Document Detail

DNA adduct formation by 7H-dibenzo[c,g]carbazole and its tissue- and organ-specific derivatives in Chinese hamster V79 cell lines stably expressing cytochrome P450 enzymes.
MedLine Citation:
PMID:  15534862     Owner:  NLM     Status:  MEDLINE    
The cytochrome P4501A subfamily (CYP1A) is involved in the metabolic activation of 7H-dibenzo[c,g]carbazole (DBC) and its tissue- and organ-specific derivatives, N-methyldibenzo[c,g]carbazole (MeDBC)and 5,9-dimethyldibenzo[c,g]carbazole (diMeDBC). In this study, we have evaluated the relationship between the tissue specificity and (32)P-postlabeled adduct patterns produced by these compounds by using a panel of Chinese hamster V79 cell lines stably expressing human CYP1A1 and CYP1A2 and/or N-acetyltransferase. Treatment of the parental cell lines V79MZ and V79NH, which are devoid of any CYP activity, with DBC and its derivatives did not result in detectable adducts. The highest DNA adduct levels were found in CYP1A1-expressing V79MZh1A1 cells after DBC and MeDBC treatment (24.5 +/- 7.2 and 16.2 +/- 3.6 adducts/10(8) nucleotides, respectively). Exposure of this cell line to DBC resulted in five distinct spots, while six spots with different chromatographic mobilities were detected in MeDBC-treated cells. DiMeDBC produced only very low levels of DNA adducts in V79MZh1A1 cells. DBC and MeDBC formed relatively low levels of DNA adducts in CYP1A2-expressing V79MZh1A2 cells (0.7 +/- 0.2 and 2.1 +/- 1.2 adducts/10(8) nucleotides, respectively). DBC formed three weak spots and MeDBC five spots in V79MZh1A2 cells, and all the spots had different chromatographic mobilities. In contrast, diMeDBC did not induce any DNA adducts in these cells, although diMeDBC induced a significant dose-dependent increase in micronucleus frequency under similar treatment conditions (r = 0.76; P < 0.001). The significant increase in DNA damage in the Comet assay following incubation of exposed cells with a repair-specific endonuclease (Fpg protein) suggests that base modifications such as 8-oxodG or Fapy-adducts might be responsible for the genotoxicity of diMeDBC in V79MZh1A2 cells. The similarities between the DNA adduct patterns produced by DBC and MeDBC in V79MZh1A1 and V79MZh1A2 cells suggest that biotransformation mediated via CYP1A1 and CYP1A2 might depend on a PAH-type pathway involving the aromatic ring system.
Alena Gábelová; Blanka Binková; Zuzana Valovicová; Radim J Srám
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Environmental and molecular mutagenesis     Volume:  44     ISSN:  0893-6692     ISO Abbreviation:  Environ. Mol. Mutagen.     Publication Date:  2004  
Date Detail:
Created Date:  2004-12-14     Completed Date:  2005-03-08     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  8800109     Medline TA:  Environ Mol Mutagen     Country:  United States    
Other Details:
Languages:  eng     Pagination:  448-58     Citation Subset:  IM    
Laboratory of Mutagenesis and Carcinogenesis, Cancer Research Institute, Slovak Academy of Sciences, Bratislava, Slovak Republic.
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MeSH Terms
Acetyltransferases / genetics,  metabolism*
CHO Cells / enzymology
Carbazoles / metabolism,  pharmacology*
Carcinogens / metabolism,  pharmacology*
Comet Assay
Cytochrome P-450 CYP1A1 / genetics,  metabolism*
Cytochrome P-450 CYP1A2 / genetics,  metabolism*
DNA Adducts*
DNA Damage / drug effects*
Micronuclei, Chromosome-Defective
Mutagenicity Tests
Organ Specificity
Tissue Distribution
Reg. No./Substance:
0/Carbazoles; 0/Carcinogens; 0/DNA Adducts; 194-59-2/7H-dibenzo(c,g)carbazole; EC P-450 CYP1A1; EC P-450 CYP1A2; EC 2.3.1.-/Acetyltransferases

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