CANCER RISK AND OXIDATIVE DNA-DAMAGE IN MAN

In living cells reactive oxygen species (ROS) are formed continuously as a consequence of metabolic and other biochemical reactions as well as external factors. Some ROS have important physiological functions. Thus, antioxidant defense systems cannot provide complete protection f rom noxious effects of ROS. These include oxidative damage to DNA, whi ch experimental studies in animals and in vitro have suggested are an important factor in carcinogenesis. Despite extensive repair oxidative ly modified DNA is abundant in human tissues, in particular in tumors, i.e., in terms of 1-200 modified nucleosides per 10(5) intact nucleos ides. The damaged nucleosides accumulate with age in both nuclear and mitochondrial DNA. The products of repair of these lesions are excrete d into the urine in amounts corresponding to a damage rate of up to 10 (4) modifications in each cell every day. The most abundant of these l esions, 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), is also the mos t mutagenic, resulting in GT transversions which are frequently found in tumor relevant genes. A series of other oxidative modifications of base and sugar residues occur frequently in DNA, but they are less wel l studied and their biological significance less apparent. The biomark ers for study of oxidative DNA damage in humans include urinary excret ion of oxidized nucleosides and bases as repair products and modificat ions in DNA isolated from target tissue or surrogate cells, such as ly mphocytes. These biomarkers reflect the rate of damage and the balance between the damage and repair rate, respectively. By means of biomark ers a number of important factors have been studied in humans. Ionizin g radiation, a carcinogenic and pure source of ROS, induced both urina ry and leukocyte biomarkers of oxidative DNA damage. Tobacco smoking, another carcinogenic source of ROS, increased the oxidative DNA damage rate by 35-50% estimated from the urinary excretion of 8-oxodG, and t he level of 8-oxodG in leukocytes by 20-50%. The main endogenous sourc e of ROS, the oxygen consumption, showed a close correlation with the 8-oxodG excretion rate although moderate exercise appeared to have no immediate effect. So far, cross-sectional study of diet composition an d intervention studies, including energy restriction and antioxidant s upplements, have generally failed to show an influence on the oxidativ e DNA modification. However, a diet rich of Brussels sprouts reduced t he oxidative DNA damage rate, estimated by the urinary excretion of 8- oxodG, and the intake of vitamin C was a determinant for the level of 8-oxodG in sperm DNA. A low-fat diet reduced another marker of oxidati ve DNA damage in leukocytes. In patients with diseases associated with a mechanistically based increased risk of cancer, including Fanconi a nemia, chronic hepatitis, cystic fibrosis, and various autoimmune dise ases, the biomarker studies indicate an increased rate of oxidative DN A damage or in some instances deficient repair. Human studies support the experimentally based notion of oxidative DNA damage as an importan t mutagenic and apparently carcinogenic factor. However, the proof of a causal relationship in humans is still lacking. This could possibly be supported by demonstration of the rate of oxidative DNA damage as a n independent risk factor for cancer in a prospective study of biobank material using a nested case control design. In addition, oxidative d amage may be important for the aging process, particularly with respec t to mitochondrial DNA and the pathogenesis of inflammatory diseases.