The kinetics and primary products of uracil chlorination

Gould, Joseph P.; Richards, John T.; Miles, Malcolm G.

doi:10.1016/0043-1354(84)90070-8

Cited by 34 publications

(24 citation statements)

References 6 publications

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“…Many different groups have demonstrated the reaction of HOCl with -NH 2 groups on DNA bases generating chloramines (19,21,23). These secondary oxidants may give rise to the continuing slower formation of particular base lesions, especially 5-Cl uracil, after the initial "burst" on HOCl addition that was observed in this study.…”

Section: Discussionmentioning

confidence: 78%

Hypochlorous Acid-Induced Base Modifications in Isolated Calf Thymus DNA

Whiteman

Jenner

Halliwell

1997

Chem. Res. Toxicol.

157

105

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Exposure of calf thymus DNA to hypochlorous acid/hypochlorite leads to extensive DNA base modification. Large concentration-dependent increases in pyrimidine oxidation products [thymine glycol (cis/trans), 5-hydroxycytosine, 5-hydroxyuracil, 5-hydroxyhydantoin] but not purine oxidation products (8-hydroxyguanine, 2- and 8-hydroxyadenine, FAPy guanine, FAPy adenine) were observed at pH 7.4. In addition, large increases in 5-chlorouracil (probably formed from 5-chlorocytosine during sample preparation), a novel chlorinated base, were observed. Addition of HOCl to DNA already damaged by .OH generated by a mixture of ascorbate, copper(II) chloride, and hydrogen peroxide showed that hypochlorous acid led to a loss of 8-hydroxyguanine, 2- and 8-hydroxyadenine, FAPy guanine, FAPy adenine, and 5-hydroxycytosine in a concentration- and pH-dependent manner. Nevertheless, time course studies suggested that the formation of purine oxidation products in isolated DNA by hypochlorous acid was not a major oxidation pathway. If this pattern of damage, especially the production of 5-chlorocytosine, is unique to hypochlorous acid, it might act as a "fingerprint" of damage to DNA by HOCl.

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Section: Discussionmentioning

confidence: 78%

Hypochlorous Acid-Induced Base Modifications in Isolated Calf Thymus DNA

Whiteman

Jenner

Halliwell

1997

Chem. Res. Toxicol.

157

105

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“…4A). This is likely due to the fact that dC may be primarily oxidized to the chloramine, in contrast to dU which can be directly converted to 5-ClUra (20). The yield from chlorination of dC is higher under slightly acidic conditions (pH 5), compared with pH 7, which is likely due to the formation of molecular chlorine from HOCl under acidic conditions, which then chlorinates dC to 5-chlorocytidine (12).…”

Section: -Chlorouracilmentioning

confidence: 90%

“…It has been shown that the reaction of HOCl with nucleobases primarily leads to extensive damage to pyrimidines such as cytosine, uracil and thymine, but minor damage to purines (11,12,22). HOCl oxidizes uracil to 5-ClUra (20), and primarily oxidizes cytosine to chloramines under neutral pH or 5-chlorocytosine at acidic pH (12). Chloramine-cytosine slowly gives rise to other base lesions, including 5-ClUra (23-25).…”

Section: Discussionmentioning

confidence: 99%

5-Chlorouracil, a Marker of DNA Damage from Hypochlorous Acid during Inflammation

Jiang

Blount²,

Ames

2003

Journal of Biological Chemistry

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Hypochlorous acid (HOCl), generated from H 2 O 2 and Cl ؊ by myeloperoxidase in activated neutrophils, causes tissue damage during inflammation. We have developed a simple, sensitive (ϳ0.2 fmol on column) and specific GC-MS assay for the detection of 5-chlorouracil (5-ClUra), a signature product of HOCl-mediated damage to nucleobases. In this assay, 5-ClUra is released from isolated DNA by a digestion with nuclease P1, alkaline phosphatase, and thymidine phosphorylase (TP), or from chlorinated nucleosides in biological fluids by TP. The freed 5-ClUra is derivatized with 3, 5-bis-(trifluoromethyl)-benzyl bromide, which is detected by negative chemical ionization mass spectrometry. The assay can be used to simultaneously detect other halogenated uracils including bromouracil. Using this assay, we showed that 5-ClUra is generated by the reaction of low micromolar HOCl with (deoxy)cytidine, (deoxy)uridine, and DNA. In cell cultures, an increase of 5-ClUra was detected in DNA when cells were treated with sublethal doses of HOCl and allowed to proliferate. The elevation of 5-ClUra was markedly accentuated when physiologically relevant concentrations of (deoxy)uridine, (deoxy) cytidine, uracil, or cytosine were present in the medium during HOCl treatment. In the carrageenan-induced inflammation model in rats, chlorinated nucleosides was significantly increased, compared with controls, in the exudate fluid isolated from the inflammation site. Our study provides the direct evidence that chlorinated nucleosides are found in the inflammation site and can be incorporated in DNA during cell/tissue proliferation. These findings may be relevant to the carcinogensis associated with chronic inflammation.

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“…8-Chlorinated products of 2Ј-deoxyadenosine (28,29) and 2Ј-deoxyguanosine (30) have also been identified in the reaction with HOCl. Alternatively, in contrast to these stable carbon-chlorinated products, the formation of semistable or unstable nitrogen-chlorinated products, chloramines (RNHCl and RRЈNCl), was also observed (31)(32)(33)(34). Unstable nucleoside chloramines, such as thymidine chloramine, are suggested to initiate DNA single and double strand breaks via nitrogencentered radicals and to transfer their chlorine atoms to other nucleosides (35,36).…”

mentioning

confidence: 99%

Endogenous Formation of Novel Halogenated 2′-Deoxycytidine

Kawai

Morinaga

Kondo

et al. 2004

Journal of Biological Chemistry

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A potential role of DNA damage by leukocyte-derived reactive species in carcinogenesis has been suggested. Leukocyte-derived peroxidases, such as myeloperoxidase and eosinophil peroxidase, use hydrogen peroxide and halides (Cl ؊ and Br ؊ ) to generate hypohalous acids (HOCl and HOBr), halogenating intermediates. It has been suggested that these oxidants lead to the formation of halogenated products upon reaction with nucleobases. To verify the consequences of phagocyte-mediated DNA damage at the site of inflammation, we developed a novel monoclonal antibody (mAb2D3) that recognizes the hypohalous acid-modified DNA and found that the antibody most significantly recognized HOCl/HOBr-modified 2-deoxycytidine residues. The immunoreactivity of HOCl-treated oligonucleotide was attenuated by excess methionine, suggesting that chloramine-like species may be the plausible epitopes of the antibody. On the basis of further characterization combined with mass spectrometric analysis, the epitopes of mAb2D3 were determined to be novel N 4 ,5-dihalogenated 2-deoxycytidine residues. The formation of the dihalogenated 2-deoxycytidine in vivo was immunohistochemically demonstrated in the lung and liver nuclei of mice treated with lipopolysaccharides, an experimental inflammatory model. These results strongly suggest that phagocyte-derived oxidants, hypohalous acids, endogenously generate the halogenated DNA bases such as a novel dihalogenated 2-deoxycytidine in vivo. Halogenation (chlorination and/or bromination) of DNA therefore may constitute one mechanism for oxidative DNA damage at the site of inflammation.

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The kinetics and primary products of uracil chlorination

Cited by 34 publications

References 6 publications

Hypochlorous Acid-Induced Base Modifications in Isolated Calf Thymus DNA

Hypochlorous Acid-Induced Base Modifications in Isolated Calf Thymus DNA

5-Chlorouracil, a Marker of DNA Damage from Hypochlorous Acid during Inflammation

Endogenous Formation of Novel Halogenated 2′-Deoxycytidine

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