Journal Article

One-electron oxidation is not a major route of metabolic activation and DNA binding for the carcinogen 7H-dibenzo[<i>c</i>,<i>g</i>]carbazole <i>in vitro</i> and in mouse liver and lung

Heather V. Dowty, Weiling Xue, Kathy LaDow, Glenn Talaska and David Warshawsky

in Carcinogenesis

Volume 21, issue 5, pages 991-998
Published in print May 2000 | ISSN: 0143-3334
Published online May 2000 | e-ISSN: 1460-2180 | DOI:
One-electron oxidation is not a major route of metabolic activation and DNA binding for the carcinogen 7H-dibenzo[c,g]carbazole in vitro and in mouse liver and lung

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7H-Dibenzo[c,g]carbazole (DBC) is a potent multi-site, multi-species carcinogen present in a variety of complex mixtures derived from the incomplete combustion of organic matter. Like many carcinogens, DBC requires metabolic activation to an electrophilic species to exert its mutagenic and carcinogenic effects. One-electron oxidation, leading to the formation of radical cation intermediates, has been proposed as a mechanism of metabolic activation for DBC in vitro resulting in unstable DNA adducts. The purpose of this research was to determine whether one-electron oxidation is a mechanism of activation and DNA binding for DBC in vivo. Specific depurinating DBC–DNA adducts formed by one-electron oxidation were analyzed in mouse liver at 4 h following a single i.p. dose of 40 mg/kg of 11 μCi [14C]DBC. In addition to five previously published adduct standards, two newly identified adduct standards were characterized by mass spectrometry and NMR, namely DBC-6-N7-Ade and DBC-6-N1-Ade; however, neither was observed in mouse liver. Only the DBC-5-N7-Gua adduct was observed in mouse liver extracts at a level of 6.5 ± 1.8 adducts/106 nucleotides. In addition, the formation of AP sites and stable DBC–DNA adducts was analyzed in mouse liver and lung at 4, 12 and 24 h following a single i.p. dose of 0.4, 4 or 40 mg/kg DBC (n = 3/group). There was a distinct time– and dose–response of stable DBC–DNA adducts detected by 32P-post-labeling. There was not a clear dose–response for formation of AP sites; however, a significant increase over control levels was observed at the 4 and 40 mg/kg dose groups at 4 and 12 h post dosing, respectively. Quantitative comparisons indicate that the depurinating DBC-5-N7-Gua adduct constitutes ~0.4% of total adducts measured whereas the stable adducts detected by 32P-post-labeling constitute 99.6% of total adducts measured following a 40 mg/kg dose and a 4 h time-point. The data indicate that one-electron oxidation does occur in mouse liver in vivo. However, one-electron oxidation is a minor mechanism of activation in that the percentage of total adducts formed through this route constitutes a minor percentage of the total adducts formed.

Keywords: AP sites, apurinic sites; ARP, aldehyde reacting probe; DBC, 7H-dibenzo[c,g]carbazole; HRP, horseradish peroxidase; PAHs, polycyclic aromatic hydrocarbons.

Journal Article.  5681 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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