Nitrosamines and Related N-Nitroso Compounds. Chemistry and Biochemistry

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For the subgroup analyses, matched sets were broken and unconditional logistic regression was used to maximize the sample size available for stratified statistical analysis. The matching factors age, year of biospecimen collection, and neighborhood of residence at recruitment were included in all unconditional logistic regression models as covariates.

The presence of H. These factors were included in the multivariable logistic regression models when examining the independent effect of NOCs on gastric cancer risk. Statistical computing was conducted using SAS version 9. The mean age standard deviation of case patients at cancer diagnosis was The average time interval between biospecimen collection and cancer diagnosis was 5. Individuals who developed gastric cancer consumed more cigarettes and alcohol, and were more likely to be seropositive for IgG antibodies to H.

The correlation coefficients among nitrate, nitrite and four NOCs ranged from 0. Table 3 shows geometric means of urinary NOCs, nitrite, and nitrate among control subjects. Smokers or those positive for antibodies to H. There was no significant relation for other urinary NOCs or their precursors with alcohol intake, cigarette smoking or history of H. We also examined the association between intake frequencies of fresh dark green vegetables or preserved foods and urinary levels of NOCs or their precursors among control subjects.

Among controls who consumed one or more times of salted or pickled vegetables per week, the corresponding figures were Overall there was no significant difference in urinary concentrations of nitrate, nitrite or any NOCs measured between gastric cancer patients and control subjects Table 4. Compared with low levels i. Given that infection with H. Among individuals negative to H. There was no evidence for effect modification of H. The association between urinary levels of nitrate, nitrite or NOCs and risk of cardia or non-cardia cancer was examined.

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Overall no statistically significant association was found for urinary NOCs or their precursors with risk of either cardia or non-cardia cancer data not shown. To the best of our knowledge, the present study was the first utilizing a biomarker approach to investigate the association between NOCs and their precursors and the risk of developing gastric cancer in a prospective cohort study.

We observed a statistically significant positive association between urinary nitrate and gastric cancer risk among individuals negative for IgG antibodies to H.

In addition, elevated levels of urinary nitrite were associated with seropositivity to H. Furthermore, the present study demonstrated a novel dose-dependent relationship between alcohol consumption and urinary levels of NMTCA, suggesting that alcohol intake could play a role in the formation of NOCs in vivo. Infection with H.

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An elevated level of urinary nitrite in individuals seropositive for antibodies to H. The interactive role of H. Among individuals seronegative for IgG antibodies to H. Chronic infection with H.

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It is not surprising that the association between nitrate and gastric cancer risk was more apparent among individuals without H. The findings of the present study suggest that the effect of nitrate through the nitrosation pathway could be masked by H. Given the small sample size and multiple comparison issues, the interpretation of the present study findings with a positive association between urinary nitrate and gastric cancer risk among individuals with negative H. The future studies with a larger sample size are warranted to confirm these results. This study shows that higher levels of NMTCA in the urine of alcohol drinkers compared to non-drinkers.

Studies have shown that co-administration of acetaldehyde a metabolite of ethanol , L-cysteine and nitrite significantly increased urinary excretion of NMTCA in man [ 24 ]. The present study demonstrated for the first time in free-living individuals that alcohol consumption resulted in a significantly increased level of urinary NMTCA.

Our findings were consistent with the result from a recent study showing that NMTCA were often detected in processed meat products [ 36 , 37 ]. This effect could be due to the reduction of nitrate to nitrite that could be catalyzed by bacteria containing nitrate reductase[ 40 ]. In the present study, we found that several NOCs levels in urine were correlated with each other. Due to the complexities of the assays for multiple NOCs in a single batch run, limited data on the relationships among NOCs on an individual basis have been reported.

The in vivo administration of nitrate and their respective secondary amine precursor has shown high efficiency in the production of endogenous NTCA and NPRO [ 22 , 23 ], resulting in their correlation with nitrate. Nitrate and nitrite are classified as probably carcinogenic to humans under conditions likely to cause endogenous nitrosation [ 8 ]. A positive association between dietary intake of nitrites and nitrosamines and gastric cancer risk has been observed in several case-control studies [ 41 — 44 ].

The consumption of processed meat, preserved fish and preserved vegetables was associated with increased risk of gastric cancer with an OR being from 1.


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However, several cohort studies showed inconsistent results. For instance, a large multicenter European cohort study reported that individuals with the highest propensity for endogenous NOCs formation had an elevated risk for gastric cancer [ 45 ]. In contrast, a large Finnish cohort study found no association between estimated intake of nitrites, nitrates and N -nitrosodimethylamine and risk of gastric cancer [ 46 ].

In the present study, we found a statistically significant, positive association between prediagnostic urinary nitrate level and risk of gastric cancer among H. The lack of an overall positive association between urinary levels of selected NOCs and their precursors and risk of gastric cancer could be due to the high prevalence of H. The strong effect of H. Our study had several strengths. A prospective study design and the availability of prediagnostic urine samples minimized the possible influence of disease symptoms on dietary intake and other lifestyle factors.

The prospective design of the study also ruled out the possibility of recall bias on exposure. Considering the limitation of food frequency questionnaire in the estimation of exposure levels to both endogenous and exogenous NOCs [ 19 ], urinary levels of NOCs as exposure biomarkers may overcome such limitations and capture both sources of NOCs. The simultaneous adjustment for cigarette smoking, alcohol drinking, H. The almost complete follow-up for incident cancer and death minimized the potential bias on results due to the loss to follow-up.

The present study has several potential limitations. One cannot presume that NOCs levels in a randomly timed, single void urine sample represented the long-term exposure to both exogenous and endogenous NOCs. It would be ideal, but rarely feasible, to assess NOC exposure at multiple time points prior to disease occurrence, especially using a biomarker approach as this study, due to the high cost and logistical complexity involved in the collection of biospecimens at multiple points of time for each subject from a prospective study of large number of participants such as this one.

Therefore, the non-differential misclassification due to the use of a single spot urine sample may be the underlying reason for the null findings of urinary NOCs and gastric cancer risk. Another major limitation of the present study was the relatively small sample size, especially those negative for H. In summary, the present study did not show an overall statistically significant association between urinary levels of selected NOCs or their precursors and risk of gastric cancer in a high-risk population with high prevalence of H.

A statistically significant positive association between prediagnosic urinary levels of nitrate and risk of gastric cancer was observed among individuals negative for antibodies to H. This positive nitrate-gastric cancer risk association was independent of cigarette smoking, alcohol consumption and antioxidant status. The present study also found a strong, dose dependent relationship for the consumption of alcohol or preserved meats and fishes with urinary levels of NMTCA, which sheds some light on our understanding the mechanism of alcohol and preserved protein-rich food items on gastric carcinogenesis.

The role of N -nitroso-compounds in the development of gastric cancer in humans is warranted for further investigation. We thank Ms. We also thank the Shanghai Cancer Registry for assistance with identification of cancer outcomes in the Shanghai Cohort Study. Browse Subject Areas? Click through the PLOS taxonomy to find articles in your field.

Abstract Background N -Nitroso compounds are thought to play a significant role in the development of gastric cancer. Methods A nested case-control study within a prospective cohort of 18, middle-aged and older men in Shanghai, China, was conducted to examine the association between urinary level of N -nitroso compounds and risk of gastric cancer. Results Compared with controls, gastric cancer patients had overall comparable levels of urinary nitrate, nitrite, and N -nitroso compounds. Conclusion The present study demonstrates that exposure to nitrate, a precursor of N -nitroso compounds, may increase the risk of gastric cancer among individuals without a history of H.

This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited Data Availability: All relevant data are within the paper.

Introduction Despite the decrease in incidence and mortality rates of stomach cancer worldwide over the past three decades, gastric cancer is the fourth most commonly diagnosed cancer and the third most common cause of cancer death [ 1 ].

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Laboratory Assays The aliquots of urine samples of the subjects were pulled from the biospecimen repository and then sorted into the matched case-control sets. Statistical Analysis Of cases and controls, urine samples of 6 cases and 18 their matched controls and additional 4 controls had missing values of one or more urinary measurements. Results The mean age standard deviation of case patients at cancer diagnosis was Download: PPT. Table 1. Demographic and lifestyle characteristics of gastric cancer patients cases and the control subjects controls , The Shanghai Cohort Study.

Table 2.

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Spearman correlation coefficients among urinary N -nitroso compounds measured among control subjects, The Shanghai Cohort Study. Table 3. Geometric mean levels of urinary N -nitroso compounds by status of drinking, smoking and H. Table 4. Median range levels of urinary N -nitroso compounds in gastric cancer cases and control subjects, The Shanghai Cohort Study. Table 5. Levels of urinary N -nitroso compounds in relation to risk of gastric cancer, The Shanghai Cohort Study. Table 6. Urinary level of N -nitroso compounds in relation to the risk of gastric cancer stratified by H.

Discussion To the best of our knowledge, the present study was the first utilizing a biomarker approach to investigate the association between NOCs and their precursors and the risk of developing gastric cancer in a prospective cohort study. Conclusions In summary, the present study did not show an overall statistically significant association between urinary levels of selected NOCs or their precursors and risk of gastric cancer in a high-risk population with high prevalence of H.

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Acknowledgments We thank Ms. References 1. Forman D, Ferlay J The global and regional burden of cancer. World Cancer Report CA Cancer J Clin 74— CA Cancer J Clin 69— CA Cancer J Clin — Lijinsky W In vivo testing for carcinogenicity.