DNA Adducts in Human Carcinogenesis

Abstract

The rationale and biological basis for measuring DNA adducts as relevant biomarkers of the adverse health effects of carcinogens in humans are summarized. By integrating highly sensitive and specific analytical ’ detection methods into well-designed epidemiological studies, the following contributions to etiology and mechanisms in human carcinogenesis can be gained: (i) Adduct measurement allows new insights into disease etiology as the adduct analysis permits the identification of hitherto unknown DNA-reactive chemicals and of carcinogenic components in complex exposures, thus increasing the power to establish causal relationships. (ii) Highly exposed individuals can be more timely identified, leading to avoidance or lowering of exposure to carcinogenic risk factors. (iii) Subgroups in the population (pharmacogenetic variants) that are more susceptible to the action of environmental carcinogens, due to genetic polymorphism of xenobiotic-metabolizing enzymes are identifiable by a combination of genotyping and DNA-adduct measurements. (iv) Repeated applications of dosimetry methods for macromolecular adducts can evaluate the effectiveness of intervention studies, either by reduction of carcinogen exposure or through chemopreventive strategies. (v) Incorporation of DNA-adduct measurements (and other data on critical parameters involved in carcinogenesis) will reduce (a) the enormous uncertainties associated today with high-to-low dose and species-to-species extrapolation and (b) yield information on interindividual and interethnic differences among human populations that can be integrated into risk assessment procedures. (vi) the role of specific carcinogens may be implicated in the etiology of cancers retrospectively by analyzing mutational spectra in tumors that arise from exogenous and endogenous mutagens by reaction with DNA; this is based on the assumption that carcinogens and their adducts leave specific mutational fingerprints in critical genes involved in human carcinogenesis, and that fingerprints are still found in tumors or precursor lesions so that they could be used to trace etiological agents that caused the tumors several decades ago. (vii) Adducts may be useful to study pathogenesis and preventive approaches of degenerative diseases other than cancer. Recent advances in these areas are illustrated by specific examples from the author’s own research activities, covering benzo[a]pyrene diolepoxide-, etheno-and 3-alkyladenine-DNA adducts.