Interaction of 7H-dibenzo[c,g]carbazole and its organspecific derivatives with hepatic mitochondrial and nuclear DNA in the mouse

• Published in: Environmental and molecular mutagenesis Vol. 25; no. 3; p. 202
• Main Authors: Périn-Roussel, O, Périn, F, Barat, N, Plessis, M J, Zajdela, F
• Format: Journal Article
• Language: English
• Published: United States 1995
• Subjects: Animals; Autoradiography; Binding Sites; Carbazoles - metabolism; Carbazoles - toxicity; Carcinogens - toxicity; Cell Nucleus - drug effects; Chromatography, Thin Layer; DNA Adducts - drug effects; DNA Adducts - genetics; Female; Isotope Labeling; Liver - cytology; Liver - drug effects; Mice; Mitochondria, Liver - drug effects; Mitochondria, Liver - pathology; Phosphorus Radioisotopes; Structure-Activity Relationship; Tissue Fixation
• ISSN: 0893-6692
• DOI: 10.1002/em.2850250306

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 plays a role in one or more stages of carcinogenesis. In order to investigate whether differences in the metabolic activation of carcinogens have qualitative and quantitative effects on ml- and nuclear DNA (nuDNA) adduct formation, mice were exposed to the potent hepatocarcinogenic and sarcomagenic polycyclic hydrocarbon 7H-dibenzo[c,g]carbazole (DBC) and to three of its derivatives that show large differences in enzymatic activation: N-acetyl-DBC (N-AcDBC), which is carcinogenic for several tissues; 5,9-dimethyl-DBC (DiMeDBC), which is exclusively hepatocarcinogenic; and N-methyl-DBC (N-MeDBC), which is exclusively sarcomagenic. Adduct formation and toxic effects were measured over 48 hr. With a moderate 5 mumol/kg dose of DBC, the adduct level in liver 24 hr after treatment was always higher in nuDNA than in mtDNA; after 48 hr a substantial increase in the level of adducts in mtDNA was observed, with 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 non-hepatocarcinogenic N-MeDBC induced a very small number of adducts. In order to obtain a nearly identical level of adducts in nu- and mtDNA at 24 hr, the dose of DBC must be three times higher (15 mumol/kg); this and higher dose levels had a strong cytotoxic effect in liver cells. Qualitative differences in adduct distribution were observed on chromatograms of mtDNA and nuDNA, showing that the access to mtDNA is a complex process. Our results confirm that mouse liver mtDNA is a major target for DBC and its hepatocarcinogenic derivatives. The possible interference of genotoxic alterations in mtDNA with carcinogenic mechanisms is discussed.