Genotoxicity of 7H-dibenzo[c,g]carbazole and its methyl derivatives in human keratinocytes

• Published in: Mutation research Vol. 743; no. 1-2; pp. 91 - 98
• Main Authors: Valovičová, Zuzana, Mesárošová, Monika, Trilecová, Lenka, Hrubá, Eva, Marvanová, Soňa, Krčmář, Pavel, Milcová, Alena, Schmuczerová, Jana, Vondráček, Jan, Machala, Miroslav, Topinka, Jan, Gábelová, Alena
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 18.03.2012; Elsevier BV
• Subjects: Apoptosis; Carbazoles - chemistry; Carbazoles - toxicity; Carcinogens; Carcinogens - toxicity; Cell Line; CYP1A1 mRNA expression; Cytochrome P-450 CYP1A1 - metabolism; Deoxyribonucleic acid; Dibenzo[c,g]carbazoles; DNA; DNA adducts; DNA Breaks, Single-Stranded; DNA strand-breaks; Gene expression; Human keratinocytes; Humans; Keratinocytes - drug effects; Keratinocytes - metabolism; Metabolism; Micronuclei; Mutagenicity Tests; Mutagens - toxicity; Organ Specificity; Phosphorylation; CYP1A1 mRNA expression; DNA adducts; Human keratinocytes; Dibenzo[c,g]carbazoles; Micronuclei; DNA strand-breaks
• ISSN: 1383-5718; 0027-5107; 1879-3592
• DOI: 10.1016/j.mrgentox.2011.12.030

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.