DNA-ADDUCTS IN HUMAN CARCINOGENESIS - ETIOLOGIC RELEVANCE AND STRUCTURE-ACTIVITY RELATIONSHIP

Sensitive methods for quantifying DNA adducts from (i) benzo[a]pyrene (BP), (ii) alkylation exposure, and (iii) etheno(epsilon)-DNA adduct-f orming chemicals were developed and applied to humans and animal model s. The aims were to identify hitherto unknown sources and mechanisms o f exogenous and endogenous DNA damage, to examine the effect of drug p olymorphism on BP adduct levels, and to develop QSAR between tumorigen ic potency, heritable genetic damage and structural elements of alkyla ting carcinogens (Vogel and Nivard (1994) Mutation Res., 395, 13-32). (i) BP-DNA adducts: An HPLC/fluorimetry assay suitable for measuring()-anti-BP-diol-epoxide (BPDE) adducts in human tissues and white blood cells (WBC) was developed (Alexandrov et al. (1992) Cancer Res., 52, 6248-6253). In smokers, a positive correlation was found between pulmo nary CYP1A1-related catalytic activity (AHH) and the level of lung BPD E-DNA adducts. In coke oven workers, an enhancing effect of smoking on BPDE-adduct levels in WBC was demonstrated (Rojas et al. (1995) Carci nogenesis, 16, 1373-1376). (ii) 3-Alkyladenines (3-alkAde): Alkylating carcinogens form 3-alkAde adducts in DNA which depurinate to yield 3- alkAde in urine, for which a detection method was developed (Friesen e t al. (1991) Chem. Res. Toxicol., 4, 102-106; Prevost et al. (1990) Ca rcinogenesis, 11, 1747-1751), using immunoaffinity purification and GC -MS analysis. The usefulness of 3-alkAde analysis for the determinatio n of the whole-body dose of alkylating agents derived from exogenous a nd endogenous sources was demonstrated. (iii) Etheno-DNA adduct-formin g agents: Etheno(epsilon)-DNA base adducts (epsilon dA,epsilon dC,epsi lon dG) are promutagenic DNA lesions that are formed by occupational ( vinyl halides) and environmental (urethane) carcinogens. An ultrasensi tive detection method was developed (Nair et al. (1995) Carcinogenesis , 16, 613-617), based on immunoaffinity purification and P-32-postlabe lling of epsilon-nucleoside 3'-monophosphates. Liver DNA from unexpose d rats, mice and from human samples contained background levels of eps ilon dA and epsilon dC (Bartsch et al. (1994) Drug Metab. Rev., 26, 34 9-371). As formation of epsilon dA and epsilon dC adducts by lipid per oxidation products was demonstrated (El Ghissassi et al. (1995) Chem. Res. Toxicol., 8, 278-283), they may serve as markers for oxidative st ress. Results from testing this hypothesis are presented.