Nitrate

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Nitrate discussed on WaiTalk

Nitrate compounds (eg sodium nitrate) are found naturally on earth as large deposits. Nitrate (NO3−) naturally results from the breakdown of animal (or human) waste, but nitrate in groundwater mainly comes from fertilizers (eg ammonium nitrate) used in agriculture. Nitrate is much less toxic than ammonia. Nitrate is naturally consumed by growing plants, which convert nitrate to amino acids, for constructional purposes. Particularly vegetables (the roots, stem and leaves of a plant) may contain high levels of nitrate, as the uptake of nitrate in plants may regularly exceed its assimilation, due to little sunlight exposure (cloudy days), and/or undersupply of molybdenum and iron.

The bioavailability of dietary nitrate is extremely high; almost 100%. [1]. In humans, dietary nitrate inhibits iodide uptake, which may disrupt thyroid functioning [2]. A few studies found associations between dietary nitrate and hypothyroidism [3] [4] [5] or even thyroid cancer [6] [7]

Nitrite (NO2−)

The salivary glands extract and concentrate plasma nitrate. Bacteria in the mouth convert nitrate to nitrite. The nitrite ion is known to bond to metal centers in various ways. Nitrites are also used in the food production industry for curing meat or fish, by the addition of a combination of salt, nitrates, nitrite or sugar. That nitrite will mainly be reduced to NO, which may bind to various compounds, such as amines (forming nitrosamines), Hb (forming metHb) or the heme in myoglobin (forming nitrosomyoglobin when raw, and nitrosyl-heme when cooked). Besides spontaneous degradation (in low oxygen conditions), nitrite is also converted to NO by enzymes such as xanthine oxidoreductase, NO synthase and nitrite reductase, and eventually to ammonium and ureum.

Nitric Oxide (NO)

Gastric juices convert nitrite to nitrous acid (HNO2, a powerful free radical), which produces NO. NO is also a by-product of combustion of substances in the air; exhaust fumes are loaded with free radicals such as NO. More NO means more oxidative damage. Antioxidants such as the glutathione system regulate NO and HNO2 levels. NO is essential as a signalling molecule, regulates Th17-cell development, and influences cell metabolism. NO has various properties in various tissues, including anti-inflammatory (because its a free radical), anti-artherosclerotic (because its a 'cleansing agent') and anti-hypertensive because its a powerful vasodilator (increasing blood flow by widening the blood vessels). NO is anti-bacterial (including both harmful and beneficial bacteria), though it protects some harmful bacteria (by inducing resistance of Gram-positive and -negative bacteria to aminoglycosides [8]). Elevated NO is associated with rheumatic diseases, including systemic lupus erythematosus and rheumatoid arthritis [9] and T-cell dysfunction [10][11]. UVB directly induces the production of reactive oxygen species (ROS), increasing nitric oxide synthase [12] and subsequent NO activity. [13] Vitamin D3 and a nitric oxide synthase inhibitor both reduce UV-induced ("nitrative") DNA damage, including by suppressing the accumulation of nitric oxide derivatives (incl. nitrite). [14]. NO levels also need to remain unelevated to protect organs such as the liver from ischemic damage, to protect the gastric mucosa and to protect against metHb induced hypoxia. In specific conditions, additional NO may be beneficial (eg myointimal hyperplasia). There are various pathways to create the required NO from protein (by nitric oxide synthases), as arginine (supplying the NO) may be converted from other amino acids (eg other amino acids > glutamate > ornithine > citrulline > arginine). Physical exercise (induced local hypoxia) naturally increases endogenous NO production, because more NO is required (increasing blood flow during exercise).

Nitrosamines

In the stomach (not in colon = neutral pH) nitrite forms HNO2, which produces NO. Adding NO to a compound is called nitrosation. Nitrosation of amines leads to the formation of nitrosamines. Most nitrosamines are carcinogenic. Additional nitrosation leads to the formation of N-nitroso compounds, which are even more carcinogenic. High nitrite (from nitrate or food directly), high protein (amines) and high heme (red meat) favor formation of nitroso compounds. Unsaturated fats (as scavengers of nitrosating agents[15]) inhibit formation of some nitrosamines [16]. Vitamin C (and other antioxidants) favors nitrosylation instead of nitrosation, thus also inhibiting formation of nitroso compounds. This property is however reversed in the presence of "fats" [17] (but not olive oil[18] nor coconut oil[19]), except for the antioxidants ferulic and caffeic acid. [20]. Soy sauce produced in Japan[21][22], Dried fish, bean paste and pickled vegetables are susceptible to nitrosation, but not soy sauce produced in the US.[23] The greatest increase in mutagenicity by nitrosation is caused in vegetables, pickles, seaweed and alcoholic beverages.[24] Various compounds may act as mutagenic precursors upon nitrosation (eg indoles in Chinese cabbage[25], tyramine (yielding mutagenic 4-(2-aminoethyl)-6-diazo-2,4-cyclohexadienone)[26] in processed meats, fermented foods (incl. soy sauce))

Nitrosation also increases mutagenicity of HCAs. Nitrite increases mutagenicity of MeIQ up to 3-fold, while that of nitrosated MeIQ was further enhanced up to 15-fold. [27] Nitrosated or N-hydroxylated TRP-P-2 directly induces DNA recombination. [28]

Studies have found positive correlations between dietary nitrate intake and digestive malignancy morbidity rates [29] risk of epithelial ovarian cancer [30] breast cancer risk [31] T-cell lymphoma [32] gastric cancer risk [33], [34], [35] and non-Hodgkin lymphoma and colorectal cancer [36][37].

Peroxynitrite (NO3-)

When NO reacts with superoxide (a free radical of the immune system), peroxynitrite is formed [38]. Peroxynitrite has the same formula as nitrate (NO3-), but a different structure. Its extremely reactive and may damage many molecules, including DNA and proteins. Most of the damage done by peroxynitrite is due to the free radicals it produces (carbonate radical and nitrogen dioxide). Peroxynitrite predominantly reacts with carbon dioxide to form nitrosoperoxycarbonate, which forms carbonate radical and nitrogen dioxide, as a pair of caged radicals. These two radicals either recombine to form carbon dioxide and nitrate, or become free radicals.

Methemoglobinemia

Methemoglobinemia (a type of anemia) is characterized by elevated levels of oxidized hemoglobin (= methemoglobin = metHb). Normally, metHb levels are below 1% (of total Hb). Only when oxidative stress cannot sufficiently be prevented, the normal Fe2+ in hemoglobin (Hb) is oxidized to Fe3+ (in metHb). This results in a decreased capacity to release oxygen to tissues. The higher the level of metHb, the less oxygen released, which may lead to hypoxia. Normally, spontaneously formed metHb is reduced to Hb by mainly NADH metHb reductase, but also the vitamin C and glutathione enzyme systems. Exposure to nitrates may accelerate the rate of formation of metHb up to one-thousandfold, overwhelming the protective enzyme systems and acutely increasing metHb levels. One study found a direct proportionate relationship between nitrate ingestion and serum metHb level [39]. Another study found a direct correlation between nitrate levels in water samples and serum metHb level [40].

Infants are particularly vulnerable to methemoglobinemia due to nitrate metabolizing triglycerides present at higher concentrations than at other stages of development. Children drinking high-nitrate water are more likely to have methemoglobinemia [41]. Young children may also get severe methemoglobinemia from consuming high-nitrate vegetables [42]

Other causes/contributing factors of methemoglobinaemia include dehydration caused by diarrhea, sepsis, the use of antibiotics (trimethoprim, sulfonamides and dapsone [43]), local anesthetics (especially articaine and prilocaine [44]), and others such as aniline dyes, metoclopramide, chlorates and bromates.

Nutrient

In humans, the nutrient that supplies nitrogen (N) is protein (which may yield NO, to the extend that it is required). All amino acids (protein) contain N. Excess protein is eliminated through the ammonium > ureum pathway (not via NO). Amino acids are required for endogenous protein production (constructional purposes) and mono-amines (eg serotonin, dopamin, adrenalin), and NO. A lack of dietary protein will primarily result in muscle degradation before resulting in a lack of signalling molecules (NO, serotonin, dopamin etc). A number of amino acids cannot be endogenously produced by humans. Plants can synthesize all amino acids from N obtained from the soil, hence nitrate being a nutrient for plants. In humans increased dietary nitrate (unlike dietary protein) results in elevated NO rather than amino acid synthesis, evoking drug-like effects rather than being a nutrient. Nitrate belongs to a group of drugs, the nitrates.

Drug

Nitrates are a large group of drugs, including nitroglycerin, isosorbide dinitrate (Isordil) and isosorbide mononitrate (Imdur, Ismo, Monoket). In our mitochondria, all these nitrates are converted to NO by aldehyde dehydrogenase. NO is a potent vasodilator. Another group of drugs are the alkyl nitrites, including amyl nitrites. Their nitrite-group is responsible for their biological properties, which includes vasolidation (and psychoactive as an inhalant), as its a source of NO. Many of these drugs are used as heart medication.

Physiologically, blood pressure is constantly monitored through pressure receptors and osmoreceptors, and regulated through prostaglandins, bradykinin, adrenergic stimulation and calcium concentrations in vascular smooth muscle cells. Vasolidation may be cGMP mediated (activated by NO), and it may be cAMP mediated (through adrenergic stimulation). UV exposure increases NO, but reduces cAMP. [45]

Athletic Performance

A local lack of oxygen (hypoxia) stimulates NO release locally. NO is a powerful vasodilator; it widens the blood vessels (decreasing blood pressure), resulting in increased blood flow, enabling the supply of more oxygen where needed (eg muscles), evoked by local hypoxia. Increased nitrate intake increases athletic performance in the last phase of a run [46], when hypoxia in muscles is at its peak. Baseline plasma nitrite level independently predicts exercise capacity in highly trained professionals [47]. Nitrate supplementation (eg beetroot juice) increases athletic performance [48], all due to increased supply of oxygen to hypoxic muscles.


Author

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Author of this article is Thijs Klompmaker, born in 1966