# Metabolomics/Nutrition/Vitamin C

Vitamin C is a water-soluble nutrient essential for life and is used by the human body for many purposes. To the best of scientific knowledge, all animals and plants synthesize their own vitamin C, except for a small number of animals, including humans.

### Introduction
## What can vitamin C do for your health?

By Kathleen Zelman, MPH, RD/LD WebMD Weight Loss Clinic - Feature
Reviewed by Louise Chang, MD
Vitamin C is one of the safest and most effective nutrients. The benefits of vitamin C may include protection against immune system deficiencies, cardiovascular disease, prenatal health problems, eye disease, and even skin wrinkling.
A recent study published in Seminars in Preventive and Alternative Medicine that looked at over 100 studies over 10 years revealed a growing list of benefits of vitamin C.
"Vitamin C has received a great deal of attention, and with good reason. Higher blood levels of vitamin C may be the ideal nutrition marker for overall health," says study researcher Mark Moyad, MD, MPH, of the University of Michigan. "The more we study vitamin C, the better our understanding of how diverse it is in protecting our health, from cardiovascular, cancer, stroke, eye health [and] immunity to living longer."
"But," Moyad notes, "the ideal dosage may be higher than the recommended dietary allowance."

## How Much Vitamin C Is Enough?

Most of the studies Moyad and his colleagues examined used 500 daily milligrams of vitamin C to achieve health results. That's much higher than the RDA of 75-90 milligrams a day for adults. So unless you can eat plenty of fruits and vegetables, you may need to take a dietary supplement of vitamin C to gain all the benefits, Moyad says. He suggests taking 500 milligrams a day, in addition to eating five servings of fruits and vegetables. He also notes that only 10% to 20% of adults get the recommended nine servings of fruits and vegetables daily.
Moyad says: "The safe upper limit for vitamin C is 2,000 milligrams a day, and there is a great track record with strong evidence that taking 500 milligrams daily is safe," he says.

## The foods and beverages you'd need to consume to reach 500 milligrams (mg):

•Cantaloupe, 1 cup: 59 mg Vitamin C •Orange juice, 1 cup: 97 mg •Broccoli, cooked, 1 cup: 74 mg •Red cabbage, 1/2 cup: 40 mg •Green pepper, 1/2 cup, 60 mg •Red pepper, 1/2 cup, 95 mg •Kiwi, 1 medium: 70 mg •Tomato juice, 1 cup: 45 mg

## The Health Benefits of Vitamin C

According to recent research, vitamin C may offer health benefits in these areas:
1. Stress. "A recent meta-analysis showed vitamin C was beneficial to individuals whose immune system was weakened due to stress -- a condition which is very common in our society," says Moyad. And, he adds, "because vitamin C is one of the nutrients sensitive to stress, and [is] the first nutrient to be depleted in alcoholics, smokers, and obese individuals, it makes it an ideal marker for overall health."
2. Colds. When it comes to the common cold, vitamin C may not be a cure. But studies show that it can help prevent more serious complications. "There is good evidence taking vitamin C for colds and flu can reduce the risk of developing further complications, such as pneumonia and lung infections," says Moyad.
3. Stroke. A recent study in the American Journal of Clinical Nutrition found that those with the highest concentrations of vitamin C in their blood were associated with 42% lower stroke risk than those with the lowest concentrations. The reasons for this are not completely clear. But what is clear is that people who eat plenty of fruits and vegetables have higher blood levels of vitamin C.
4. Skin Aging. Vitamin C affects cells on the inside and outside of the body. A study published in the American Journal of Clinical Nutrition examined links between nutrient intakes and skin aging in 4,025 women aged 40-74. It found that higher vitamin C intakes were associated with a lower likelihood of a wrinkled appearance, dryness of the skin, and a better skin-aging appearance.
Other studies have suggested that vitamin C may also:
•Improve macular degeneration. •Reduce inflammation. •Reduce the risk of cancer and cardiovascular disease.

## Vitamin C's Role in the Body

Vitamin C, also known as ascorbic acid, is necessary for the growth, development and repair of all body tissues. It's involved in many body functions, including formation of collagen, absorption of iron, the immune system, wound healing, and the maintenance of cartilage, bones, and teeth.
Vitamin C is one of many antioxidants that can protect against damage caused by harmful molecules called free radicals, as well as toxic chemicals and pollutants like cigarette smoke. Free radicals can build up and contribute to the development of health conditions such as cancer, heart disease, and arthritis.
Vitamin C is not stored in the body (excess amounts are excreted), so overdose is not a concern. But it's still important not to exceed the safe upper limit of 2,000 milligrams a day to avoid stomach upset and diarrhea.
Water-soluble vitamins must be continuously supplied in the diet to maintain healthy levels. Eat vitamin-C-rich fruits and vegetables raw, or cook them with minimal water so you don't lose some of the water-soluble vitamin in the cooking water.
Vitamin C is easily absorbed both in food and in pill form, and it can enhance the absorption of iron when the two are eaten together.
Deficiency of vitamin C is relatively rare, and primarily seen in malnourished adults. In extreme cases, it can lead to scurvy -- characterized by weakness, anemia, bruising, bleeding, and loose teeth.
Scurvy symptoms arise as a result of the deactivation of many ascorbic acid dependent enzymes, classified as 2-oxoglutarate dependent dioxygenases (2-ODD’s). This class of enzymes, which are widely present in all animal cells is involved in the incorporation of O2 into organic substrates. To be catalytically active, these enzymes require Fe2+ and ascorbic acid as co substrates. The reaction catalyzed by 2-ODD’s involves the splitting of the dioxygen molecule to generate an oxygen-iron complex which is then used to hydroxylate a proline residue that is then used in many biochemical pathways. Some of these reactions include ring closures and post-translational hydroxylations. Since the enzymatic activity in highly dependent on the presence of ascorbic acid, it is proposed that 2-ODD’s and ascorbic acid (ASC) evolved together to carry out these biological reactions.
In the absence of ASC, one of the 2-ODD’s, P4H self oxidizes and becomes inactive. This inactivation was the first determined causes of scurvy symptoms. P4H, which carries out the hydroxylation of peptidyl-proline, is required for collagen folding. Without the hydroxylation the trimers that are a key to mature collagen formation cannot form. This leads to decreased melting point and an increased flexibility under biological conditions.
This is just one of many biological pathways that, as a result of a decreased dietary intake of ASC can lead to the symptoms observed in scurvy.

## The foods richest in vitamin C are:

Citrus fruits, green peppers, strawberries, tomatoes, broccoli, white potatoes, and sweet potatoes. Other good sources include dark leafy greens, cantaloupe, papaya, mango, watermelon, brussels sprouts, cauliflower, cabbage, red peppers, raspberries, blueberries, winter squash, and pineapples.
Published April 04, 2008

## SOURCES:

Mark A. Moyad, MD, MPH, senior research associate and Phil F. Jenkins Director, Complementary and Alternative Medicine, University of Michigan Urology Center. Phyo K. Myint, MRCP, department of public health, University of Cambridge, England. Dee Sandquist, MS, RD, director, Center for Weight Management, Southwest Washington Medical Center; spokeswoman, American Dietetic Association. U.S. Department of Agriculture 2005 US Dietary Guidelines. Seminars in Preventive and Alternative Medicine (1) Sept, 24, 2007; 3-1; pp 25-35). Myint, P.K., American Journal of Clinical Nutrition, January 2008; vol 87: pp 64-69. American Journal of Public Health, May 2004; vol 94: pp 870-875. Jeffrey S Hampl, PhD, RD; Christopher A. Taylor, PhD, RD; and Carol S. Johnston, PhD, RD, Vitamin C Deficiency and Depletion in the United States: The Third National Health and Nutrition Examination Survey, 1988 to 1994. American Journal of Clinical Nutrition, October 2007; vol 86; pp 1125-31. WebMD Medical News: "Veggie Eaters Have Fewer Strokes."
©2008 WebMD, LLC. All rights reserved.

## Sources
### Plant sources

Citrus fruits (lime, lemon, orange, grapefruit), tomatoes, and potatoes are good common sources of vitamin C. Other foods that are good sources of vitamin C include papaya, broccoli, brussels sprouts, black currants, strawberries, cauliflower, spinach, cantaloupe, and kiwifruit. Also, cranberries and red peppers are good sources of the vitamin.
The amount of vitamin C in foods of plant origin depends on:
* the precise variety of the plant,
* the soil condition
* the climate in which it grew,
* the length of time since it was picked,
* the storage conditions,
* the method of preparation. Cooking in particular is often said to destroy vitamin C - but see the section on Food preparation.
The following table is approximate and shows the relative abundance in different raw plant sources. The amount is given in mg per 100 grams of fruit:
| Plant source | Amount |
| Camu Camu | 2800 |
| Tibetan Goji berry | 2500 |
| Rosehip | 2000 |
| Acerola | 1600 |
| Jujube | 500 |
| Baobab | 400 |
| Blackcurrant | 200 |
| Guava | 100 |
| Kiwifruit | 90 |
| Broccoli | 90 |
| Loganberry | 80 |
| Redcurrant | 80 |
| Brussels sprouts | 80 |
| Lychee | 70 |
| Persimmon | 60 |
| Papaya | 60 |
| Strawberry | 50 |
| Orange | 50 |
| Plant source | Amount |
| Lemon | 40 |
| Melon, cantaloupe | 40 |
| Cauliflower | 40 |
| Grapefruit | 30 |
| Raspberry | 30 |
| Tangerine | 30 |
| Mandarin orange | 30 |
| Passion fruit | 30 |
| Spinach | 30 |
| Cabbage raw green | 30 |
| Lime | 20 |
| Mango | 20 |
| Melon, honeydew | 20 |
| Raspberry | 20 |
| Tomato | 10 |
| Blueberry | 10 |
| Pineapple | 10 |
| Pawpaw | 10 |
| Plant source | Amount |
| Grape | 10 |
| Apricot | 10 |
| Plum | 10 |
| Watermelon | 10 |
| Banana | 9 |
| Carrot | 9 |
| Avocado | 8 |
| Crabapple | 8 |
| Peach | 7 |
| Apple | 6 |
| Blackberry | 6 |
| Beetroot | 5 |
| Pear | 4 |
| Lettuce | 4 |
| Cucumber | 3 |
| Eggplant | 2 |
| Fig | 2 |
| Bilberry | 1 |

### Animal sources

It was only realised in the 1920s that some cuts of meat and fish are also a source of vitamin C for humans. The muscle and fat which make up the modern western diet are however poor sources. As with fruit and vegetables cooking destroys the vitamin C content.
The following table shows the relative abundance of vitamin C in various foods of animal origin, given in mg of vitamin C per 100 grams of food:
| Food | Amount |
| Calf liver (raw) | 36 |
| Beef liver (raw) | 31 |
| Oysters (raw) | 30 |
| Cod roe (fried) | 26 |
| Pork liver (raw) | 23 |
| Lamb brain (boiled) | 17 |
| Chicken liver (fried) | 13 |
| Lamb liver (fried) | 12 |
| Lamb heart (roast) | 11 |
| Food | Amount |
| Lamb tongue (stewed) | 6 |
| Human milk (fresh) | 4 |
| Goat milk (fresh) | 2 |
| Cow milk (fresh) | 2 |
| Beef steak (fried) | 0 |
| Hen's egg (raw) | 0 |
| Pork bacon (fried) | 0 |
| Calf veal cutlet (fried) | 0 |
| Chicken leg (roast) | 0 |

## Functions in the body

* As a participant in hydroxylation, vitamin C is needed for the production of collagen in the connective tissue. These fibres are ubiquitous throughout the body; providing firm but flexible structure. Some tissues have a greater percentage of collagen, especially: skin, mucous membranes, teeth and bones.
* Vitamin C is required for synthesis of dopamine, noradrenaline and adrenaline in the nervous system or in the adrenal glands.
* Vitamin C is also needed to synthesise carnitine, important in the transfer of energy to the cell mitochondria.
* It is a strong antioxidant.
* The tissues with greatest percentage of vitamin C — over 100 times the level in blood plasma — are the adrenal glands, pituitary, thymus, corpus luteum, and retina.
* The brain, spleen, lung, testicle, lymph nodes, liver, thyroid, small intestinal mucous membrane|mucosa, leukocytes, pancreas, kidney and salivary glands usually have 10 to 50 times the concentration present in plasma.
No bodily organ stores ascorbate as a primary function, and so the body soon depletes itself of ascorbate if fresh supplies do not continue to arrive though the digestive system, eventually leading to death if unresolved.
Only a few animal species including humans (primates) and guinea pigs are unable to synthesize ascorbic acid (ASC). There are several theories as to why this has been eliminated from the genetic code including the fact that dietary intake of ASC is often enough. It has even been suggested that the loss of this gene might have conferred an advantage to primates since hydrogen peroxide is generated as a byproduct of the synthesis of ASC.

## Vitamin C deficiency

Lack of ascorbic acid in the daily diet leads to a disease called scurvy, a form of avitaminosis that is characterized by:
* loose teeth
* superficial bleeding
* fragility of blood vessels
* poor healing
* compromised immunity
* mild anaemia.

## Daily requirement

There is a continuing debate within the scientific community over the optimum amount of vitamin C for humans.
A healthy person on a balanced western diet should be able to get all the vitamin C needed to prevent the symptoms of scurvy from their daily diet. However, a person who is just freed from a scorbutic condition with only a small amount of ascorbate (i.e. RDA quantities) is arguably a very unhealthy individual, and certainly not one in optimum health. People who smoke, those under stress and women in pregnancy have a slightly higher requirement.
The amount of vitamin C needed to avoid deficiency symptoms of scurvy has been set by variously national agencies as follows:
    40 mg per day UK Food Standards Agency
    60–95 mg per day US Food and Nutrition Board 2001 revision.
Some researchers have calculated the amount needed for an adult human to achieve similar blood serum levels as Vitamin C synthesising mammals as follows:
    400 mg per day – Linus Pauling Institute & US National Institutes of Health (NIH) Recommendation.
    3000 mg per day – Vitamin C Foundation's recommendation.
    6000-12000 mg per day – Thomas Levy, Colorado Integrative Medical Centre recommendation.
    6000-18000 mg per day – Linus Pauling's daily recommendation
    from 3000 mg to 200,000 mg based on bowel tolerance levels (see Cathcart below)
High doses (thousands of mg) may result in diarrhoea, which is harmless if the dose is reduced immediately. Some researchers (Cathcart) claim the onset of diarrhoea to be an indication of where the body’s true vitamin C requirement lies. Both Cathcart and Cameron have demonstrated that very sick patients with cancer or influenza do not display any evidence of diarrhoea at all until ascorbate intake reaches levels as high as 200 grams (1/2 pound).
The small size of the ascorbic acid molecule means the kidneys cannot retain it in the body. Some other explanation is required to explain why very sick persons retain such huge quantities of vitamin C without any discharge. Quite a low level in the blood serum will cause traces to be present in the urine. All vitamin C synthesising mammals have traces in the urine at all times. The fact that animals like rats pass ascorbate into their urinary tract, after expending valuable energy manufacturing it, implies that there is a benefit to having vitamin C passing through, and this does not represent waste.
The RDA is based on blood plasma and white blood cell saturation data. In 2004, the validity of the pharmacokinetic research from the National Institutes of Health (NIH) that gave this data was challenged by Hickey and Roberts 4. According to these authors, the doses required to achieve blood, tissue and body "saturation" are much larger than previously believed. They allege that the Institute of Medicine (IoM) and the NIH have ignored an open letter from Drs Steve Hickey, Hilary Roberts, Ian Brighthope, Robert Cathcart, Abram Hoffer, Archie Kalokerinos, Tom Levy, Richard Passwater, Hugh Riordan, Andrew Saul and Patrick Holford, calling for revision of the RDA, and have refused to reconsider their low-dose recommendations. Hickey and Roberts have issued their open scientific challenge in the form of a book, which was submitted to the IoM and NIH prior to publication.

## Food preparation

It is important to choose a suitable method of food preparation. When cooking vegetables, one should seek to minimize or not discard the water used in their preparation, e.g. by frying the food – which unfortunately increases fat content, steam cooking or by making soup.
Recent observations suggest that the impact of temperature and cooking on vitamin C may have been overestimated:
* Since it is water-soluble, vitamin C will strongly leach into the cooking water while cooking most vegetables — but this doesn't necessarily mean the vitamin is destroyed — it's still there, but it's in the cooking water. (This may also suggest how the apparent misconception about the extent to which boiling temperatures destroy vitamin C might have been the result of flawed research: If the vitamin C content of vegetables (and not of the water) was measured subsequent to cooking them, then that content would have been much lower, though the vitamin has not actually been destroyed.)
* Not only the temperature, but also the exposure time is significant. Contrary to what was previously and is still commonly assumed, it can take much longer than two or three minutes to destroy vitamin C at boiling point.
It also appears that cooking does not necessarily leach vitamin C in all vegetables at the same rate; it has been suggested that the vitamin is not destroyed when boiling broccoli., this may however just be a result of vitamin C leaching into the cooking water at a slower rate from this vegetable. Copper pots will destroy the vitamin.
Vitamin C enriched teas and infusions have increasingly appeared on supermarket shelves. Such products would be nonsense if boiling temperatures did indeed destroy vitamin C at the rate it had previously been suggested. It should be noted however that as of 2004 most academics not directly involved in vitamin C research still teach that boiling temperatures will destroy vitamin C very rapidly.

## Reported potential harmful effects

Reports of harmful effects of vitamin C tend to receive great prominence in the world's media. Many such reports have never been published in peer reviewed journals, which casts some suspicion on their credibility.
* In April 1998 Nature reported alleged carcinogenic and teratogenic effects of excessive doses of vitamin C. The effects were noted in test tube experiments and on only two of the 20 markers of free radical damage to DNA. They have not been supported by further evidence from living organisms. Almost all mammals manufacture their own vitamin C in amounts equivalent to human doses of thousands of milligrams per day.
* University of Southern California researchers in April 2000, reported a thickening of the arteries of the neck in persons taking high vitamin C doses. It was pointed out by vitamin C advocates that vitamin C's collagen synthesising role would lead to thicker and stronger artery walls. This research did not measure the blood velocity, which after simple mathematics, gives a more precise estimate of cross sectional area of the blood vessel.
* In June 2004, Duke University researchers reported an increased susceptibility to osteo-arthritis in guinea pigs fed a diet high in vitamin C. However, a 2003 study at Umeå University in Sweden, found that "the plasma levels of vitamin C, retinol and uric acid were inversely correlated to variables related to rheumatoid arthritis disease activity."
* "Rebound scurvy" is an often quoted theoretical, and never observed, condition that occurs when the amount of daily intake of Vitamin C is rapidly reduced from a very large amount to a relatively lower amount. This is an exaggeration of the rebound effect that occurs because ascorbate-dependent enzyme reactions continue for 24-48 hours, and use up vitamin C in the blood that is not being replenished. The effect is to lower one's serum vitamin C blood concentration to less than normal for a short amount of time. During this period of time there is a slight risk of cold of flu infection through reduced resistance. Within a couple of days the enzyme reactions shut down and blood serum returns to the normal level of someone not taking high supplements. This is not scurvy, which takes weeks of zero vitamin c consumption to produce symptoms. It is something people who take large vitamin C supplements need to be aware of in order to manage phased rather than sudden changes to the amount taken.
* Kidney stones are a much cited harmful side effect of taking vitamin C in larger than normal amounts. However research has shown this not to be the case

## Therapeutic uses

Vitamin C is needed in the diet to prevent scurvy. It also has a reputation for being useful in the treatment of colds and flu. The evidence to support this idea, however, is ambiguous, unless the studies are divided by dose size and dosing regime. When that is done, it is remarkable that most of the studies showing little or no effect employ quite small doses of ascorbate such as 100mg to 500mg per day. ("small" according to the vitamin C advocates) The Vitamin C foundation (1) recommends 8 grams of vitamin C every half hour in order to show an effect on the symptoms of a cold infection that is in progress.

## References

* Pauling, Linus (1986), How to Live Longer and Feel Better, W. H. Freeman and Company, ISBN 0-380-70289-4
* Thomas Levy (September 2002), Vitamin C, Infectious Diseases, and Toxins, Xlibris Corporation (Paperback). ISBN 1401069630 (Note: Xlibris is a print on demand self-publishing house.)
* Hickey, Steve & Roberts, Hilary; (May, 2004), Ascorbate: The Science of Vitamin C, Lulu Press, Inc. ISBN 1411607244 (Note: Lulu is a print on demand self-publishing house.)

## External links

* United Kingdom Foods Standards Agency Official UK view on vitamin C.
* The Vitamin C Foundation Vitamin C high dosage advocacy organisation with links to much research supporting their view.
* Vitamin C in human health and disease is still a mystery? An overview among all time most-viewed articles published by BioMed Central (free access)
* AscorbateWeb "An historical review of the medical & scientific literature attesting to the efficacy of Ascorbate (Ascorbic Acid, Cevitamic Acid, Sodium Ascorbate etc. a.k.a. “Vitamin C”) in the treatment and prevention of human and animal ills, conditions and diseases."

## Footnotes

$^1$ Combs GF. The Vitamins, Fundamental Aspects in Nutrition and Health. 2nd ed. San Diego, CA: Academic Press, 2001:245-272. $^2$ British pharmacology professors debate with the US National Institutes of Health over the optimum vitamin c dose (from PR Newswire - 6th July 2004)
$^3$ The Linus Pauling Institute at Oregon State University, "What About Vitamin C and Kidney Stones? "
$^4$ Hickey, Steve & Roberts, Hilary; (March, 2005), Ridiculous Dietary Allowance, Lulu Press, Inc. ISBN 1411622219.(Note: Lulu is a print on demand publisher.)