Nitrate

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, including fruit trees. The bioavailability of dietary nitrate is extremely high; almost 100%. van Velzen AG et al. Particularly vegetables may contain high levels of nitrate due to (besides nitrate fertilization) reduced sunlight exposure, undersupply of molybdenum and iron, and/or reduced assimilation of nitrate in the plant. Dietary nitrate inhibits iodide uptake, which may disrupt thyroid functioning De Groef B et al. A few studies found associations between dietary nitrate and hypothyroidism Ward MH et al Aschebrook-Kilfoy B et al Mukhopadhyay S et al or even thyroid cancer Kilfoy BA et al Ward MH et al

Nitrite (NO2−)

The salivary glands extract and concentrate plasma nitrate. Bacteria in the mouth convert nitrate to nitrite. It is claimed that nitrite increases vascular health because it enhances athletic performance in athletes. 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 also an important signalling molecule and the nitrate to NO pathway influences blood flow and cell metabolism. NO has various properties (in various tissues), including anti-hypertensive, anti-inflammatory and anti-artherosclerotic, and its a powerful vasodilator. Therefore, in specific conditions, additional NO may be beneficial (eg myointimal hyperplasia). NO levels need to be low to protect organs such as the liver from ischemic damage, to protect the gastric mucosa and to protect against hypoxia.

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. Vitamin C favors nitrosylation instead of nitrosation, thus inhibiting formation of nitroso compounds. High nitrite (from saliva or food), high protein (amines) and high heme (red meat) favor formation of nitroso compounds.

Studies have found positive correlations between dietary nitrate intake and digestive malignancy morbidity rates Assesorova IuIu et al risk of epithelial ovarian cancer Aschebrook-Kilfoy B et al breast cancer risk Yang YJ et al T-cell lymphoma Kilfoy BA et al gastric cancer risk Hernández-Ramírez RU et al, Sandor J et al, Palli D et al and non-Hodgkin lymphoma and colorectal cancer Gulis G et al.

Methemoglobinemia

Methemoglobinemia 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 Zeman C et al. Another study found a direct correlation between nitrate levels in water samples and serum metHb level Niţuc E et al.

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 Sadeq M et al. Young children may also get severe methemoglobinemia from consuming high-nitrate vegetables Savino F et al

Other causes/contributing factors of methemoglobinaemia include dehydration caused by diarrhea, sepsis, the use of antibiotics (trimethoprim, sulfonamides and dapsone Zosel A et al), local anesthetics (especially articaine and prilocaine Adams V et al), and others such as aniline dyes, metoclopramide, chlorates and bromates.

Athletic Performance

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). A lack of oxygen (also as in hypoxia) stimulates NO release.