DNA Damage by Phenoxyl Radicals

Manderville, Richard A.

doi:10.1002/9780470526279.ch14

Cited by 9 publications

(22 citation statements)

References 84 publications

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“…Bulky DNA adducts produced by chlorophenols stems from oxidative pathways that generate quinone and phenoxyl radical electrophiles (Fig. ) . Increased Cl‐substitution of the phenol ring increases phenol toxicity and favors the formation of O‐linked C8‐dG adducts following phenoxyl radical production through peroxidase activation .…”

Section: Resultsmentioning

confidence: 99%

“…Phenols are a class of structurally diverse molecules that cause a wide range of biological effects in mammalian systems . Phenols cause toxicity under oxidative conditions to afford phenoxyl radicals, reactive oxygen species (ROS), ortho ‐ and para ‐quinones and quinone methide electrophiles . 2′‐Deoxyguanosine (dG) is the most electron‐rich nucleobase and preferentially reacts with phenol‐derived electrophiles to produce a wide variety of dG adducts (Fig.…”

Section: Introductionmentioning

confidence: 99%

“…2′‐Deoxyguanosine (dG) is the most electron‐rich nucleobase and preferentially reacts with phenol‐derived electrophiles to produce a wide variety of dG adducts (Fig. ) . Phenoxyl radicals, which have been directly correlated to phenol toxicity, react at C8 to afford C8‐dG adducts .…”

Section: Introductionmentioning

confidence: 99%

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Chlorine substitution promotes phenyl radical loss from C8-phenoxy-2′-deoxyguanosine adducts: implications for biomarker identification from chlorophenol exposure

et al. 2015

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Chlorophenols are persistent organic pollutants, which undergo peroxidase-mediated oxidation to afford phenolic radical intermediates that react at the C8-site of 2'-deoxyguanosine (dG) to generate oxygen-linked C8-dG adducts. Such adducts are expected to contribute to chlorophenol toxicity and serve as effective dose biomarkers for chlorophenol exposure. Electrospray ionization mass spectrometry (ESI-MS) was employed to study collision induced dissociation (CID) for a family of such phenolic O-linked C8-dG adducts. Fragmentation of the deprotonated nucleosides demonstrates that an unexpected homolytic cleavage of the ether linkage to release phenyl radicals and a nucleoside distonic ion with m/z 281 competes effectively with commonly observed breakage of the glycosidic bond to release the deprotonated nucleobase. Increased chlorination of the phenyl ring enhances phenyl radical loss. Density functional theory calculations demonstrate that Cl-substitution decreases phenyl radical stability but promotes homolytic breakage of the C8-phenyl bond in the C8-dG adduct. The calculations suggest that phenyl radical loss is driven by destabilizing steric (electrostatic repulsion) interactions between the ether oxygen atom and ortho-chlorines on the phenyl ring. The distonic ion at m/z 281 represents a unique dissociation product for deprotonated O-linked C8-dG adducts and may prove useful for selective detection of relevant biomarkers for chlorophenol exposure by tandem mass spectrometry using selective reaction monitoring.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chlorine substitution promotes phenyl radical loss from C8-phenoxy-2′-deoxyguanosine adducts: implications for biomarker identification from chlorophenol exposure

et al. 2015

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“…Human exposure to phenolic toxins occurs predominately through industrial activities, tobacco smoke, and inhalation of polluted air [4,5]. Phenol toxicity stems from their oxidative metabolism by peroxidase or cytochrome P450 enzymes to generate hydroquinone/quinone redox pairs, reactive oxygen species (ROS) and phenoxyl radicals that are well-known DNA-damaging agents [1,[6][7][8]. Human exposure to damaging radicals [9,10] and quinone electrophiles [6,7] are associated with cancer and aging.…”

Section: Introductionmentioning

confidence: 99%

“…Phenols are ubiquitous compounds that possess many biological properties including toxicity [1][2][3]. Human exposure to phenolic toxins occurs predominately through industrial activities, tobacco smoke, and inhalation of polluted air [4,5].…”

Section: Introductionmentioning

confidence: 99%

Mutagenicity Analysis of C8-Phenoxy-Guanine in the NarI Recognition DNA Sequence

2014

J Toxins

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Phenoxyl radicals can covalently attach to the C8-site of 2′-deoxyguanosine (dG) to generate oxygen-linked biaryl ether C8-dG adducts. To determine the mutagenicity of an O-linked C8-dG adduct, C8-phenoxy-dG (PhOdG) was incorporated into the G 3 position (X) of the NarI recognition sequence within a 22-mer oligonucleotide template (5′-CTCGGCX-CCATCCCTTACGAGC, where X = dG, or PhOdG) using solid-phase DNA synthesis. The NarI (22) template was annealed to a 15-mer primer and in vitro mutagenicity was assessed using primer-extension assays with a high-fidelity replicative polymerase, Escherichia coli pol I Klenow fragment exo− (Kf − ), and a lesion-bypass Y-family polymerase, Sulfolobus solfataricus P2 DNA polymerase IV (Dpo4). These studies predict that the O-linked C8-dG lesion PhOdG will have a low mutagenic effect, and is unlikely to contribute strongly to phenol toxicity.

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Understanding the Mutagenicity of O-Linked and C-Linked Guanine DNA Adducts: A Combined Experimental and Computational Approach

Manderville

Wetmore

2016

Chem. Res. Toxicol.

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The formation of DNA adducts by the attack of intermediates derived from toxic substances at C8 of 2'-deoxyguanosine (dG) is a common damaging event. Although the majority of studies on C8-dG adducts have focused on lesions containing a C8-N-C tether between the bulky moiety and the nucleobase, the formation of O-linked lesions with a similar tether topology and C-linked adducts involving direct C8-C connectivity have also been uncovered. Several studies have been done to try to better understand the structural impact and mutagenicity of O-linked and C-linked aryl C8-dG adducts, including lesions arising from unsubstituted and chloro-substituted phenols and the food mutagen ochratoxin A (OTA). Information about the structural preferences of the adducts in duplexes containing the NarI sequence has been gained from optical spectroscopy (UV-vis, CD, and fluorescence), F NMR spectroscopy, and computational chemistry (density functional theory calculations at the nucleobase, nucleoside, and nucleotide levels and molecular dynamics simulations of adducted duplexes). The replication of select adducts has also been investigated using primer-elongation assays, and model high-fidelity and Y-family polymerases. Although the (unsubstituted) O-linked phenoxy-dG adduct preferentially induces a single duplex conformation and is replicated as per natural dG, chloro substitution blocks DNA replication. In contrast, the unsubstituted C-linked phenyl-dG adduct induces mismatches, while the C-linked ortho- and para-phenoxy-dG lesions lead to conformational heterogeneity of adducted DNA indicative of strong mutagenic potential. Finally, the C-linked OTA-derived lesion exhibits the greatest conformational flexibility in duplexes, which provides structural explanations for observed outcomes in OTA-exposed cells. Overall, the variation in the conformational preferences of DNA containing O-linked and C-linked aryl-dG adducts highlights the fact that the type of C8 linkage, the presence and location of functional groups in the bulky moiety, the adduct ionization state, and the sequence context can have profound effects on the conformational outcomes of adducted DNA, which directly dictate the activity of the original toxin.

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DNA Damage by Phenoxyl Radicals

Cited by 9 publications

References 84 publications

Chlorine substitution promotes phenyl radical loss from C8-phenoxy-2′-deoxyguanosine adducts: implications for biomarker identification from chlorophenol exposure

Chlorine substitution promotes phenyl radical loss from C8-phenoxy-2′-deoxyguanosine adducts: implications for biomarker identification from chlorophenol exposure

Mutagenicity Analysis of C8-Phenoxy-Guanine in the NarI Recognition DNA Sequence

Understanding the Mutagenicity of O-Linked and C-Linked Guanine DNA Adducts: A Combined Experimental and Computational Approach

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