Identification and quantification of the depurinating DNA adducts formed in mouse skin treated with dibenzo[a,l]pyrene (DB[a,l]P) or its metabolites and in rat mammary gland treated with DB[a,l]P

Ercole Cavalieri, Eleanor G Rogan, Kai Ming Li, Rosa Todorovic, Freek Ariese, Ryszard Jankowiak, Nenad Grubor, Gerald J. Small

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Abstract

Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogenic polycyclic aromatic hydrocarbon and has been identified in the environment. Comparative tumorigenicity studies in mouse skin and rat mammary gland indicate that DB[a,l]P is slightly more potent than DB[a,l]P-11,12-dihydrodiol and much more potent than (±)-syn-DB[a,l]P-11,12-dihydrodiol-13,14-epoxide {(±)-syn-DB[a,l]PDE} and (±)-anti-DB[a,l]PDE. We report here the identification and quantification of the depurinating adducts formed in mouse skin treated with DB[a,l]P, DB[a,l]P-11,12-dihydrodiol, (±)-syn-DB[a,l] PDE, or (±)-anti-DB[a,l]PDE and rat mammary gland treated with DB [a,l] P. The biologically formed adducts were compared with standard adducts by their retention times on HPLC and their spectra obtained by fluorescence line-narrowing spectroscopy at low temperature. In mouse skin treated with DB[a,l]P, depurinating adducts comprised 99% of the total adducts. Most of the depurinating adducts were formed by one-electron oxidation, with 63% at Ade and 12% at Gua. The remainder were formed by the diol epoxide, with 18% at Ade and 6% at Gua. When mouse skin was treated with DB[a,l]P-11,12-dihydrodiol, depurinating adducts comprised 80% of the total, and the predominant one was with Ade (69%). Treatment of skin with (±)-syn-DB[a,l]PDE resulted in 32% depurinating adducts, primarily at Ade (25%), whereas treatment with (±)-anti-DB[a,l]PDE produced 97% stable adducts. The formation of depurinating adducts following treatment of rat mammary gland with DB[a,l]P resulted in approximately 98% depurinating adducts, with the major adducts formed by one-electron oxidation. Only one depurinating diol epoxide adduct was formed. Tumorigenicity, mutations, and DNA adduct data suggest that depurinating Ade adducts play a major role in the initiation of tumors by DB[a,l]P.

Original languageEnglish (US)
Pages (from-to)976-983
Number of pages8
JournalChemical Research in Toxicology
Volume18
Issue number6
DOIs
StatePublished - Jun 1 2005

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DNA Adducts
Human Mammary Glands
Metabolites
Rats
Skin
Epoxy Compounds
Electrons
Oxidation
Polycyclic Aromatic Hydrocarbons
Tumors
Spectrum Analysis
Fluorescence
High Pressure Liquid Chromatography
dibenzo(a,l)pyrene
Spectroscopy
Mutation
Temperature
dibenzo(a,l)pyrene 11,12-dihydrodiol
Neoplasms

ASJC Scopus subject areas

  • Toxicology

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Identification and quantification of the depurinating DNA adducts formed in mouse skin treated with dibenzo[a,l]pyrene (DB[a,l]P) or its metabolites and in rat mammary gland treated with DB[a,l]P. / Cavalieri, Ercole; Rogan, Eleanor G; Li, Kai Ming; Todorovic, Rosa; Ariese, Freek; Jankowiak, Ryszard; Grubor, Nenad; Small, Gerald J.

In: Chemical Research in Toxicology, Vol. 18, No. 6, 01.06.2005, p. 976-983.

Research output: Contribution to journalArticle

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abstract = "Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogenic polycyclic aromatic hydrocarbon and has been identified in the environment. Comparative tumorigenicity studies in mouse skin and rat mammary gland indicate that DB[a,l]P is slightly more potent than DB[a,l]P-11,12-dihydrodiol and much more potent than (±)-syn-DB[a,l]P-11,12-dihydrodiol-13,14-epoxide {(±)-syn-DB[a,l]PDE} and (±)-anti-DB[a,l]PDE. We report here the identification and quantification of the depurinating adducts formed in mouse skin treated with DB[a,l]P, DB[a,l]P-11,12-dihydrodiol, (±)-syn-DB[a,l] PDE, or (±)-anti-DB[a,l]PDE and rat mammary gland treated with DB [a,l] P. The biologically formed adducts were compared with standard adducts by their retention times on HPLC and their spectra obtained by fluorescence line-narrowing spectroscopy at low temperature. In mouse skin treated with DB[a,l]P, depurinating adducts comprised 99{\%} of the total adducts. Most of the depurinating adducts were formed by one-electron oxidation, with 63{\%} at Ade and 12{\%} at Gua. The remainder were formed by the diol epoxide, with 18{\%} at Ade and 6{\%} at Gua. When mouse skin was treated with DB[a,l]P-11,12-dihydrodiol, depurinating adducts comprised 80{\%} of the total, and the predominant one was with Ade (69{\%}). Treatment of skin with (±)-syn-DB[a,l]PDE resulted in 32{\%} depurinating adducts, primarily at Ade (25{\%}), whereas treatment with (±)-anti-DB[a,l]PDE produced 97{\%} stable adducts. The formation of depurinating adducts following treatment of rat mammary gland with DB[a,l]P resulted in approximately 98{\%} depurinating adducts, with the major adducts formed by one-electron oxidation. Only one depurinating diol epoxide adduct was formed. Tumorigenicity, mutations, and DNA adduct data suggest that depurinating Ade adducts play a major role in the initiation of tumors by DB[a,l]P.",
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AU - Cavalieri, Ercole

AU - Rogan, Eleanor G

AU - Li, Kai Ming

AU - Todorovic, Rosa

AU - Ariese, Freek

AU - Jankowiak, Ryszard

AU - Grubor, Nenad

AU - Small, Gerald J.

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N2 - Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogenic polycyclic aromatic hydrocarbon and has been identified in the environment. Comparative tumorigenicity studies in mouse skin and rat mammary gland indicate that DB[a,l]P is slightly more potent than DB[a,l]P-11,12-dihydrodiol and much more potent than (±)-syn-DB[a,l]P-11,12-dihydrodiol-13,14-epoxide {(±)-syn-DB[a,l]PDE} and (±)-anti-DB[a,l]PDE. We report here the identification and quantification of the depurinating adducts formed in mouse skin treated with DB[a,l]P, DB[a,l]P-11,12-dihydrodiol, (±)-syn-DB[a,l] PDE, or (±)-anti-DB[a,l]PDE and rat mammary gland treated with DB [a,l] P. The biologically formed adducts were compared with standard adducts by their retention times on HPLC and their spectra obtained by fluorescence line-narrowing spectroscopy at low temperature. In mouse skin treated with DB[a,l]P, depurinating adducts comprised 99% of the total adducts. Most of the depurinating adducts were formed by one-electron oxidation, with 63% at Ade and 12% at Gua. The remainder were formed by the diol epoxide, with 18% at Ade and 6% at Gua. When mouse skin was treated with DB[a,l]P-11,12-dihydrodiol, depurinating adducts comprised 80% of the total, and the predominant one was with Ade (69%). Treatment of skin with (±)-syn-DB[a,l]PDE resulted in 32% depurinating adducts, primarily at Ade (25%), whereas treatment with (±)-anti-DB[a,l]PDE produced 97% stable adducts. The formation of depurinating adducts following treatment of rat mammary gland with DB[a,l]P resulted in approximately 98% depurinating adducts, with the major adducts formed by one-electron oxidation. Only one depurinating diol epoxide adduct was formed. Tumorigenicity, mutations, and DNA adduct data suggest that depurinating Ade adducts play a major role in the initiation of tumors by DB[a,l]P.

AB - Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogenic polycyclic aromatic hydrocarbon and has been identified in the environment. Comparative tumorigenicity studies in mouse skin and rat mammary gland indicate that DB[a,l]P is slightly more potent than DB[a,l]P-11,12-dihydrodiol and much more potent than (±)-syn-DB[a,l]P-11,12-dihydrodiol-13,14-epoxide {(±)-syn-DB[a,l]PDE} and (±)-anti-DB[a,l]PDE. We report here the identification and quantification of the depurinating adducts formed in mouse skin treated with DB[a,l]P, DB[a,l]P-11,12-dihydrodiol, (±)-syn-DB[a,l] PDE, or (±)-anti-DB[a,l]PDE and rat mammary gland treated with DB [a,l] P. The biologically formed adducts were compared with standard adducts by their retention times on HPLC and their spectra obtained by fluorescence line-narrowing spectroscopy at low temperature. In mouse skin treated with DB[a,l]P, depurinating adducts comprised 99% of the total adducts. Most of the depurinating adducts were formed by one-electron oxidation, with 63% at Ade and 12% at Gua. The remainder were formed by the diol epoxide, with 18% at Ade and 6% at Gua. When mouse skin was treated with DB[a,l]P-11,12-dihydrodiol, depurinating adducts comprised 80% of the total, and the predominant one was with Ade (69%). Treatment of skin with (±)-syn-DB[a,l]PDE resulted in 32% depurinating adducts, primarily at Ade (25%), whereas treatment with (±)-anti-DB[a,l]PDE produced 97% stable adducts. The formation of depurinating adducts following treatment of rat mammary gland with DB[a,l]P resulted in approximately 98% depurinating adducts, with the major adducts formed by one-electron oxidation. Only one depurinating diol epoxide adduct was formed. Tumorigenicity, mutations, and DNA adduct data suggest that depurinating Ade adducts play a major role in the initiation of tumors by DB[a,l]P.

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