Carcinogen-DNA adducts are addition products formed by covalent binding of all or part of a carcinogen molecule to chemical moieties in DNA; adducts are formed when an activated chemical species (electrophilic, positively charged metabolite) binds covalently to negatively charged moieties in DNA. Carcinogen-DNA adducts of exogenous genotoxic chemical carcinogens may induce errors in DNA sequence (mutations). Subsequent transcription on a damaged template may result in the formation of abnormal proteins or the absence of protein. DNA adduct formation and mutagenesis are considered to bring about changes in gene expression that produce clonal expansions of cells lacking in growth control (tumors). A substantial period of time is required for a tumor to become evident, and DNA damage is considered to be necessary but not sufficient for tumorigenesis, since other events must also take place. DNA adduct levels, measured at any point in time, reflect tissue-specific rates of damage processing that include DNA adduct formation and removal (DNA repair), DNA adduct instability, tissue turnover and other events. In experimental model systems dose-response associations have been observed for DNA adduct formation, mutagenesis, and tumorigenesis. Reductions in tumor incidences have been observed when DNA adduct levels have been lowered, either by DNA repair processes or by administration of chemopreventive agents that inhibit DNA adduct formation with no change in dose.
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