Identification of 5-(deoxyguanosin-N2-yl)-1,2-dihydroxy-1,2- dihydro-6-aminochrysene as the major DNA lesion in the mammary gland of rats treated with the environmental pollutant 6-nitrochrysene

Karam El-Bayoumy, Arun Sharma, Jyh ming Lin, Jacek Krzeminski, Telih Boyiri, Leon C. King, Guy Lambert, William Padgett, Stephen Nesnow, Shantu Amin

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Abstract

The environmental pollutant 6-nitrochrysene (6-NC) is a potent carcinogen in several animal models including the rat mammary gland. 6-NC can be activated to intermediates that can damage DNA by simple nitroreduction, ring oxidation, or a combination of ring oxidation and nitroreduction. Only the first pathway (nitroreduction) has been clearly established, and DNA adducts derived from this pathway have been fully characterized in in vitro systems. We also showed previously that the second pathway, ring oxidation leading to the formation of the bay region diol epoxide of 6-NC, is not responsible for the formation of the major DNA adduct in the mammary gland of rats treated with 6-NC. Therefore, in the present study, we explored the validity of the third pathway that involves the combination of both ring oxidation and nitroreduction of 6-NC to form trans-1,2-dihydroxy-1,2-dihydro-6-hydroxylaminochrysene (1,2-DHD-6-NHOH-C). During the course of this study, we synthesized for the first time 1,2-DHD-6-NHOH-C, N-(deoxyguanosin-8-yl)-6-aminochrysene, and N-(deoxyguanosin-8-yl)-1,2-dihydroxy-1,2-dihydro-6-aminochrysene. Incubation of 1,2-DHD-6-NHOH-C with calf thymus DNA resulted in the formation of three adducts. Upon LC/MS combined with 1H NMR analyses, the first eluting adduct was identified as 5-(deoxyguanosin-N2-yl)-1,2-dihydroxy-1,2- dihydro-6-aminochrysene [5-(dG-N2-yl)-1,2-DHD-6-AC], the second eluting adduct was identified as N-(deoxyguanosin-8-yl)-1,2-dihydroxy-1,2- dihydro-6-aminochrysene, and the last was identified as N-(deoxyinosin-8-yl)-1, 2-dihydroxy-1,2-dihydro-6-aminochrysene. We also report here for the first time that among those adducts identified in vitro, only 5-(dG-N2-yl)-1,2- DHD-6-AC is the major DNA lesion detected in the mammary glands of rats treated with 6-NC.

Original languageEnglish (US)
Pages (from-to)1591-1599
Number of pages9
JournalChemical Research in Toxicology
Volume17
Issue number12
DOIs
StatePublished - Dec 1 2004

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Environmental Pollutants
Human Mammary Glands
Rats
DNA
Oxidation
DNA Adducts
Epoxy Compounds
Carcinogens
DNA Damage
6-nitrochrysene
5-(deoxyguanosin-N2-yl)- 1,2-dihydroxy-1,2-dihydro-6-aminochrysene
Animals
Animal Models
Nuclear magnetic resonance
6-aminochrysene-1,2-dihydrodiol

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

@article{abfdf43536114d14b169de77d1fe6278,
title = "Identification of 5-(deoxyguanosin-N2-yl)-1,2-dihydroxy-1,2- dihydro-6-aminochrysene as the major DNA lesion in the mammary gland of rats treated with the environmental pollutant 6-nitrochrysene",
abstract = "The environmental pollutant 6-nitrochrysene (6-NC) is a potent carcinogen in several animal models including the rat mammary gland. 6-NC can be activated to intermediates that can damage DNA by simple nitroreduction, ring oxidation, or a combination of ring oxidation and nitroreduction. Only the first pathway (nitroreduction) has been clearly established, and DNA adducts derived from this pathway have been fully characterized in in vitro systems. We also showed previously that the second pathway, ring oxidation leading to the formation of the bay region diol epoxide of 6-NC, is not responsible for the formation of the major DNA adduct in the mammary gland of rats treated with 6-NC. Therefore, in the present study, we explored the validity of the third pathway that involves the combination of both ring oxidation and nitroreduction of 6-NC to form trans-1,2-dihydroxy-1,2-dihydro-6-hydroxylaminochrysene (1,2-DHD-6-NHOH-C). During the course of this study, we synthesized for the first time 1,2-DHD-6-NHOH-C, N-(deoxyguanosin-8-yl)-6-aminochrysene, and N-(deoxyguanosin-8-yl)-1,2-dihydroxy-1,2-dihydro-6-aminochrysene. Incubation of 1,2-DHD-6-NHOH-C with calf thymus DNA resulted in the formation of three adducts. Upon LC/MS combined with 1H NMR analyses, the first eluting adduct was identified as 5-(deoxyguanosin-N2-yl)-1,2-dihydroxy-1,2- dihydro-6-aminochrysene [5-(dG-N2-yl)-1,2-DHD-6-AC], the second eluting adduct was identified as N-(deoxyguanosin-8-yl)-1,2-dihydroxy-1,2- dihydro-6-aminochrysene, and the last was identified as N-(deoxyinosin-8-yl)-1, 2-dihydroxy-1,2-dihydro-6-aminochrysene. We also report here for the first time that among those adducts identified in vitro, only 5-(dG-N2-yl)-1,2- DHD-6-AC is the major DNA lesion detected in the mammary glands of rats treated with 6-NC.",
author = "Karam El-Bayoumy and Arun Sharma and Lin, {Jyh ming} and Jacek Krzeminski and Telih Boyiri and King, {Leon C.} and Guy Lambert and William Padgett and Stephen Nesnow and Shantu Amin",
year = "2004",
month = "12",
day = "1",
doi = "10.1021/tx049849+",
language = "English (US)",
volume = "17",
pages = "1591--1599",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "12",

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TY - JOUR

T1 - Identification of 5-(deoxyguanosin-N2-yl)-1,2-dihydroxy-1,2- dihydro-6-aminochrysene as the major DNA lesion in the mammary gland of rats treated with the environmental pollutant 6-nitrochrysene

AU - El-Bayoumy, Karam

AU - Sharma, Arun

AU - Lin, Jyh ming

AU - Krzeminski, Jacek

AU - Boyiri, Telih

AU - King, Leon C.

AU - Lambert, Guy

AU - Padgett, William

AU - Nesnow, Stephen

AU - Amin, Shantu

PY - 2004/12/1

Y1 - 2004/12/1

N2 - The environmental pollutant 6-nitrochrysene (6-NC) is a potent carcinogen in several animal models including the rat mammary gland. 6-NC can be activated to intermediates that can damage DNA by simple nitroreduction, ring oxidation, or a combination of ring oxidation and nitroreduction. Only the first pathway (nitroreduction) has been clearly established, and DNA adducts derived from this pathway have been fully characterized in in vitro systems. We also showed previously that the second pathway, ring oxidation leading to the formation of the bay region diol epoxide of 6-NC, is not responsible for the formation of the major DNA adduct in the mammary gland of rats treated with 6-NC. Therefore, in the present study, we explored the validity of the third pathway that involves the combination of both ring oxidation and nitroreduction of 6-NC to form trans-1,2-dihydroxy-1,2-dihydro-6-hydroxylaminochrysene (1,2-DHD-6-NHOH-C). During the course of this study, we synthesized for the first time 1,2-DHD-6-NHOH-C, N-(deoxyguanosin-8-yl)-6-aminochrysene, and N-(deoxyguanosin-8-yl)-1,2-dihydroxy-1,2-dihydro-6-aminochrysene. Incubation of 1,2-DHD-6-NHOH-C with calf thymus DNA resulted in the formation of three adducts. Upon LC/MS combined with 1H NMR analyses, the first eluting adduct was identified as 5-(deoxyguanosin-N2-yl)-1,2-dihydroxy-1,2- dihydro-6-aminochrysene [5-(dG-N2-yl)-1,2-DHD-6-AC], the second eluting adduct was identified as N-(deoxyguanosin-8-yl)-1,2-dihydroxy-1,2- dihydro-6-aminochrysene, and the last was identified as N-(deoxyinosin-8-yl)-1, 2-dihydroxy-1,2-dihydro-6-aminochrysene. We also report here for the first time that among those adducts identified in vitro, only 5-(dG-N2-yl)-1,2- DHD-6-AC is the major DNA lesion detected in the mammary glands of rats treated with 6-NC.

AB - The environmental pollutant 6-nitrochrysene (6-NC) is a potent carcinogen in several animal models including the rat mammary gland. 6-NC can be activated to intermediates that can damage DNA by simple nitroreduction, ring oxidation, or a combination of ring oxidation and nitroreduction. Only the first pathway (nitroreduction) has been clearly established, and DNA adducts derived from this pathway have been fully characterized in in vitro systems. We also showed previously that the second pathway, ring oxidation leading to the formation of the bay region diol epoxide of 6-NC, is not responsible for the formation of the major DNA adduct in the mammary gland of rats treated with 6-NC. Therefore, in the present study, we explored the validity of the third pathway that involves the combination of both ring oxidation and nitroreduction of 6-NC to form trans-1,2-dihydroxy-1,2-dihydro-6-hydroxylaminochrysene (1,2-DHD-6-NHOH-C). During the course of this study, we synthesized for the first time 1,2-DHD-6-NHOH-C, N-(deoxyguanosin-8-yl)-6-aminochrysene, and N-(deoxyguanosin-8-yl)-1,2-dihydroxy-1,2-dihydro-6-aminochrysene. Incubation of 1,2-DHD-6-NHOH-C with calf thymus DNA resulted in the formation of three adducts. Upon LC/MS combined with 1H NMR analyses, the first eluting adduct was identified as 5-(deoxyguanosin-N2-yl)-1,2-dihydroxy-1,2- dihydro-6-aminochrysene [5-(dG-N2-yl)-1,2-DHD-6-AC], the second eluting adduct was identified as N-(deoxyguanosin-8-yl)-1,2-dihydroxy-1,2- dihydro-6-aminochrysene, and the last was identified as N-(deoxyinosin-8-yl)-1, 2-dihydroxy-1,2-dihydro-6-aminochrysene. We also report here for the first time that among those adducts identified in vitro, only 5-(dG-N2-yl)-1,2- DHD-6-AC is the major DNA lesion detected in the mammary glands of rats treated with 6-NC.

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U2 - 10.1021/tx049849+

DO - 10.1021/tx049849+

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VL - 17

SP - 1591

EP - 1599

JO - Chemical Research in Toxicology

JF - Chemical Research in Toxicology

SN - 0893-228X

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