Nitrous Acid And Nitrosation

Turney, T. A.; Wright, Graham A.

doi:10.1021/cr50027a004

Cited by 151 publications

(64 citation statements)

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“…While nitrosative deamination of nucleobases in DNA and RNA can occur in acidified solutions of nitrite (NO 2 − ),66–68 inflammation-induced deamination of DNA and RNA bases in vivo is thought to be mediated primarily by the nitrosative chemistry of N 2 O 3 29. As shown in Figure 2, products of nitrosative deamination for canonical nucleobases are hypoxanthine (2-deoxyinosine/dI and inosine/rI as nucleosides) derived from adenine; uracil (2-deoxyuridine/dU, uridine/rU) from cytosine; xanthine (2-deoxyxanthosine/dX, xanthosine/rX) and oxanine (2-deoxyoxanosine/dO, oxanosine/rO) derived from guanine.…”

Section: The Chemistry Of Dna Damage Occurring In Chronic Inflammationmentioning

confidence: 99%

Reactive species and DNA damage in chronic inflammation: reconciling chemical mechanisms and biological fates

Lonkar

Dedon

2011

Intl Journal of Cancer

244

224

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Chronic inflammation has long been recognized as a risk factor for many human cancers. One mechanistic link between inflammation and cancer involves the generation of nitric oxide, superoxide and other reactive oxygen and nitrogen species by macrophages and neutrophils that infiltrate sites of inflammation. Although pathologically high levels of these reactive species cause damage to biological molecules, including DNA, nitric oxide at lower levels plays important physiological roles in cell signaling and apoptosis. This raises the question of inflammation-induced imbalances in physiological and pathological pathways mediated by chemical mediators of inflammation. At pathological levels, the damage sustained by nucleic acids represents the full spectrum of chemistries and likely plays an important role in carcinogenesis. This suggests that DNA damage products could serve as biomarkers of inflammation and oxidative stress in clinically accessible compartments such as blood and urine. However, recent studies of the biotransformation of DNA damage products before excretion point to a weakness in our understanding of the biological fates of the DNA lesions and thus to a limitation in the use of DNA lesions as biomarkers. This review will address these and other issues surrounding inflammation-mediated DNA damage on the road to cancer. More Than an Association Between Chronic Inflammation and CancerStemming from the original observations by Virchow, 1 the link between chronic inflammation and cancer is now recognized as essentially a cause-and-effect relationship. 2-7 Epidemiological evidence suggests that more than 20% of all cancers are caused by chronic infection or other types of chronic inflammation, 8 with multiple lines of evidence from laboratory-and population-based studies pointing to a persistent local inflammatory state in organspecific carcinogenesis 9-15 even for tumors not epidemiologically linked to infection or inflammation. There are extremely strong correlations between chronic exposure to asbestos and mesotheloima, 16,17 and chronic infections and cancer for liver flukes (O. viverrini) and cholangiocarcinoma, 18,19 Helicobacter pylori and gastric cancer, 20-22 viral hepatitis and liver cancer 23 and Schistosoma haematobium and bladder cancer. 24,25 Although the epidemiological evidence is well established, the mechanisms underlying the link between chronic inflammation and cancer are not. These mechanisms can be arbitrarily divided into biological and chemical as illustrated in Figure 1 for infection-induced inflammation. The initial infection leads to cell death and changes in cell phenotype, with the release of cytokines and chemotactic factors that cause infiltration of macrophages, neutrophils, lymphocytes and other immune cells. The biological side of chronic inflammation entails the effects of cytokines and chemokines on host cell cycle and apoptosis, whereas the chemical side involves generation of a variety of reactive oxygen and nitrogen species by activated phagocytes with the goal of er...

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Section: The Chemistry Of Dna Damage Occurring In Chronic Inflammationmentioning

confidence: 99%

Reactive species and DNA damage in chronic inflammation: reconciling chemical mechanisms and biological fates

Lonkar

Dedon

2011

Intl Journal of Cancer

244

224

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“…The electron-rich amine nitrogen attacks the nitrogen of nitrous anhydride, replacing the nitrite group, which splits off. The reactants are the unprotonated amine R 1 R 2 NH and two molecules of nitrous acid, to give the following kinetic equation (Turney & Wright, 1959):…”

Section: Aminesmentioning

confidence: 99%

Assessment of the risk of formation of carcinogenic N-nitroso compounds from dietary precursors in the stomach

Shephard

Schlatter

Lutz

1987

Food and Chemical Toxicology

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Summary-A Iiterature review has shown that the daily intakes of various N -nitroso-precursor classes in a typical European diet span five orders of magnitude. Amides in the form of protein, and guanidines in the form of creatine and creatinine, are the nitrosatable groups found most abundantly in the diet, approaching Ievels of 100 g/day and 1 gjday, respectively. Approximately 100 mg of primary amines and amino acids are consumed daily, whereas aryl amines, secondary amines and ureas appear to lie in the 1-10 mg range. The ease of nitrosation of each precursor was estimated, the reactivities being found to span seven orders of magnitude, with ureas at the top and amines at the bottom of the scale. From this infonnation and an assessment of the carcinogenicity of the resulting N-nitroso derivatives, the potential health risk due to gastric in vivo nitrosation was calculated. The combined effects of these risk variables were analysed using a simple mathematical model: Risk = [daily intake of precursor] x [gastric concen· tration of nitrite]" x [nitrosatability rate constant} x [carcinogenicity of derivative]. The risk estimates for the various dietary components spanned nine orders of magnitude. Dietary ureas and aromatic amines combined with a high nitrite burden could pose as great a risk as the intake of preformed dimethylnitrosamine in the diet. In contrast, the risk posed by the in vivo nitrosation of primary and secondary amines is probably negligib1y small. The risk contribution by amides (including protein), guanidines and primary amino acids is intermediate between these two extremes. Thus three priorities for future work are a comprehensive study of the sources and Ievels of arylamines and ureas in the diet, determination of the carcinogenic potencies of key nitrosated products to replace the necessarily vague categories used so far, and the development of short-term in situ tests for studying the alkylating power or genotoxicity of N-nitroso compounds too unstable for inclusion in long-term studies.

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“…Analysis of the reaction at 4 hours showed a significant loss of the nitrosated cimetidines (4% compared to 38% at 1/2 hour) and a corresponding increase in cimctidine (96% compared to 62% at 1/2 hour). Apparently the nitrosation of cimetidine is a reversible reaction, reversal occurring as nitrosation species are lost to the atmosphere from an open vessel (16). Consequently all subsequent comparative nitrosations were carried out in closed vials.…”

Section: Comparative Nitrosation Of Cimetidine and Etintidinementioning

confidence: 99%

Comparative nitrosation of etintidine and cimetidine

Montzka¹,

Juby²,

Matiskella³

et al. 1983

Can. J. Chem.

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Etintidine (4), a new histamine H2-receptor antagonist, was compared with cimetidine (1) for susceptibility to in vitro nitrosation at pH 1 and pH 3. Each agent formed two mono-N-nitrosoguanidine derivatives: N-cyano-N′-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethyl}-N″-nitroso-N″-(2-propynyl)guanidine (5) and N-cyano-N′-{2-[5-methyl-1H-imidazol-4-yl)methylthio]ethyl}- N′-nitroso-N″-(2-propynyl)guanidine (6) from etintidine and N-cyano-N′-methyl-N″-{2-[(5-methyl-1H-imidazol-4-yl)methylthio]ethyl}- N′-nitrosoguanidinc (2) and N-cyano-N′-methyl-N"-{2-[(5-methyl-1H-imidazol-4-yl)methyl-thio]ethyl}-N′-nitrosoguanidine (11) from cimetidine. The N-nitroso derivative 5 from etintidine cyclized to 2-cyanoimino-3-{2-((5-methyl-1H-imidazol-4-yl)methylthio]ethyl}-N″-methylene-1-nitroso-imidazoline (7) at neutral or basic pH's. Both agents were nitrosated less at pH 3 than at pH 1, and at both pH's nitrosation of etintidine was considerably less than that of cimetidine. At pH 1, with a nitrite concentration about 150–500 times that expected in fasting human gastric juice, formation of 5 and 6 from etintidine was barely detectable (each < 0.5%). Comments are made on the standard WHO conditions for investigating nitrosation of drugs.

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Nitrous Acid And Nitrosation

Cited by 151 publications

References 29 publications

Reactive species and DNA damage in chronic inflammation: reconciling chemical mechanisms and biological fates

Reactive species and DNA damage in chronic inflammation: reconciling chemical mechanisms and biological fates

Assessment of the risk of formation of carcinogenic N-nitroso compounds from dietary precursors in the stomach

Comparative nitrosation of etintidine and cimetidine

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