Endogenous Formation of Novel Halogenated 2′-Deoxycytidine

Kawai, Yoshichika; Morinaga, Hiroshi; Kondo, H.; Miyoshi, Noriyuki; Nakamura, Yoshimasa; Uchida, Koji; Osawa, Toshihiko

doi:10.1074/jbc.m408210200

Cited by 55 publications

(21 citation statements)

References 49 publications

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“…A summary of the various immunostainings can be seen in Table 1. N 4 ,5-diCldC was previously detected by immunohistochemistry in LPS-treated mice (21). The time course of N 4 ,5-diCldC immunostaining was consistent with that of 8-halo-dGs (Table 1).…”

Section: Preparation and Characterization Of Monoclonal Antibody To 8supporting

confidence: 59%

Chemical and Immunochemical Detection of 8-Halogenated Deoxyguanosines at Early Stage Inflammation

Asahi

Kondo

Masuda

et al. 2010

Journal of Biological Chemistry

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Myeloperoxidase (MPO) generates reactive halogenating species that can modify DNA. The aim of this study was to investigate the formation of 8-halogenated 2-deoxyguanosines (8-halo-dGs) during inflammatory events. 8-Bromo-2-dG (8-BrdG) and 8-chloro-2-dG (8-CldG) were generated by treatment of MPO with hydrogen peroxide at physiological concentrations of Cl ؊ and Br ؊ . The formation of 8-halo-dGs with other oxidative stress biomarkers in lipopolysaccharide-treated rats was assessed by liquid chromatography tandem mass spectrometry and immunohistochemistry using a novel monoclonal antibody (mAb8B3) to 8-BrdG-conjugated keyhole limpet hemocyanin. The antibody recognized both 8-BrdG and 8-CldG. In the liver of lipopolysaccharide-treated rats, immunostaining for 8-halodGs, halogenated tyrosines, and MPO were increased at 8 h, whereas those of 8-oxo-2-dG (8-OxodG) and 3-nitrotyrosine were increased at 24 h. Urinary excretion of both 8-CldG and 8-BrdG was also observed earlier than those of 8-OxodG and modified tyrosines (3-nitrotyrosine, 3-chlorotyrosine, and 3-bromotyrosine). Moreover, the levels of the 8-halo-dGs in urine from human diabetic patients were 8-fold higher than in healthy subjects (n ‫؍‬ 10, healthy and diabetic, p < 0.0001), whereas there was a moderate difference in 8-OxodG between the two groups (p < 0.001). Interestingly, positive mAb8B3 antibody staining was observed in liver tissue from hepatocellular carcinoma patients but not in liver tissue from human cirrhosis patients. These data suggest that 8-halo-dGs may be potential biomarkers of early inflammation.Oxidative damage is implicated in the pathogenesis of many diseases including atherosclerosis and cancer (1-4). Involvement of myeloperoxidase (MPO), 2 a heme protein secreted by activated leukocytes such as neutrophils and monocytic cells, is a potential cause of oxidative damage during inflammation. At sites of inflammation, activated leukocytes play a major role in host defense against microorganisms using oxidants such as HOCl and HOBr. However, excessive oxidant release can also induce damage; DNA bases (5-8) and proteins and lipids (9 -12), for instance, are putative targets of oxidants. At plasma halide concentrations (100 mM Cl Ϫ , 20 -100 M Br Ϫ ) (13), MPO converts HOCl to HOBr using Br Ϫ as a halide exchange (14). HOBr is also generated by eosinophil peroxidase using H 2 O 2 and Br Ϫ , such as by the MPO-H 2 O 2 -Cl Ϫ system. Because MPO catalyzes halogenation, oxidation, and nitration (15-17), MPO and its product may be important general markers for evaluating oxidative damage to the body during inflammation. Halogenation is a key reaction for the formation of an MPO activity marker because the presence of halogen in the marker molecule directly indicates a contribution of the halogenating species at the site of oxidative damage. Moreover, no other halogenating pathways have been reported except for MPO and eosinophil peroxidase-derived damage. Therefore, halogenated products have the potential to be specific markers of inflammatio...

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Section: Preparation and Characterization Of Monoclonal Antibody To 8supporting

confidence: 59%

Chemical and Immunochemical Detection of 8-Halogenated Deoxyguanosines at Early Stage Inflammation

Asahi

Kondo

Masuda

et al. 2010

Journal of Biological Chemistry

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“…However, it is now recognized that ONE is more reactive than HNE toward the DNA bases 2Ј-deoxyguanosine (20,22), 2Ј-deoxyadenosine (33,34), and 2Ј-deoxycytidine (35)(36)(37), generating a variety of bulky DNA adducts such as 2-oxo-heptyl-substituted etheno-type adducts. In the present study, we identified ONE as a potential inducer of the p53 response in the human neuroblastoma cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Lipid Peroxidation Product as a Potential Trigger of the p53 Pathway

Shibata

Iio

Kawai

et al. 2006

Journal of Biological Chemistry

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The tumor suppressor and transcription factor p53 is a key modulator of cellular stress responses, and activation of p53 can trigger apoptosis in many cell types, including neurons. We found that this nuclear protein was significantly phosphorylated when human neuroblastoma SH-SY5Y cells were exposed to in vitro oxidized polyunsaturated fatty acids. To identify an oxidized lipid that induces p53 phosphorylation, we conducted a screening of lipid peroxidation products in human neuroblastoma SH-SY5Y cells and identified 4-oxo-2-nonenal (ONE), a recently identified aldehyde originating from the peroxidation of 6 polyunsaturated fatty acids, as a potential inducer of the p53 phosphorylation. We also found that ONE induced the phosphorylation of ataxia telangiectasia-mutated, which plays an essential role in transmitting DNA damage signals by the phosphorylation of p53. In addition, exposure of the cells to ONE resulted in an accumulation of ubiquitinated proteins and in a significant inhibition of proteasome activities, suggesting that ONE acted on the ubiquitin-proteasome pathway, a regulatory mechanism of p53 turnover. In addition, the observation that the ONE-induced p53 response was associated with the induction of apoptosis suggested that ONE activated the p53-dependent apoptosis mechanism via activation of the p53 signaling pathway and down-regulation of the p53 turnover. Finally, we observed that the ONE-2-deoxyguanosine adduct, 7-(2-oxo-heptyl)-substituted 1,N 2 -etheno-2-deoxyguanosine, was accumulated in the spinal cord motor neurons of patients with sporadic amyotrophic lateral sclerosis. These data may suggest the potential critical role for ONE in the induction of a neuronal apoptosis program during oxidative processes.

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“…Chlorinated nucleosides that might induce genotoxicity have been identified in several tissues and are often discussed with regard to diseases such as inflammation and atherosclerosis. 5,[16][17][18] Taken together, chlorinated nucleosides can be regarded as useful specific biomarkers for HOCl-(and also activated neutrophil-) induced oxidative damage in vivo. In the present study, we examined the effects of several antioxidative compounds on the formation of biomarker Cl-Guo in vitro for the first time using three reaction systems, the HOClinduced chemical reaction, the human MPO-induced enzymatic reaction, and activated human neutrophilinduced cellular reaction system.…”

Section: Discussionmentioning

confidence: 99%

“…1,2) Recently, HOCl was reported to react with nucleic acid bases to form chlorinated and oxidized compounds, e.g., 8-chloroguanosine (Cl-Guo), 8-chloroadenine, 8-chloro-2 0 -deoxyguanosine, 5-chloro-2 0 -deoxycytidine, and 8-oxo-deoxyGuo. [2][3][4][5][6][7][8] In addition, tertiary amines such as nicotine and trimethylamine at physiologically relevant concentrations have been found strongly to enhance Cl-Guo formation mediated by HOCl. 3,9) The G-463A polymorphism of the mpo gene, which reduces the expression of MPO mRNA, has been reported to be associated with reduced risk of lung cancer in cigarette smokers.…”

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confidence: 99%

Inhibition by Polyphenolic Phytochemicals and Sulfurous Compounds of the Formation of 8-Chloroguanosine Mediated by Hypochlorous Acid, Human Myeloperoxidase, and Activated Human Neutrophils

Nakano

Masuda

Suzuki

et al. 2012

Bioscience, Biotechnology, and Biochemistry

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Hypochlorous acid (HOCl) produced by myeloperoxidase (MPO) of activated neutrophils can react with nucleic acid bases to form chlorinated nucleosides such as 8-chloroguanosine (Cl-Guo). Chlorination is enhanced by nicotine. We investigated the effects of various natural antioxidants including polyphenolic phytochemicals on the formation of Cl-Guo by HOCl in the presence and the absence of nicotine. Polyphenols, including catechins, curcumin, resveratrol, silibinin, and sulfurous compound -lipoic acid, were found to inhibit both HOCl-and human MPO-induced Cl-Guo formation dose-dependently. Among the test compounds, (À)-epigallocatechin gallate (EGCG) showed the strongest inhibitory effect. Cl-Guo formation, mediated by activated human neutrophils in the presence of nicotine, was inhibited by EGCG, silibinin, and -lipoic acid. These results suggest that polyphenols and sulfurous compounds have the potential to inhibit the induction of nucleobase damage mediated by chlorination, with possible application to reducing DNA damage associated with inflammation and cigarettesmoke inhalation.

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Endogenous Formation of Novel Halogenated 2′-Deoxycytidine

Cited by 55 publications

References 49 publications

Chemical and Immunochemical Detection of 8-Halogenated Deoxyguanosines at Early Stage Inflammation

Chemical and Immunochemical Detection of 8-Halogenated Deoxyguanosines at Early Stage Inflammation

Identification of a Lipid Peroxidation Product as a Potential Trigger of the p53 Pathway

Inhibition by Polyphenolic Phytochemicals and Sulfurous Compounds of the Formation of 8-Chloroguanosine Mediated by Hypochlorous Acid, Human Myeloperoxidase, and Activated Human Neutrophils

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