INTERACTION OF 7H-DIBENZO[C,G]CARBAZOLE AND ITS ORGANSPECIFIC DERIVATIVES WITH HEPATIC MITOCHONDRIAL AND NUCLEAR-DNA IN THE MOUSE

The recent observation of a high level of adducts in mitochondrial DNA (mtDNA) of cells exposed to chemical carcinogens aroused new interest in the hypothesis that carcinogen-induced damage in mitochondria play s a role in one or more stages of carcinogenesis. In order to investig ate whether differences in the metabolic activation of carcinogens hav e qualitative and quantitative effects on mt- and nuclear DNA (nuDNA) adduct formation, mice were exposed to the potent hepatocarcinogenic a nd sarcomagenic polycyclic hydrocarbon 7H-dibenzo[c,g]carbazole (DEC) and to three of its derivatives that show large differences in enzymat ic activation: N-acetyl-DBC (N-AcDBC), which is carcinogenic for sever al tissues; 5,9-dimethyl-DBC (DiMeDBC), which is exclusively hepatocar cinogenic; and N-methyl-DBC (N-MeDBC), which is exclusively sarcomagen ic. Adduct formation and toxic effects were measured over 48 hr. With a moderate 5 mu mol/kg dose of DEC, the adduct level in liver 24 hr af ter treatment was always higher in nuDNA than in mtDNA; after 48 hr a substantial increase in the level of adducts in mtDNA was observed, wi th a parallel decrease in the level in nuDNA. With DiMeDBC, a 4.9-fold increase in mtDNA was seen at 48 hr, whereas, at the same dose, the n on-hepatocarcinogenic N-MeDBC induced a very smell number of adducts. In order to obtain a nearly identical level of adducts in nu- and mtDN A at 24 hr, the dose of DEC must be three times higher (15 mu mol/kg); this and higher dose levels had a strong cytotoxic effect in liver ce lls. Qualitative differences in adduct distribution were observed on c hromatograms of mtDNA and nuDNA, showing that the access to mtDNA is a complex process. Our results confirm that mouse liver mtDNA is a majo r target for DEC and its hepatocarcinogenic derivatives. The possible interference of genotoxic alterations in mtDNA with carcinogenic mecha nisms is discussed. (C) 1995 Wiley-Liss, Inc.