Genotoxicity of 7H-dibenzo[c,g]carbazole and its methyl derivatives in human keratinocytes.
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.
Laboratory of Mutagenesis and Carcinogenesis, Cancer Research Institute, SAS, 833 91 Bratislava, Slovakia.
Zuzana
Z
Valovičová
Monika
M
Mesárošová
Lenka
L
Trilecová
Eva
E
Hrubá
Soňa
S
Marvanová
Pavel
P
Krčmář
Alena
A
Milcová
Jana
J
Schmuczerová
Jan
J
Vondráček
Miroslav
M
Machala
Jan
J
Topinka
Alena
A
Gábelová
D002227:Carbazoles / Q000737:chemistry / Q000633:toxicity*; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D053904:DNA Breaks, Single-Stranded; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity*; D009928:Organ Specificity
D002227:Carbazoles; D002273:Carcinogens; D009153:Mutagens; D019363:Cytochrome P-450 CYP1A1; C013478:7H-dibenzo(c,g)carbazole