FP6 priority

1.1.1   Genomics and Biotechnology for Health

1.1.1.1

Title of the proposal

Tissue and organ specificity of chemical carcinogens

Institute

Slovak Academy of Sciences, Cancer Research Institute
Vlarska 7, 833 91 Bratislava, Slovak Republic

Contact

Research subject for a potential FP6 project

Characteristic hallmark of many chemical carcinogens is their strict organ- or tissue-specificity. A number of approaches have been undertaken to identify the factors responsible for this phenomenon. Various reasons might be involved in the tissue specificity of chemical carcinogens including the chemical structure of the molecule which determines the mechanisms of bio-transformation; differences in the expression of drug-metabolizing enzymes between tissues, the chromatin organization due to specific gene expression, DNA repair capacity of the cells, etc. In our laboratory we use 7H-dibenzo[c,g]carbazole (DBC) and its two tissue specific derivatives as model agents. N-methylDBC is a specific sarcomagen; it induces sarcomas, respiratory tumors and papillomas, but lacks hepatocarcinogenic potential. MeDBC even when administered at very high doses initiates only trace level of DNA binding in the liver. DimethylDBC is a strict hepato-carcinogen. Hepatocarcinogenicity of diMeDBC is followed with severe cytotoxicity manifested by mitochondrial vacuolisation and destruction. Cytochromes P450 play a key role in biotrans-formation of DBC derivatives. Two ways of DBC activation are suggested: i) at its ring-carbon atoms, as with PAH; and ii) at nitrogen atom. It is supposed that the heterocyclic nitrogen strongly affects the biological activity of DBC and plays an important role in liver carcinogenicity. Our recent experiments confirmed that CYP1A1 is entirely involved in the metabolic activation of sarcomagenic DBC derivatives while CYP1A2 mediates the biotransformation of all DBC derivatives. Reactive intermediates, however, formed due to CYP1A2 activation were substrate for NAT2, a phase II enzyme. Subsequent acetylation of proximate intermediates led to the elimination of any mutagenicity of DBC derivatives. These data indeed indicate that CYP1A2 is not the ultimate cytochrome P450 involved in hepatocarcinogenicity of DBC derivatives. Further experiments will be aimed to elucidate the role of other drug-metabolising and conjugating enzymes or other intracellular interactions that may play a crucial role in the tissue specificity of DBC derivatives.

Recent international cooperation of the research team

Medical Research Council Toxicology Unit, Leicester, UK; Genotoxicity and Carcinogenesis, Institute Curie, France; Lab. of Genetic Ecotoxicology, Institute of Experimental Medicine, Czech Republic

Proposer´s relevant publications related to the research subject

Gabelova, A., Perin-Roussel, O., Jounaidi, Y., Perin, F.: DNA-adduct formation in primary mouse embryo cells induced by 7H-dibenzo[c,g]carbazole and its organ-specific carcinogenic derivatives. Environ. and Mol. Mutagenesis, 30, 56-64, 1997
Gabelova, A., Bacova, G., Slamenova, D., Perin, F.: Use of repair endonucleases for characterization of DNA damage induced by N-heterocyclic aromatic hydrocarbons. Acta Biochimica Polonica, 45, 18-23, 1998
Gabelova, A., Bacova, G., Ruzekova, L., Farkasova, T.: Role of cytochrome P4501A1 in biotransformation of sarcomagenic derivative of N-methyldibenzo[c,g]carbazole. Mutat. Res., 269, 259-269, 2000
Farkasova, T., Gabelova, A., Slamenova, D.: Induction of micronuclei by 7H-dibenzo[c,g]carbazole and its tissue specific derivative in Chinese hamster V79MZh1A1 cells. Mutat. Res., 491, 87-96, 2001
Gabelova, A., Farkasova, T., Bacova, G., Robichova, S.: Mutagenicity of 7H-dibenzo[c,g]carbazole and its tissue specific derivatives in genetically engeneered Chinese hamster V79 cell lines stably expressing cytochrome P450. Mutat. Res. (in press).