Nitrite and Nitrate Are Formed by Endogenous Synthesis in the Human Intestine

Tannenbaum, S.R.; Fett, D.; Young, Vernon R.; Land, P. D.; Bruce, W. R.

doi:10.1126/science.663630

Cited by 270 publications

(88 citation statements)

References 19 publications

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“…The association between endogenous production of nitric oxide radical, as mediated by macrophages, involved in the infectious and inflammatory response has been a topic of interest and toxicologic research for more than 10 years (43)(44)(45)(46)(47)(48). Debate remains concerning the significance and amount of this endogenous nitric oxide production in terms of the organism's overall oxidative stress (49,50).…”

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confidence: 99%

A nested case-control study of methemoglobinemia risk factors in children of Transylvania, Romania.

Zeman

Kross

Vlad

2002

Environ Health Perspect

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In this nested case-control study, we investigated the risk factors for methemoglobinemia (MHG) in 71 children in the Transylvania region of Romania. This study was unique in that the exposures for cases and controls were calculated as continuous values and were reported in milligrams per kilogram per day of nitrate/nitrite based on careful dietary reconstruction and environmental sampling. This procedure allowed us to compare point estimates of nitrate/nitrite exposure with other continuous, categoric, and ranked risk factors such as the presence or absence of diarrheal disease, reported severity of diarrheal disease, the use of vitamin supplements, the presence, absence, and/or duration of breast-feeding, and whether or not first-generation relatives experienced MHG. Analysis of these factors and exposure levels using both univariate and multivariate whole-model tests was performed to understand the relative significance of risk factors at varying levels of exposure to the development of MHG. Univariate and multifactorial analysis of risk factors for MHG underscored that, for this population, MHG is most strongly associated with nitrate/nitrite exposure through the dietary route (p = 0.0318), via feeding of formula and tea made with water containing high levels of nitrates, and that breast-feeding protects infants younger than 6 months of age (p = 0.0244). Our findings also raise questions about the role of diarrheal disease in the development of MHG, as likelihood ratios (likelihood 4.323, p = 0.0376) and multifactorial analysis indicated a significant role for diarrheal disease for some individuals.

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confidence: 99%

A nested case-control study of methemoglobinemia risk factors in children of Transylvania, Romania.

Zeman

Kross

Vlad

2002

Environ Health Perspect

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“…Many studies have been devoted to problems related to the fate of ingested nitrate and nitrite in the body (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). It is certain from the literature that increased ingested nitrate or nitrite results in increased urinary excretion of nitrate and nitrite, but the details of the major metabolic pathway are not sufficiently known.…”

Section: Absorption and Conversion Of No In Bloodmentioning

confidence: 99%

“…Tannenbaum et al (33) suggested that nitrate and nitrite are produced de novo in the intestine as a result of heterophic nitrification. According to the research of Witter et al (34), who studied 1NO in humans and rats, the 13N compound administered was not rapidly absorbed through the stomach wall; the concentration was increased in the lower intestine, and a portion of the 13N was retained in the body.…”

Section: Absorption and Conversion Of No In Bloodmentioning

confidence: 99%

Biotransformation of Nitric Oxide

Yoshida¹,

Kasama²

1987

Environmental Health Perspectives

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Previous investigations into the health effects of nitrogen oxides (NOJ) have mostly been conducted with special reference to nitrogen dioxide (NO2) and its direct effects on the respiratory system, while the study of nitric oxide (NO) has been disregarded. We carried out a study on NO by exposing rats and mice to 15NO or administering 15N-nitrite and 15N-nitrate to these animals by IP injection in order to elucidate the metabolic fate of NO.The results of our study and previous findings led us to assume that the major metabolic path of inhaled NO is as follows: inhaled NO reacts with hemoglobin, forming nitrosyl-hemoglobin (NOHb), and from NOHb, nitrite (NO-) and nitrate (NO-) are generated. Major quantities of NO-are discharged into the urine and a certain amount is discharged into the oral cavity through the salivary glands and transformed to NO-. Part of this NO is converted to N2 gas in the stomach. Nitrate in the intestine is partly reduced to ammonia (NH3) through NO-, reabsorbed into the body, and converted to urea. Most of the metabolites of inhaled NO are excreted rapidly from the body within 48 hr.

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“…A number of studies have now established that mammals on low nitrate diets excrete more nitrate than they ingest (1)(2)(3). At first it was thought that this excess urinary nitrate was the product of intestinal microbial metabolism (1), but subsequent studies with germ-free and conventional rats showed that the process of nitrate biosynthesis was by a mammalian pathway (2).…”

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confidence: 99%

Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide.

Stuehr

Marletta

1985

Proc. Natl. Acad. Sci. U.S.A.

963

456

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Escherichia coli lipopolysaccharide (LPS)-induced nitrate biosynthesis was studied in LPS-sensitive C3H/He and LPS-resistant C3H/HeJ mice. Intraperitoneal injection of 15 ,ug ofLPS led to a temporary 5-to 6-fold increase in blood nitrate concentration in the C3H/He strain. Levels of nitrate excreted in the urine were also increased. In contrast, no increase was observed in the C3H/HeJ strain with LPS injections up to 175 ,ug. Furthermore, thioglycolate-elicited peritoneal macrophages from C3H/He, but not from C3H/HeJ mice, produced nitrite (60%) and nitrate (40%) when cultured with LPS (10 jig/ml). T-lymphocyte addition/depletion experiments showed the presence of T cells enhanced this response. However, LPS did not cause nitrite or nitrate production in cultures of spleen lymphocytes from either strain. LPS-induced nitrate synthesis was also observed with nude mice and CBA/N mice, indicating that neither functional T lymphocytes nor LPS-responsive B lymphocytes were required for the response in vivo. This was consistent with the in vitro results showing macrophages alone were competent. Mycobacterium bovis infection of C3H/He and C3H/HeJ mice resulted in a large increase in nitrate production over the course of the infection for both strains, suggesting T-lymphocyte-mediated activation of macrophages as a potent stimulus for nitrate biosynthesis.The synthesis of nitrite is significant in that it can directly participate in the endogenous formation of nitrosamines and may also be involved in some aspect of the chemistry of cytotoxicity.A number of studies have now established that mammals on low nitrate diets excrete more nitrate than they ingest (1-3). At first it was thought that this excess urinary nitrate was the product of intestinal microbial metabolism (1), but subsequent studies with germ-free and conventional rats showed that the process of nitrate biosynthesis was by a mammalian pathway (2). The concern for this process stems from the demonstrated carcinogenicity of nitrosamines (4), the association between exposure to high levels of nitrate (NO-) and stomach cancer (5-8), and the potential for the endogenous formation of nitrosamines by reaction of nitrite derived from nitrate by bacterial reduction (9-11) with endogenous or exogenous amines.Tannenbaum and colleagues (12) Frederick, MD). All mice used were 9-12 weeks old except for the BALB/c and CBA mice, which were 7 and 5 weeks old, respectively.Housing and Urine Collection. Mice were housed three to a cage in Nalgene metabolic cages (Thomas) and were given a nutritionally complete low-nitrate diet (12) and distilled drinking water. The urine from three mice was automatically pooled and collected every 24 hr. The cages were cleaned daily with germicidal soap. In all cases, the amount of nitrate in the urine after a 24-hr collection period for three mice was divided by three and reported as the mean daily nitrate production per mouse. As an additional precaution against infection, nude mice were housed in an isolated cubicle, given sterile...

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Nitrite and Nitrate Are Formed by Endogenous Synthesis in the Human Intestine

Cited by 270 publications

References 19 publications

A nested case-control study of methemoglobinemia risk factors in children of Transylvania, Romania.

A nested case-control study of methemoglobinemia risk factors in children of Transylvania, Romania.

Biotransformation of Nitric Oxide

Mammalian nitrate biosynthesis: mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide.

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