2012
Valovičová, Zuzana; Mesárošová, Monika; Trilecová, Lenka; Hrubá, Eva; Marvanová, Soňa; Krčmář, Pavel; Milcová, Alena; Schmuczerová, Jana; Vondráček, Jan; Machala, Miroslav; Topinka, Jan; Gábelová, Alena
Genotoxicity of 7H-dibenzo[c,g]carbazole and its methyl derivatives in human keratinocytes. Journal Article
In: Mutation research, vol. 743, no. 1-2, pp. 91–98, 2012, ISSN: 0027-5107, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: Carbazoles/chemistry/*toxicity, Carcinogens/*toxicity, Cell Line, Cytochrome P-450 CYP1A1/metabolism, DNA Breaks, Humans, Keratinocytes/*drug effects/metabolism, Mutagenicity Tests, Mutagens/*toxicity, Organ Specificity, Single-Stranded
@article{valovicova_genotoxicity_2012,
title = {Genotoxicity of 7H-dibenzo[c,g]carbazole and its methyl derivatives in human keratinocytes.},
author = {Zuzana Valovičová and Monika Mesárošová and Lenka Trilecová and Eva Hrubá and Soňa Marvanová and Pavel Krčmář and Alena Milcová and Jana Schmuczerová and Jan Vondráček and Miroslav Machala and Jan Topinka and Alena Gábelová},
doi = {10.1016/j.mrgentox.2011.12.030},
issn = {0027-5107},
year = {2012},
date = {2012-03-01},
journal = {Mutation research},
volume = {743},
number = {1-2},
pages = {91–98},
abstract = {Differences between tissues in the expression of drug-metabolizing enzymes may substantially contribute to tissue-specificity of chemical carcinogens. To verify this hypothesis, the spontaneously immortalized human keratinocytes HaCaT were used, in order to evaluate the genotoxic potential of 7H-dibenzo[c,g]carbazole (DBC), a known hepatocarcinogen and sarcomagen, and its synthetic tissue-specific derivatives, 5,9-dimethyl-DBC (DiMeDBC) and N-methyl-DBC (N-MeDBC), which manifest specific tropism to the liver and skin, respectively. HaCaT cells mainly express cytochrome P4501A1 (CYP1A1), which is involved in metabolism of DBC and N-MeDBC, but not DiMeDBC [10]. Both DBC and the sarcomagen N-MeDBC induced significant levels of DNA strand-breaks, micronuclei, and DNA adducts followed by the phosphorylation of the p53 protein and histone H2AX in HaCaT cells. In contrast, the specific hepatocarcinogen DiMeDBC was devoid of any significant genotoxic activity in this cell line. Our study demonstrates that the absence of drug-metabolizing enzyme(s) involved in DiMeDBC metabolism may contribute substantially to the tissue-specific genotoxicity of this hepatocarcinogen.},
note = {Place: Netherlands},
keywords = {Carbazoles/chemistry/*toxicity, Carcinogens/*toxicity, Cell Line, Cytochrome P-450 CYP1A1/metabolism, DNA Breaks, Humans, Keratinocytes/*drug effects/metabolism, Mutagenicity Tests, Mutagens/*toxicity, Organ Specificity, Single-Stranded},
pubstate = {published},
tppubtype = {article}
}
Differences between tissues in the expression of drug-metabolizing enzymes may substantially contribute to tissue-specificity of chemical carcinogens. To verify this hypothesis, the spontaneously immortalized human keratinocytes HaCaT were used, in order to evaluate the genotoxic potential of 7H-dibenzo[c,g]carbazole (DBC), a known hepatocarcinogen and sarcomagen, and its synthetic tissue-specific derivatives, 5,9-dimethyl-DBC (DiMeDBC) and N-methyl-DBC (N-MeDBC), which manifest specific tropism to the liver and skin, respectively. HaCaT cells mainly express cytochrome P4501A1 (CYP1A1), which is involved in metabolism of DBC and N-MeDBC, but not DiMeDBC [10]. Both DBC and the sarcomagen N-MeDBC induced significant levels of DNA strand-breaks, micronuclei, and DNA adducts followed by the phosphorylation of the p53 protein and histone H2AX in HaCaT cells. In contrast, the specific hepatocarcinogen DiMeDBC was devoid of any significant genotoxic activity in this cell line. Our study demonstrates that the absence of drug-metabolizing enzyme(s) involved in DiMeDBC metabolism may contribute substantially to the tissue-specific genotoxicity of this hepatocarcinogen.