Inefficient nucleotide excision repair in human cell extracts of the N -(deoxyguanosin-8-yl)-6-aminochrysene and 5-(deoxyguanosin-N 2-yl)-6-aminochrysene adducts derived from 6-nitrochrysene

Jacek Krzeminski, Konstantin Kropachev, Marina Kolbanovskiy, Dara Reeves, Alexander Kolbanovskiy, Byeong Hwa Yun, Nicholas E. Geacintov, Shantu Amin, Karam El-Bayoumy

Research output: Contribution to journalArticle

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Abstract

Ubiquitous environmental agents [e.g., polynuclear aromatic hydrocarbons (PAHs) and their nitrated derivatives (NO2-PAHs)] that are known to induce mammary cancer in rodents are regarded as potential human risk factors for inducing analogous human cancers. Although 6-nitrochrysene (6-NC) is less abundant than other NO2-PAHs in the environment, it is the most potent mammary carcinogen in the rat; its carcinogenic potency is not only higher than that of the carcinogenic PAH, benzo[a]pyrene (B[a]P), but also of the well-known carcinogenic heterocylic aromatic amine, 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP). Studies in rats and in vitro assays have indicated that 6-NC can be activated by simple nitroreduction leading to the formation of 6-hydroxylaminochrysene (N-OH-6-AC); this metabolite yielded N-(deoxyguanosin-8-yl)-6-aminochrysene (N-[dG-8-yl]-6-AC) and 5-(deoxyguanosin-N2-yl)-6-aminochrysene (5-[dG-N2-yl]-6- AC. These lesions are likely to cause mutations if they are not removed by cellular defense mechanisms before DNA replication occurs. However, nothing is known about the susceptibility of these adducts to nucleotide excision repair (NER), the major cellular repair system that removes bulky adducts. In order to address this issue, we synthesized the N-(dG-8-yl)-6-AC and 5-(dG-N 2-yl)-6-AC lesions and site-specifically inserted these lesions into 135-mer DNA duplexes. These constructs were incubated with NER-competent nuclear extracts from human HeLa cells. The efficiency of repair of these lesions was ∼8 times less efficient than that in the case of the well-known and excellent substrate of NER, the intrastrand cross-linked cis- diaminodichloroplatinum II adduct in double-stranded DNA (cis-Pt), but similar to N2-dG adducts derived from the (+)-bay region diol epoxide of B[a]P [(+)-trans-B[a]P-N2-dG]. The results support the hypothesis that the N-(dG-8-yl)-6-AC and 5-(dG-N2-yl)-6-AC lesions may be slowly repaired and thus persistent in mammalian tissue which could, in part, account for the potent tumorigenic activity of 6-NC in the rat mammary gland.

Original languageEnglish (US)
Pages (from-to)65-72
Number of pages8
JournalChemical Research in Toxicology
Volume24
Issue number1
DOIs
StatePublished - Jan 14 2011

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Cell Extracts
DNA Repair
Repair
Nucleotides
Cells
Polycyclic Aromatic Hydrocarbons
Benzo(a)pyrene
Rats
DNA
Epoxy Compounds
Human Mammary Glands
Metabolites
3-(3-(1,2,4)-triazolo)-oxatriazolium-5-olate
N-(deoxyguanosin-8-yl)-6-aminochrysene
6-nitrochrysene
5-(deoxyguanosin-N(2)-yl)-6-aminochrysene
DNA Replication
HeLa Cells
Carcinogens
Amines

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

@article{aaa3ec8da7cf446d942bd006ac61b557,
title = "Inefficient nucleotide excision repair in human cell extracts of the N -(deoxyguanosin-8-yl)-6-aminochrysene and 5-(deoxyguanosin-N 2-yl)-6-aminochrysene adducts derived from 6-nitrochrysene",
abstract = "Ubiquitous environmental agents [e.g., polynuclear aromatic hydrocarbons (PAHs) and their nitrated derivatives (NO2-PAHs)] that are known to induce mammary cancer in rodents are regarded as potential human risk factors for inducing analogous human cancers. Although 6-nitrochrysene (6-NC) is less abundant than other NO2-PAHs in the environment, it is the most potent mammary carcinogen in the rat; its carcinogenic potency is not only higher than that of the carcinogenic PAH, benzo[a]pyrene (B[a]P), but also of the well-known carcinogenic heterocylic aromatic amine, 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP). Studies in rats and in vitro assays have indicated that 6-NC can be activated by simple nitroreduction leading to the formation of 6-hydroxylaminochrysene (N-OH-6-AC); this metabolite yielded N-(deoxyguanosin-8-yl)-6-aminochrysene (N-[dG-8-yl]-6-AC) and 5-(deoxyguanosin-N2-yl)-6-aminochrysene (5-[dG-N2-yl]-6- AC. These lesions are likely to cause mutations if they are not removed by cellular defense mechanisms before DNA replication occurs. However, nothing is known about the susceptibility of these adducts to nucleotide excision repair (NER), the major cellular repair system that removes bulky adducts. In order to address this issue, we synthesized the N-(dG-8-yl)-6-AC and 5-(dG-N 2-yl)-6-AC lesions and site-specifically inserted these lesions into 135-mer DNA duplexes. These constructs were incubated with NER-competent nuclear extracts from human HeLa cells. The efficiency of repair of these lesions was ∼8 times less efficient than that in the case of the well-known and excellent substrate of NER, the intrastrand cross-linked cis- diaminodichloroplatinum II adduct in double-stranded DNA (cis-Pt), but similar to N2-dG adducts derived from the (+)-bay region diol epoxide of B[a]P [(+)-trans-B[a]P-N2-dG]. The results support the hypothesis that the N-(dG-8-yl)-6-AC and 5-(dG-N2-yl)-6-AC lesions may be slowly repaired and thus persistent in mammalian tissue which could, in part, account for the potent tumorigenic activity of 6-NC in the rat mammary gland.",
author = "Jacek Krzeminski and Konstantin Kropachev and Marina Kolbanovskiy and Dara Reeves and Alexander Kolbanovskiy and Yun, {Byeong Hwa} and Geacintov, {Nicholas E.} and Shantu Amin and Karam El-Bayoumy",
year = "2011",
month = "1",
day = "14",
doi = "10.1021/tx100284h",
language = "English (US)",
volume = "24",
pages = "65--72",
journal = "Chemical Research in Toxicology",
issn = "0893-228X",
publisher = "American Chemical Society",
number = "1",

}

Inefficient nucleotide excision repair in human cell extracts of the N -(deoxyguanosin-8-yl)-6-aminochrysene and 5-(deoxyguanosin-N 2-yl)-6-aminochrysene adducts derived from 6-nitrochrysene. / Krzeminski, Jacek; Kropachev, Konstantin; Kolbanovskiy, Marina; Reeves, Dara; Kolbanovskiy, Alexander; Yun, Byeong Hwa; Geacintov, Nicholas E.; Amin, Shantu; El-Bayoumy, Karam.

In: Chemical Research in Toxicology, Vol. 24, No. 1, 14.01.2011, p. 65-72.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Inefficient nucleotide excision repair in human cell extracts of the N -(deoxyguanosin-8-yl)-6-aminochrysene and 5-(deoxyguanosin-N 2-yl)-6-aminochrysene adducts derived from 6-nitrochrysene

AU - Krzeminski, Jacek

AU - Kropachev, Konstantin

AU - Kolbanovskiy, Marina

AU - Reeves, Dara

AU - Kolbanovskiy, Alexander

AU - Yun, Byeong Hwa

AU - Geacintov, Nicholas E.

AU - Amin, Shantu

AU - El-Bayoumy, Karam

PY - 2011/1/14

Y1 - 2011/1/14

N2 - Ubiquitous environmental agents [e.g., polynuclear aromatic hydrocarbons (PAHs) and their nitrated derivatives (NO2-PAHs)] that are known to induce mammary cancer in rodents are regarded as potential human risk factors for inducing analogous human cancers. Although 6-nitrochrysene (6-NC) is less abundant than other NO2-PAHs in the environment, it is the most potent mammary carcinogen in the rat; its carcinogenic potency is not only higher than that of the carcinogenic PAH, benzo[a]pyrene (B[a]P), but also of the well-known carcinogenic heterocylic aromatic amine, 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP). Studies in rats and in vitro assays have indicated that 6-NC can be activated by simple nitroreduction leading to the formation of 6-hydroxylaminochrysene (N-OH-6-AC); this metabolite yielded N-(deoxyguanosin-8-yl)-6-aminochrysene (N-[dG-8-yl]-6-AC) and 5-(deoxyguanosin-N2-yl)-6-aminochrysene (5-[dG-N2-yl]-6- AC. These lesions are likely to cause mutations if they are not removed by cellular defense mechanisms before DNA replication occurs. However, nothing is known about the susceptibility of these adducts to nucleotide excision repair (NER), the major cellular repair system that removes bulky adducts. In order to address this issue, we synthesized the N-(dG-8-yl)-6-AC and 5-(dG-N 2-yl)-6-AC lesions and site-specifically inserted these lesions into 135-mer DNA duplexes. These constructs were incubated with NER-competent nuclear extracts from human HeLa cells. The efficiency of repair of these lesions was ∼8 times less efficient than that in the case of the well-known and excellent substrate of NER, the intrastrand cross-linked cis- diaminodichloroplatinum II adduct in double-stranded DNA (cis-Pt), but similar to N2-dG adducts derived from the (+)-bay region diol epoxide of B[a]P [(+)-trans-B[a]P-N2-dG]. The results support the hypothesis that the N-(dG-8-yl)-6-AC and 5-(dG-N2-yl)-6-AC lesions may be slowly repaired and thus persistent in mammalian tissue which could, in part, account for the potent tumorigenic activity of 6-NC in the rat mammary gland.

AB - Ubiquitous environmental agents [e.g., polynuclear aromatic hydrocarbons (PAHs) and their nitrated derivatives (NO2-PAHs)] that are known to induce mammary cancer in rodents are regarded as potential human risk factors for inducing analogous human cancers. Although 6-nitrochrysene (6-NC) is less abundant than other NO2-PAHs in the environment, it is the most potent mammary carcinogen in the rat; its carcinogenic potency is not only higher than that of the carcinogenic PAH, benzo[a]pyrene (B[a]P), but also of the well-known carcinogenic heterocylic aromatic amine, 2-amino-1-methyl-6- phenylimidazo[4,5-b]pyridine (PhIP). Studies in rats and in vitro assays have indicated that 6-NC can be activated by simple nitroreduction leading to the formation of 6-hydroxylaminochrysene (N-OH-6-AC); this metabolite yielded N-(deoxyguanosin-8-yl)-6-aminochrysene (N-[dG-8-yl]-6-AC) and 5-(deoxyguanosin-N2-yl)-6-aminochrysene (5-[dG-N2-yl]-6- AC. These lesions are likely to cause mutations if they are not removed by cellular defense mechanisms before DNA replication occurs. However, nothing is known about the susceptibility of these adducts to nucleotide excision repair (NER), the major cellular repair system that removes bulky adducts. In order to address this issue, we synthesized the N-(dG-8-yl)-6-AC and 5-(dG-N 2-yl)-6-AC lesions and site-specifically inserted these lesions into 135-mer DNA duplexes. These constructs were incubated with NER-competent nuclear extracts from human HeLa cells. The efficiency of repair of these lesions was ∼8 times less efficient than that in the case of the well-known and excellent substrate of NER, the intrastrand cross-linked cis- diaminodichloroplatinum II adduct in double-stranded DNA (cis-Pt), but similar to N2-dG adducts derived from the (+)-bay region diol epoxide of B[a]P [(+)-trans-B[a]P-N2-dG]. The results support the hypothesis that the N-(dG-8-yl)-6-AC and 5-(dG-N2-yl)-6-AC lesions may be slowly repaired and thus persistent in mammalian tissue which could, in part, account for the potent tumorigenic activity of 6-NC in the rat mammary gland.

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