Role of cytochrome P4501A1 in biotransformation of a tissue specific sarcomagen N-methyldibenzo[c,g]carbazole

7H-dibenzo[c,g]carbazole (DBC) is a potent liver and skin carcinogen, while its synthetic methyl derivative N-methyldibenzo [c,g]carbazole (MeDBC) is tissue specific sarcomagen. It is supposed that sarcomagenic activity of DE C depends on biotransformation at ring-carbon atoms, as with PAH, whereas t he heterocyclic nitrogen plays an important role in liver carcinogenicity. The objective of this study was to elucidate the role of cytochrome P4501A1 in metabolic activation of sarcomagenic derivatives of DEC and to characte rize the DNA damage profiles induced by DEC and MeDBC in relation to the mo de of metabolic activation. The genetically engineered V79MZh1A1 cell line with stable expression of cDNA of human cytochrome P4501A1, the parental V7 9MZ cell line lacking any cytochrome P450 activity and human hepatocarcinom a Hep G2 cells were used as a model cells. Dose-dependent decrease in colon y forming ability (CFA) was found in the V79MZh1A1 cell line after treatmen t of cells with DEC and MeDBC; however, no change in CFA was induced in par ental V79MZ cells. These results were in a good correlation with DNA damagi ng effects of these two derivatives measured by the alkaline DNA unwinding (ADU) and the modified single cell gel electrophoresis (SCGE) techniques. D ifferences in DNA damage profiles induced by DEC and MeDBC were found in V7 9MZh1A1 and Hep G2 cells. These differences were probably the result of dif ferent reactive metabolite formation depending on chemical structure of the molecule and ways of biotransformation. This study showed that the cytochr ome P4501A1 took part in activation of sarcomagenic DEC derivatives. Moreov er, V79 cell lines with stable expression of different cytochromes P450 in combination with DNA repair endonucleases should be a useful tool for chara cterization of the role of individual cytochromes in metabolic activation p athways of DEC and MeDBC. (C) 2000 Elsevier Science B.V. All rights reserve d.