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Wednesday, 4 March 2015

Nitrites and nitrates in the human diet: Carcinogens or beneficial hypotensive agents?

Journal of Ethnopharmacology
Available online 6 October 2014
In Press, Corrected Proof — Note to users
Research Paper

Nitrites and nitrates in the human diet: Carcinogens or beneficial hypotensive agents?


doi:10.1016/j.jep.2014.09.040
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  Open Access

Abstract

Ethnopharmacological relevance

The presence of nitrite in the human diet was thought to constitute a hazard as secondary nitrosamines are known to cause gastric cancers.

Materials and methods

Recent publications on the physiology of serum nitrite have been consulted. Problems: Nitrite is added to some foodstuffs as an antibotulinum agent.

Results and Discussion

The epidemiological evidence that nitrite causes gastric ulcers is weak. On the other hand, evidence that the presence of nitrite in serum lowers blood pressure is strong. This allows us to explain why a Tang dynasty treatment for angina, given in a Dunhuang medical manuscript, can be successful.

Conclusion

The presence of nitrite in food is free of danger and a diet high in nitrate is beneficial to the health.

Graphical abstract

Chemical compounds studied in this article

  • Nitrate (PubChem CID: 943);
  • Nitrite (PubChem CID: 946);
  • Nitrosamine (PubChem CID: 371830)

Keywords

  • Nitrate;
  • Nitrite;
  • Nitrosamines;
  • Gastric cancer;
  • Hypotensive agent;
  • Angina
Since the discovery, in animal studies (Swann and Magee, 1968), of the high carcinogenicity of secondary nitrosamines (RHN-NO), there has been concern that they might be formed in the human food chain. Nitrosamines are readily formed by the action of nitrite, in a mildly acidic environment, on a secondary amine (RH2N). There are several ways that this might occur in the human food chain.
(1)
Nitrite is added to processed meat to inhibit the growth of Clostridium botulinum, the cause of botulism, and there are secondary amines present in meat tissue ( Reddy et al., 1983).
(2)
A nitrosation reaction may occur when nitrite and secondary amine enter the stomach as the environment is then suitably acidic (Bartsch, 1991). Conditions are maximal for such a reaction at the gastric cardia (Suzuki et al., 2003).
(3)
Some leafy vegetables contain high concentrations of nitrate and there are bacteria in the mouth (nitrate reductases), particularly under the tongue (Duncan et al., 1995), that convert nitrate into nitrite (Lidder and Webb, 2013).
However, in spite of the situation being favourable for nitrosamine formation, there is no strong epidemiological evidence for a correlation between nitrosamine formation and incidence of gastric cancers. In 2006, when nitrite was still considered a hazard, a review of the epidemiological literature (Jakszyn and Gonzalez, 2006) found that the evidence was inconclusive. Other factors, such as smoking, are far more significant. An updated review in 2012 (Bryan et al., 2012) came to the firm conclusion that there is no association, in humans, between nitrosamine formation and gastric cancer. The Netherlands Cohort Study (Keszei et al., 2013), in which 120,000 men and women were tracked for 16.3 years, concluded that, although nitrosamines in the diet may cause oesophageal carcinomas, there was no clear association with other gastric subtypes. Although a diet of processed meat (including the wartime delicacy of Spam) may be unattractive to the discriminating palate, it does not constitute a cancer hazard. Equally a diet of nitrate-rich leafy vegetables, much promoted by dietary gurus, is not dangerous, in spite of the possibility of conversion of nitrate into nitrite in the mouth. A fair number of other studies come to the same conclusion. Would it be correct, then, to see both species, nitrate and nitrite, as benign without any positive biological activity? This is certainly the case for nitrate, which is used as the inactive anion for the excretion, in urine, of nitrogenous waste from the body. However, the biological role of nitrite has undergone something of a revolution over the last 20 years.
In 1987 it was discovered that the signalling agent for the relaxation of vascular smooth muscle was nitric oxide (NO) (Moncada et al., 1991). It is generated in the endothelial cells lining the inner surface of blood vessels. The reaction for its production is the enzyme-catalysed conversion of arginine and oxygen into citrulline and NO. The enzyme is a very large and complex one, named nitric oxide synthase (NOS). It is significant to note that production of nitric oxide requires oxygen as a reactant. Nitric oxide produced in the endothelial cells diffuses into the underlying muscles of the vascular wall, causing them to relax. This results in enlargement of the blood vessel with an increase of blood flow. As the vascular muscles of the major blood vessels to different organs relax and contract so blood flow to one organ is enhanced while that to another organ is diminished. In this way the needs of the body at different times can be met. However there is a problem here. One obvious demand for increased blood flow is when tissue becomes hypoxic (low in oxygen) but, under these circumstances, there is no oxygen with which to synthesise nitric oxide. This would suggest that NO is not the messenger molecule with which hypoxic tissue enhances blood flow. However all the other evidence is the NO is the messenger molecule effecting vascular muscle relaxation in the blood vessels of hypoxic tissue and so another route to NO production, one that did not need oxygen, was sought.
One possibility is the action of an enzyme, possibly xanthine oxidase, or other species on plasma nitrite (Li et al., 2001). Nitrite is normally present in blood plasma at a concentration of around 5 nM. Although other sources of NO have been suggested, nitrite is the most likely and its concentration decreases as it passes the arterial-venous transit, i.e. as it passes through hypoxic tissue. Also, people living at a high altitude, such as Tibetan highlanders, in atmosphere low in oxygen, have high concentrations of nitrite in their blood plasma (Ezurum et al., 2007). Thus, in recent years, nitrite has been transformed from a toxic agent, responsible for gastric cancers, into an important agent in the reoxygenation of hypoxic tissue (Lundberg and Weitzberg, 2005).
Nitrite has been known for many years as a weakly hypotensive agent but this was generally considered to be of no biological significance. Sodium nitrite administered via the stomach is largely destroyed because of the acid conditions there and causes nausea (Butler and Feelisch, 2008). However, if nitrite is administered by other routes the biological effect is very different. If a solution of potassium nitrate (not nitrite) is imbibed, around 25% of the consumed nitrate is absorbed through the stomach wall and enters the enterosalivary circulation where it is reduced to nitrite by nitrate reductases from bacteria, principally Veillonella atypica, Vitellariopsis dispar and Actinomyces odontolyticus ( Doel et al., 2005), on the dorsal surface of the tongue. From there it enters the blood stream and can cause a dramatic fall in systolic blood pressure after about one hour. A congenial way of imbibing nitrate is as beetroot juice; the subsequent changes in blood pressure have been monitored in detail ( Webb et al., 2008).
The health giving properties of nitrate were first recognised many years ago. The earliest references occur in the medical literature of Ancient China. Physician of that time were familiar with saltpetre (potassium nitrate) as it is a component of gunpowder, one of China׳s most significant inventions. It occurs in deposits in desert regions of the country and also forms as a result of the decay of nitrogenous material, giving rise to deposits on the surface of the ground, particularly in autumn. Presumably by a serendipitous process it was found to have a beneficial effect on human health, which was duly recorded. For example, in the alchemical text Sheng Xuan zi fugong tu (Master Sheng Xuan׳s Chart for Subduing Mercury) it says:
Take a decoction of saltpetre to prolong life.
Keeping blood pressure low, all other things being equal, would certainly have this effect. In the Shen Nong bencao jing (Shen Nong׳s Classic of Pharmaceutics), a text of the later Han period ( Unschuld, 1986), it says:
Long term taking of saltpetre lightens the body.
The phrase ‘lightens the body’ includes the notion of improving the health.
The most dramatic use of saltpetre in Chinese medical literature occurs in a rather obscure medical manuscript found in the vast collection of documents from Cave 17 of the Mogao Grottoes near Dunhuang in Gansu Province. The documents were discovered by a Daoist monk (Abbot Wang) who, at the end of the nineteenth century, set about restoring the Grottoes to their former glory when Dunhuang was an important city on the Silk Road, taking precious goods from China to the West. The Silk Road dwindled in importance when a faster and safer sea route was developed and the documents were stored and sealed in Cave 17 around 1000 CE. Many of the documents were sold to foreign visitors to pay for the restoration of the grottoes but this particular one was sold by Abbot Wang to a Chinese doctor living in Hebei Province and he left it to his grandson, also a doctor. Unfortunately the original was destroyed during the Cultural Revolution but several copies had been made for teaching purposes and one of these has been fully authenticated by scholars (Ma, 1998).
It has been translated by John Moffett (Butler and Moffett, 2005) and says, in essence, that the pain associated with the heart condition angina pectoris can be alleviated by placing a quantity of saltpetre under the tongue of the sufferer, leaving it there for as long as possible, and encouraging him to swallow the saliva. The conditions described are ideal for maximum conversion of nitrate to nitrite by bacterial enzymes and for entry of nitrite into the blood stream. The subsequent lowering of blood pressure should bring some relief from the pain of an angina attack. Today we use a similar approach to the problem with a puffer containing glyceryl trinitrate, although the details are different in that conversion of the drug to NO occurs in the walls of the arteries rather than under the tongue. That holding the saltpetre under the tongue for a time is necessary for the success of this Chinese treatment indicates the perceptiveness of at least one early Chinese physician.
In relation to the diet of people today, the evidence suggests that consumption of vegetables rich in nitrate is beneficial with regard to cardiovascular health but it is equally important not to kill bacteria in the mouth with an antibacterial mouthwash (Wink and Paolocci, 2008). The fact that some people rarely eat vegetables is a matter of grave concern for public health.

References

    • Butler and Moffett, 2005
    • A.R. Butler, J. Moffett
    • A treatment for cardiovascular dysfunction in a Dunhuang medical manuscript
    • V. Lo amd, C Cullen (Eds.), Medieval Chinese Medicine: The Dunhuang Medical Manuscripts, RoutledgeCurzon, Abingdon (2005)

    • Ezurum et al., 2007
    • S.C. Ezurum, S. Ghosh, A.J. Janocha, W. Xu, S. Bauer, N.S. Bryan, J. Tejero, C. Hemann, R. Hille, D.J. Stuehr, M. Feelisch, C.M. Beall
    • Higher bloodmflow and circulating NO products offset hugh-altitude hypoxia among Tibetans
    • Proceedings of the National Academy of Sciences United States of America, 104 (2007), pp. 17593–17598

    • Ma, 1998
    • Ma, J., 1998. Dunhuang Yiyao Wenxian Jijiao, Nanjing, Jiangsu Guji Chubanshe.

    • Webb et al., 2008
    • A.J. Webb, N. Patel, Loukogeorgakis, M. Okorie, Z. Aboud, S. Misra, R. Rashid, P. Miall, J. Deanfield, N. Benjamin, R. MacAllister, A. Hobbs, A. Ahluwalia
    • Acute blood pressure lowering, vasoprotective, and antiplatelet properties of dietary nitrate via bioconversion to nitrite
    • Hypertension, 51 (2008), pp. 784–790
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