O. Perinroussel et al., INTERACTION OF 7H-DIBENZO[C,G]CARBAZOLE AND ITS ORGANSPECIFIC DERIVATIVES WITH HEPATIC MITOCHONDRIAL AND NUCLEAR-DNA IN THE MOUSE, Environmental and molecular mutagenesis, 25(3), 1995, pp. 202-210
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.