Human photosynthesis – beyond vitamin D

Good_Day_Sunshine

Most people know that vitamin D is synthesised in the skin when exposed to sunshine – or more specifically to the ultraviolet (UV) radiation in sunshine.

But few people know that human skin can photosynthesise nitric oxide (NO) too. Nitric oxide is a potent vasodilator which lowers blood pressure. This may explain, in part, why we often feel positive and relaxed when outside on a sunny day. It may also account for the observation that the incidence of hypertension and cardiovascular disease (CVD) correlates with latitude and rises in winter. [1]

UVA_blood_pressureRecently, Dr Richard Weller, at the University of Edinburgh, demonstrated that the nitric oxide formed when the skin of volunteers was exposed to UVA light, led to blood pressure reduction that lasted for up to  an hour after exposure. (By using UVA the effect could not be attributed to vitamin-D production which only forms in the presence of UVB).

So profound was the effect that it led him to say:

“We suspect that the benefits to heart health of sunlight will outweigh the risk of skin cancer… Dietary vitamin D supplements alone will not be able to compensate for lack of sunlight” [2]

The standard sun-phobic advice to avoid midday sun and slap on sunscreens is based on the putative risks of UV induced skin cancers. Yet this advice has already been tentatively relaxed on the basis of vitamin D’s recognised benefits – and the acknowledgement that in the UK there is only enough UVB to make vitamin D effectively between April and September in a narrow window either side of mid-day. (See “Experts advise going out in the midday sun to keep up vitamin D levels” 2010). Adding his voice to the call for less fearful sun exposure advice Dr Weller points out that in the UK heart disease and stroke, which are linked to high blood pressure, lead to around 80 times more deaths than does skin cancer. So the blood-pressure reducing benefits of UV-induced nitric oxide could easily outweigh the skin cancer risks.

Sunlight may also improve metabolic health

Now, in collaboration with an Australian research team, Dr Weller has published a study suggesting that UV exposure from sunshine may reduce the weight gain and metabolic damage associated with an obesity- inducing diet, independent of vitamin D. [3]

The researchers overfed mice, exposing one group to UV but not the other. The UV significantly suppressed weight gain and glucose intolerance, insulin resistance and markers of non-alcoholic fatty liver disease. Serum levels of fasting insulin, glucose, and cholesterol were also improved compared to the mice without UV exposure.

Cleverly, they demonstrated that this effect was not due to vitamin D, as mice given vitamin-D supplements without UV did not gain the protection. Instead, they showed that UV-induced nitric oxide formation was responsible. Whilst this study cannot immediately be extrapolated to humans the possibility is compelling.

UVA-induced mobilization of dermal nitric oxide derivates. UVA-induced nitrite (NO2−) decomposition in the skin leads to the generation of nitric oxide (NO) and nitroso compounds (RSNO). NO can diffuse into blood vessels, where it is oxidized to nitrate by hemoglobin, or into deeper skin levels, where it is oxidized to nitrite. RSNO are vasoactive and can enter the blood system, evolving changes in blood flow and pressure.

UVA-induced mobilization of dermal nitric oxide derivates. UVA-induced nitrite (NO2−) decomposition in the skin leads to the generation of nitric oxide (NO) and nitroso compounds (RSNO). NO can diffuse into blood vessels, where it is oxidized to nitrate by hemoglobin, or into deeper skin levels, where it is oxidized to nitrite. RSNO are vasoactive and can enter the blood system, evolving changes in blood flow and pressure. – Opländer and Suschek, 2012, [5]

Man – the naked ape.

The formation of nitric oxide in human skin is particularly interesting. Unlike other primates, humans do not have fur. The evolutionary purpose of this adaptation is controversial – is it for increased vitamin D production, improved sweating, protection from fire, increased social bonding…? the list goes on. Whatever the reason, the result is that our bare skin has increased exposure to sun light compared to other primates.

A further, related adaptation is that humans store large quantities of nitrates and nitrites in the skin. [4]

The relevance of this is that when exposed to UV the stores of nitrites produce nitric oxide. Not only does nitric oxide cause dilation of blood vessels in the skin (lowering systemic blood pressure, and potentially improving skin conditions and Raynaud’s) but it also acts to protect skin cells from UV damage – a win-win adaptation!

“By reducing UVA-induced lipid peroxidation, and the coordinated effects of NO on gene expression and preservation of membrane integrity effectively protect against UVA- and reactive oxygen species (ROS)-induced apoptotic as well as necrotic cell death”

– Opländer and Suschek, 2012, [5]

The importance of nitrites

Another interesting aspect of skin nitric oxide photosynthesis is that whereas in other parts of the body, nitric oxide is created by an enzyme – nitric oxide synthase – in the skin the UV-nitrite mechanism is faster and more efficient, producing concentrations of nitric oxide that are many times higher than in any other part of the body [6]

Levels of nitrites in the skin are 25 times higher than circulating levels in the blood, and with the skin being the largest organ in the body this represents a huge store of nitrites. All of these factors indicate that sun-induced nitric oxide production gave a powerful evolutionary advantage to the naked ape, and implies that we may be wise to spend more time in the sun, and ensure we ingest nitrites to maintain our skin stores.

nitrite_foods

Dietary nitrates and nitrites in foods were once controversial, but recent research reveals an increasingly positive role in health. For example, nitrates from fertilisers getting into the water supply has lead to statutory limitations on nitrate levels in tap water, yet by far the largest exposure to nitrates (80%) comes from fruit and vegetables, especially green leafy vegetables. In the human body, nitrates are effectively inert [9]. Their role is to act as a source of nitrites, into which they can be converted. Nitrites it turns out, have a critical role in formation of nitric oxide and hence vasodilation and vascular health. In fact they are capable of bringing about vasodilation in their own right.

Apart from being formed from nitrates, nitrites naturally occur in a range of vegetables, including spinach, celery and beetroot. They are also present in cured meats like bacon, ham and salami, where saltpetre (potassium nitrite) is used as a preservative.

Whilst vegetable sources of nitrites come with a 5-a-day blessing, intake from cured meats is more controversial. This is primarily based on some epidemiological studies where an association between processed meats and bowel cancer sometimes shows up. The nitrites in the cured meats have, hitherto, been the prime suspects, but the case is far from clear.

One proposed mechanism is that nitrites in meat products break down when cooked on high heat to form nitrosamines – carcinogenic compounds implicated in bowel cancer. Supposedly, this does not happen to the nitrites in vegetables as they are protected by co-factors such as vitamin C. The problem with this argument is that some processed meats such as salami and ham, are not usually cooked at all.

A second proposed mechanism is that bacteria in the gut break down nitrites to create those pesky nitrosamines. However, that should also apply to nitrites from vegetable source yet these are considered healthy. One can almost hear the old paradigm creaking!

A study in 1999, for example, found no association between nitrate or nitrite intake and risk of cancers of the gastro-intestinal tract. However, nitosamine intake was associated with colorectal cancer, but not of other gastro-intestinal cancers. The most significant increased risk came from smoked and salted fish (!), whereas risk from cured meats was non-significant. [7]

Focusing in on colorectal cancers a more recent study summarises some of the uncertainties:

“Combined nitrate and nitrite intake has been positively associated with colorectal adenoma (two-fold increased risk) (Ward et al, 2007), as has nitrate with colorectal cancer (16% increased risk) (Cross et al, 2010). Yet, another study did not observe an association with nitrite and colorectal adenoma (OR=1.05, 95% CI=0.59–1.86) (Ferrucci et al, 2009), and both nitrite (RR=0.74, 95% CI=0.34–1.63) and nitrate (RR=1.04, 95% CI=0.54–2.02) were not related to colorectal cancer in another (Knekt et al, 1999).”   – L M Ferrucci et al, BJC Jan 2012 [8]

Fears about potassium nitrite (saltpetre) in cured meats are almost certainly overblown. In fact as long ago as 1880, saltpetre was used medicinally to lower blood pressure. [9]

One final piece of evidence that intakes of dietary nitrites are not harmful, but actually beneficial is that the largest source of nitrites entering the digestive tract comes not from food, but from the body itself. This initially startling idea indicates just how important nitrites are, and demonstrates why they cannot be harmful to the digestive tract: Nitrates, it turns out, are continually secreted into the mouth via the salivary ducts where oral bacteria turn them into nitrites which we then swallow. These nitrites enhance gastric mucin production and aid in gut nitric oxide production which is part of the anti-microbial system that keeps gut flora in balance. This mechanism for converting nitrates to nitrites evolved for a purpose and should leave us in no doubt how important nitrites are for the body.

“Normal functioning of human vasculature requires both the presence of nitrite and nitric oxide… As a result, the normal production of nitric oxide and nitrite and the ability of the endothelium to respond to these species may prevent various types of cardiovascular disease, including hypertension, atherosclerosis, and stroke.

 

Long-term consumption of diets containing high levels of nitrate and nitrite may have important implications for providing health benefits by ensuring high concentrations of nitrogen oxides as a “reserve” for tissue defense and homeostasis in stress and disease. ” – Norman G Hord et al, Am. J. Clin. Nutr. 2009 [9]

Choosing your veg

The table below can help you ensure you maximise your nitrate intake

Nitrate content (mg/100 g fresh weight) Vegetable varieties
Very low, <20 Artichoke, asparagus, broad bean, eggplant, garlic, onion, green bean, mushroom, pea, pepper, potato, summer squash, sweet potato, tomato, watermelon
Low, 20 to <50 Broccoli, carrot, cauliflower, cucumber, pumpkin, chicory
Middle, 50 to <100 Cabbage, dill, turnip, savoy cabbage
High, 100 to <250 Celeriac, Chinese cabbage, endive, fennel, kohlrabi, leek, parsley
Very high, >250 Celery, cress, chervil, lettuce, red beetroot, spinach, rocket (rucola)

Bringing it all together: nitrates, nitrites and human NO photosynthesis

Dietary nitrates and nitrites directly contribute to circulating levels and skin stores, and thus to the quantity of nitric oxide that can be synthesised when exposed to the sun. They thereby contribute to the beneficial effects on blood pressure and even protection from UV damage [6].

Green_manIt may even be that the beneficial cardiovascular effects associated with increased fruit and vegetable consumption – especially green leafy vegetables – can largely be attributed to increased nitrate and nitrite intake, rather than the vitamins, minerals fibre, polyphenols, antioxidants etc. [9]

Indeed much of the claimed cardiovascular benefits of vegetarianism may simply be due to increased nitrate and nitrite consumption – something a Palaeolithic diet can achieve without the detrimental exclusion of animal products.

How apt then that to maximise the benefits of human nitric oxide photosynthesis we need to ingest more green leaves – the photosynthetic organs of plants! Perhaps there is something in the Green Man myth after all.

Read part 2: Animal products that protect you from UV damage

References

  1. Liu D et al, UVA irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxide synthase. The journal of investigative dermatology, Jan 2014
  2. Sunshine could benefit health, The University of Edinburgh, news archive, 2013; website accessed on 27/10/14
  3. Geldenhuys S et al. Ultraviolet radiation suppresses obesity and symptoms of metabolic syndrome independently of vitamin d in mice fed a high-fat diet. Diabetes, Nov 2014
  4. Donald Liu et al, UVA Irradiation of Human Skin Vasodilates Arterial Vasculature and Lowers Blood Pressure Independently of Nitric Oxide Synthase. Journal of investigative dermatology, Jan 2014
  5. Christian Opländer and Christoph V. Suschek, The Role of Photolabile Dermal Nitric Oxide Derivates in Ultraviolet Radiation (UVR)-Induced Cell Death, International journal of molecular sciences, Dec 2012
  6. Christian Opländer and Christoph V Suschek, New Aspects of Nitrite Homeostasis in Human Skin. Journal of investigative dermatology, 2009
  7. Knekt, P et al, Risk of colorectal and other gastro-intestinal cancers after exposure to nitrate, nitrite and N-nitroso compounds: a follow-up study. International journal of cancer, Mar 1999
  8. L M Ferrucci et al, Meat consumption and the risk of incident distal colon and rectal adenoma, British journal of cancer, Jan 2012
  9. Norman G Hord et al, Food sources of nitrates and nitrites: the physiologic context for potential health benefits, American journal of nutrition, 2009

 

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