Selective modification of replicating DNA by benz(a)pyrene

The problem of whether metabolites of chemical carcinogens interact with the genetic material of the cell in random fashion, or whether targets modified by carcinogens with the greatest intensity exist in DNA is of the utmost importance for the understanding of the initial stages of chemical carcinogenesis, for it is in these targets that the probability of damage to the cell oncogens is determined. A complex multilevel system of DNA organization exists in the cells of eukaryotes, and each of its levels evidently can make its own contribution to the specificity of interaction between carcinogens and genetic material. For instance, the probability of interaction of the benz(a)pyrene metabolite antibenz(a)pyrene 7,8-dioi 9,10-epoxide with guanyl bases of protein-free DNA (leading to a break in the DNA) is determined by the nature of the neighboring bases [7]. Complex formation by DNA with histones, forming nucleosomal structures, is the reason why the highest levels of modification of DNA by benz(a)pyrene are located in the internucleosomal regions [6]. Finally, at the next level of intranuclear DNA organization, where nucleosomal structures interact with nonhistone proteins and are attached to the nuclear matrix, regions of DNA nearest to the nuclear matrix, enriched with transcription-active genes and with certain potential oncogenes, were found to undergo maximal modification in undividing cells [2].