Exocyclic DNA adducts

Abstract

The role of DNA etheno adducts in mutagenic and carcinogenic processes triggered by known occupational and environmental carcinogens, such as vinyl chloride and ethyl carbamate, has been well investigated. 1,N6-Etheno-2 -deoxyadenosine (?dAdo), 3,N4-etheno-2 -deoxycytidine (?dCyd) and N2,3-ethenoguanine (N2,3-?G) have already been detected in different tissues of rats exposed to vinyl chloride. Our laboratory have recently reported that trans, trans-2,4-decadienal (DDE), a lipid peroxidation product, is a versatile alkylating agent being able to generated after epoxidation, different adducts in its reaction with dAdo, dGuo and DNA. Our interest in the modification of DNA by ?,?-unsaturated aldehydes led us to examine in the present study the reaction of other related aldehydes with nucleosides and DNA. A screening on structure and reactivity towards DNA is required to assess the role of these compounds in cancer risks. Also, a highly sensitive method based on HPLC coupled to electrospray/tandem mass spectrometry to detected etheno adducts in small amounts of human DNA were developed in our laboratory. Etheno adduct levels were increased by several known cancer risk and were found to be progressively elevated in preneoplasias of cancer-prone patients and rodents, suggesting that these promutagenic lesions can drive cells to malignancy. For this purpose we will monitor DNA adducts in tissues of experimental animals exposed to carcinogens and to situations of increased oxidative stress (iron overload and cigarette smoke). The detection and quantification of these lesions in vivo can offer new insights in the role of these lesions in carcinogenesis. (AU)