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 Cavalieri

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

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
Volume10
Issue number2
DOIs
StatePublished - Feb 1 1997

Fingerprint

DNA Adducts
Liver Microsomes
Liver
Cations
Rats
Chemical activation
Electrons
Horseradish Peroxidase
Oxidation
Methylcholanthrene
Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry
Iodine
Cytochrome P-450 Enzyme System
Nucleophiles
High Pressure Liquid Chromatography
Ionization
Mass spectrometry
Desorption
7H-dibenzo(c,g)carbazole
Lasers

ASJC Scopus subject areas

  • Toxicology

Cite this

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

In: Chemical Research in Toxicology, Vol. 10, No. 2, 01.02.1997, p. 225-233.

Research output: Contribution to journalArticle

@article{d11b26103ed04399ab7086d62234207c,
title = "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",
abstract = "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.",
author = "Liang Chen and Devanesan, {Prabu D.} and Jaeman Byun and Gooden, {Jonathan K.} and Gross, {Michael L.} and Rogan, {Eleanor G} and Ercole Cavalieri",
year = "1997",
month = "2",
day = "1",
doi = "10.1021/tx960149h",
language = "English (US)",
volume = "10",
pages = "225--233",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "2",

}

TY - JOUR

T1 - 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

AU - Chen, Liang

AU - Devanesan, Prabu D.

AU - Byun, Jaeman

AU - Gooden, Jonathan K.

AU - Gross, Michael L.

AU - Rogan, Eleanor G

AU - Cavalieri, Ercole

PY - 1997/2/1

Y1 - 1997/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=0031054836&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0031054836&partnerID=8YFLogxK

U2 - 10.1021/tx960149h

DO - 10.1021/tx960149h

M3 - Article

C2 - 9049435

AN - SCOPUS:0031054836

VL - 10

SP - 225

EP - 233

JO - Chemical Research in Toxicology

JF - Chemical Research in Toxicology

SN - 0893-228X

IS - 2

ER -