The role of genotoxic and epigenetic mechanisms in tissue and organ specificity of chemical carcinogens; mammalian cells cultivated in vitro as a model system

This project is a continuation of previous VEGA projects (2/3004; 2/6032), which were focused on the elucidation of the role of cytochrome P4501A subfamily isoenzymes in the metabolic activation of DBC and its tissue specific derivatives and on the characterization of DNA damage profiles induced by these compounds in dependence on the mode of their activation. The main contribution of this project is a comprehensive approach in the study of the biological effects (genotoxic and epigenetic) of dibenzocarbazoles. The non-genotoxic (epigenetic) effects of dibenzocarbazoles are not known and until now has never been studied. Although the covalent binding of carcinogen to DNA is a primary step in the initiation of chemical carcinogenesis it is supposed that epigenetic effects, mainly clonal expansion of initiated cells is an essential event in tumour formation. It is possible that just these processes might play an important role in tissue specificity of chemical carcinogens. Experiments aimed on the study of the epigenetic effects could substantially contribute to the elucidation of the differences in the biological activities of particular dibenzocarbazoles. The stem-like cell line WB-F344 is a promising model system; it allows study simultaneously both the genotoxic and epigenetic effects of model carcinogens. It is suppose that mainly cytochrome P450 enzymes play a key role in biotransformation of dibenzocarbazoles. Although the role of CYP1A1 and 1A2 is relatively good understood, the role of other cytochrome P450 enzymes in the activation of tissue specific DBC derivatives is not known. The CYP3A4 has a dominant role in biotransformation of various drugs and xenobiotics in human beings. The sudy of the relationship between the biological activity and DNA damage formation is the basis to understand the mechanisms leading to mutagenesis and carcinogenesis.