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

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Abstract
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 mt‐ 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 μmol/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 μmol/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.

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