DNA-ADDUCTS AND CHRONIC DEGENERATIVE DISEASES - PATHOGENETIC RELEVANCE AND IMPLICATIONS IN PREVENTIVE MEDICINE

Chronic degenerative diseases are the leading causes of death in devel oped countries. Their control is exceedingly difficult due to their mu ltiplicity and diversity, the interconnection with a network of multip le risk factors and protective factors, the long latency and multistep pathogenesis, and the multifocal localization. Adducts to nuclear DNA are biomarkers evaluating the biologically effective dose, reflecting an enhanced risk of developing a mutation-related disease more realis tically than the external exposure dose. The localization and accumula tion of these promutagenic lesions in different organs are the composi te result of several factors, including (a) toxicokinetics (first-pass effect); (b) local and distant metabolism; (c) efficiency and fidelit y of DNA repair; and (d) cell proliferation rate. The last factor will affect not only the dilution of DNA adducts but also the possible evo lution towards either destructive processes, such as emphysema or card iomyopathies, or proliferative processes, such as benign or malignant tumors at various sites. They also include heart tumors affecting feta l myocytes after transplacental exposure to DNA-binding agents, blood vessel tumors, and atherosclerotic plaques, In this article, particula r emphasis is given to molecular alterations in the heart, which is th e preferential target for the formation of DNA adducts in smokers, and in human aorta, where an extensive molecular epidemiology project is documenting the systematic presence of adducts to the nuclear DNA of s mooth muscle cells from atherosclerotic lesions, and their significant correlation with known atherogenic risk factors. Exocyclic DNA adduct s resulting from lipid peroxidation, and age-related indigenous adduct s (I-compounds) may also originate from endogenous sources, chronic in fections and infestations, and inflammatory processes. Type II I-compo unds are bulky DNA lesions resulting from oxidative stress, whereas ty pe I I-compounds are presumably normal DNA modifications, which displa y positive correlations with median life span and are decreased in can cer and other pathological conditions. Profiles of type I I-compounds strongly depend on diet and are related to the antidegenerative effect s of caloric/dietary restriction. Even broader is the possible meaning of adducts to mitochondrial DNA, which have been detected in rodents exposed to genotoxic agents and complex mixtures, as well as in untrea ted rodents, in larger amounts when compared to the nuclear DNA of the same cells. Mutations in mitochondrial DNA increase the number of oxi dative phosphorylation-defective cells, especially in energy-requiring postmitotic tissues such as brain, heart and skeletal muscle, thereby playing an important role in aging and a variety of chronic degenerat ive diseases. A decreased formation of DNA adducts is an indicator of reduced risk of developing the associated disease. Therefore, these mo lecular dosimeters can be used as biomarkers in the prevention of chro nic degenerative diseases, pursued either by avoiding exposure to addu ct-forming agents or by using chemopreventive agents. Interventions ad dressed to the human organism by means of dietary measures or pharmaco logical agents have encountered a broad consensus in the area of cardi ovascular diseases, and are deserving a growing interest also in cance r prevention. The efficacy of chemopreventive agents can be assessed b y evaluating inhibition of nuclear DNA or mitochondrial DNA adduct for mation in vitro, in animal models, and in phase II clinical trials in high-risk individuals.