-specific mutagenesis studies using a model 1,N-2-pro panodeoxyguanosine adduct suggest that these adducts are potential promutag enic lesions. The increased levels of the propane adducts in the tissue of carcinogen-treated animals also provide suggestive evidence for their roles in carcinogenesis. The involvement of these adducts in tumor promotion is speculated on the basis that oxidative condition in tissues is believed to be associated with this process. (C) 1999 Elsevier Science B.V. All rights reserved.