DNA Lesions : Nature and Genesis
Most carcinogens are DNA damaging agents. They can act on DNA directly or indirectly. Direct action means that the primary agent or a chemical derivative of the primary agent reacts with DNA usually resulting in the formation of a covalent adduct. Indirect action means attack of DNA by active oxygen species which are formed by the reaction of the primary agent with a non-DNA target. Many carcinogens act by one or the other mechanism, others by both.
Direct action predominates for chemical carcinogens and, in general, involves the substitution of the nucleophilic centers of DNA with the electrophilic damaging agents. Each damaging agent produces a characteristic spectrum of lesions. The site of substitution and the chemical properties, size and stereochemistry of the substituent determine the effect of the lesion on DNA and chromatin configuration. The lesion distribution varies for different agents and is affected by the nucleosomal and higher order chromatin structure, e.g. bulky substituents are usually introduced in higher concentrations into nucleosomal-linker than -core DNA.
Indirect action is mediated via active oxygen species most importantly hydroxyl-radicals, superoxide radicals, singlet oxygen, (hydrogen peroxide). Independent of the primary agent which elicits the formation of active oxygen species, a similar (but not identical) spectrum of lesions is produced. Major types of lesions formed via indirect action are strand breaks, base damage (e.g. products of the 5,6-dihydroxy-dihydrothymine type), apurinic- and apyrimidinic sites and sugar damage. Indirect action can be suppressed by radical scavengers, antioxidans and enzymes such as superoxide dismutases and peroxidases.
Ionizing radiation may be considered as the prototype for indirect action since hydroxyl-radicals generated by water-radiolysis are mostly responsible for the formation of DNA damage. For ultraviolet light the contribution of direct and indirect action is wavelength dependent. Indirect action is the exception for chemical DNA damaging agents. However, these exceptions are of particular importance for cancer research. Heterocyclic-aromatic ring systems which can form quinoid structures can partake in redox-cycles resulting in the formation of active oxygen species. Important examples for this class of agents are the anticancer drugs bleomycin, streptonigrin, adriamycin, daunorubicin and probably certain polycyclic aromatic hydrocarbons. Certain membrane active compounds such as the mouse skin tumor promotors phorbol-12-myristate-13-acetate, mezerein and teleocidin elicit a burst of superoxide radicals in certain target cells and cause chromosomal damage via indirect action.
These concepts are illustrated using examples from our work on the formation and repair of chromosomal damage induced by the carcinogens aflatoxin B1, benzo(a)pyrene and N-acetoxy-2-acetylaminofluorene which operate via direct action and near-ultraviolet light and the mouse skin promotor phorbol-12-myristate-13-acetate which operate at least in part via indirect action.
KeywordsActive Oxygen Species Sister Chromatid Exchange Indirect Action Primary Agent Bloom Syndrome
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