Synthesis of depurinating DNA adducts formed by one-electron oxidation of 7H-dibenzo[c,g]carbazole and identification of these adducts after activation with rat liver microsomes

Liang Chen, Prabu D. Devanesan, Jaeman Byun, Jonathan K. Gooden, Michael L. Gross, Eleanor G. Rogan, Ercole L. Cavalieri

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It is hypothesized that 7H-dibenzo[c,g]carbazole (DBC) is metabolically activated by one-electron oxidation in accordance with its propensity to be easily oxidized to its radical cation. Iodine oxidation of DBC produces a radical cation that subsequently binds to nucleophilic groups of dG or Ade. Oxidation of DBC in the presence of dG produces three adducts: DBC-5-N7Gua, DBC-6-N7Gua, and DBC-6-C8Gua, whereas in the presence of Ade, four adducts are obtained: DBC-5-N7Ade, DBC-5-N3Ade, DBC-5-N1Ade, and DBC-6-N3Ade. Formation of these adducts demonstrates that the DBC radical cation reacts at C-5 or C-6 with the reactive nucleophiles N-7 and C-8 of dG and N-7, N-3, and N-1 of Ade. Formation of DNA adducts by DBC was studied by using horseradish peroxidase or 3-methylcholanthrene-induced rat liver microsomes for activation. Identification of the biologically-formed depurinating adducts was achieved by comparison of their retention times on HPLC in two different solvent systems and by matrix-assisted laser desorption ionization (MALDI) mass spectrometry. Quantitation of the adducts formed by rat liver microsomes shows that 96% are depurinating adducts, DBC-5-N7Gua (11%), DBC-6-N7Gua (32%), and DBC-5-N7Ade (53%), and 4% are unidentified stable adducts. Activation of DBC by horseradish peroxidase affords 32% stable unidentified adducts and 68% depurinating adducts: 19% DBC-5-N7Gua, 13% DBC-6-N7Gua, 27% DBC-5-N7Ade, and 9% DBC-5-N3Ade. Thus, activation of DBC by cytochrome P450 predominantly forms depurinating adducts by one-electron oxidation.

Original languageEnglish (US)
Pages (from-to)225-233
Number of pages9
JournalChemical Research in Toxicology
Issue number2
StatePublished - Feb 1 1997


ASJC Scopus subject areas

  • Toxicology

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