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 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.
Périn-Roussel
O
O
Institut Curie-Biologie, Centre Universitaire, Orsay, France.
Périn
F
F
Barat
N
N
Plessis
M J
MJ
Zajdela
F
F
D000818:Animals; D001345:Autoradiography; D001665:Binding Sites; D002227:Carbazoles / Q000378:metabolism / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002467:Cell Nucleus / Q000187:drug effects*; D002855:Chromatography, Thin Layer; D018736:DNA Adducts / Q000187:drug effects* / Q000235:genetics; D005260:Female; D007553:Isotope Labeling; D008099:Liver / Q000166:cytology / Q000187:drug effects; D051379:Mice; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000473:pathology; D010761:Phosphorus Radioisotopes; D013329:Structure-Activity Relationship; D016707:Tissue Fixation
D002227:Carbazoles; D002273:Carcinogens; D018736:DNA Adducts; D010761:Phosphorus Radioisotopes; C041150:N-methyl-7H-dibenzo(c,g)carbazole; C093439:N-acetyl-7H-dibenzo(c,g)carbazole; C039387:5,9-dimethyldibenzo(c,g)carbazole; C013478:7H-dibenzo(c,g)carbazole