Formation of DNA etheno adducts in rodents and humans and their role in carcinogenesis

Abstract

Ethenobases are exocyclic adducts formed with DNA by some environmental carcinogens such as vinyl chloride or urethane. In the last few years, they have received a renewed interest due to the development of sensitive techniques of analysis that made it possible to measure their formation in vivo. This minireview summarizes the information gained recently from the work of several laboratories, including ours. Increased levels of DNA etheno adducts have been measured in target tissues from rodents exposed to vinyl chloride or urethane. Hepatic tumours caused by exposure to vinyl chloride in humans and in rats and lung tumours induced by urethane in mice exhibit base pair substitution mutations in the ras and p53 genes which seem to be exposure-specific and consistent with the promutagenic properties of ethenobases. Background levels of etheno adducts have been detected in DNA from non-exposed humans or animals, pointing to an alternative, endogenous pathway of formation. This background may be affected by dietary factors. It could arise from the reaction of trans-4-hydroxy-2-nonenal (or its epoxide 2,3-epoxy-4-hydroxynonanal), a lipid peroxidation product, with nucleic acid bases. Elevated levels of etheno adducts are found in hepatic DNA from humans and rodents with genetic predisposition to oxidative stress and lipid peroxidation in the liver, and with an associated increased risk of liver cancer. These data suggest that DNA ethenobases could serve as new biomarkers of oxidative stress/lipid peroxidation.