Vitamin C

What is Vitamin C?

Ascorbic acid, or ascorbate, is another name for vitamin C, which is a water-soluble vitamin that is present in a wide variety of fruits and vegetables. It can also be purchased as a dietary supplement and used as an ingredient in topical “serum” treatments for wrinkles and dark spots on the face.

Scurvy is treated and prevented with it. Vitamin C is a vital nutrient that is involved in collagen creation, tissue healing, and the enzymatic synthesis of certain neurotransmitters.

It is essential for the proper operation of the immune system and is needed for the action of several enzymes. It has antioxidant properties as well. The majority of animals can produce vitamin C on their own.

But monkeys and humans (albeit not all primates), most bats, some rodents, and a few other creatures need to obtain it by eating certain foods.

Regular supplement use appears to not prevent infection, but it may shorten the duration of the common cold, according to some data.

The impact of supplements on the risk of dementia, heart disease, or cancer is unknown. It can be given intravenously or orally.

In general, vitamin C is well tolerated. Excessive dosages may result in headaches, flushing of the skin, gastric distress, and difficulty sleeping. It is safe to take normal amounts when pregnant. It is advised against taking high amounts by the US Institute of Medicine.

The first vitamin to be chemically manufactured, vitamin C was discovered in 1912, isolated in 1928, and synthesized in 1933. It is included in the List of Essential Medicines by the World Health Organization.

There are low-cost generic and over-the-counter forms of vitamin C available. In part due to its discovery, The 1937 Nobel Prizes in Physiology and Medicine went to Albert Szent-Györgyi and Walter Norman Haworth, respectively.

Citrus fruits, kiwifruit, guava, broccoli, Brussels sprouts, bell peppers, potatoes, and strawberries are among the foods high in vitamin C. Foods that have been cooked or stored for a long time may have less vitamin C.

Definition

Certain species, including humans, require vitamin C as a necessary nutrient. Several vitamins that have vitamin C activity in animals are included in the phrase “vitamin C.” Certain nutritional supplements contain ascorbate salts, like calcium and sodium ascorbate.

When they are digested, ascorbate is released. The body naturally contains both ascorbate and ascorbic acid because the two forms interconvert based on pH.

Reducing agents transform the molecule’s oxidized forms, such as dehydroascorbic acid, back into ascorbic acid.

In animals (including humans), vitamin C serves as a cofactor in numerous enzymatic activities that mediate a range of crucial biological processes, such as collagen formation and wound healing.

A vitamin C deficit in humans results in decreased collagen synthesis, which exacerbates the more severe scurvy symptoms. Vitamin C also functions as a reducing agent and antioxidant in biology by providing electrons to a variety of enzymatic and non-enzymatic processes.

By doing this, vitamin C is changed into an oxidized form, which can be either dehydroascorbic acid or semi-dehydroascorbic acid.

Enzymatic processes that rely on glutathione and NADPH can return these substances to their reduced form.

Deficiency

Saturated blood serum levels of vitamin C are defined as > 65 µmol/L (1.1 mg/dL), which can be attained by consuming amounts that are at or over the Recommended Dietary Allowance; sufficient levels, on the other hand, are defined as = 50 µmol/L.

Vitamin C deficiency occurs at =11.4 µmol/L and hypovitaminosis is defined as = 23 µmol/L. The National Health and Nutrition Examination Survey conducted in the United States between 2003 and 2004 revealed mean and median serum values for individuals aged 20 years and above to be 49.0 and 54.4 µmol/L, respectively. 7.1% of respondents said they were insufficient.

Scurvy is a condition brought on by a vitamin C shortage. Without this vitamin, the body’s production of collagen is too unstable to carry out its intended job, and various other enzymes malfunction.

Corkscrew hair growth, spongy gums, patches on the skin, bleeding beneath the skin, and slow wound healing are all signs of scurvy. The disease manifests as pale, depressed, and partially immobile skin lesions, with the thighs and legs having the highest concentration of lesions.

Advanced scurvy causes open, purulent wounds, tooth loss, irregularities in the bone structure, and, in the end, death.

Prominent investigations on the effects of artificially generated scurvy on human diet were carried out on conscientious objectors in Britain during World War II and on Iowa state prisoners from the late 1960s to the 1980s.

The men in the British study took six to eight months to show symptoms of scurvy, possibly because they were given a 70 mg/day supplement six weeks prior to starting the scorbutic diet.

In contrast, the men in the prison study showed symptoms of scurvy four weeks after beginning the vitamin C-free diet. By the time the men in both studies showed symptoms of scurvy, their blood levels of ascorbic acid were too low to assess with accuracy.

Both of these investigations found that supplementation could totally eliminate all noticeable scurvy symptoms with only 10 mg daily.

Individuals experiencing sepsis or septic shock may be deficient in some micronutrients, such as vitamin C.

Medical Uses

Scurvy is a deficiency-related disease that can only be effectively treated with vitamin C. Beyond that, there is debate regarding vitamin C’s potential to prevent or treat a variety of ailments, with contradicting reviews presenting differing findings.

Supplementing with vitamin C had no effect on overall mortality, according to a 2012 Cochrane analysis. It is included in the List of Essential Medicines by the World Health Organization.

Scurvy

Vitamin C-rich foods and dietary supplements can help prevent and treat scurvy, a disease that is caused by a shortage of this vitamin. Before symptoms appear, there must be minimal to no vitamin C for at least a month.

Malaise and sluggishness are the initial symptoms, which then develop into breathing difficulties, bone pain, bleeding gums, bruising susceptibility, delayed wound healing, fever, convulsions, and finally death.

The damage is reversible up until a very late stage of the illness because vitamin C replacement from healthy collagen replaces the damaged collagen.

Treatment options include intramuscular or intravenous injections, as well as oral vitamin supplements.

Hippocrates was aware of scurvy during the classical period. In 1747, James Lind, a surgeon in the Royal Navy, conducted a controlled trial on board HMS Salisbury and found that citrus fruits could prevent the sickness. Lemon juice was distributed to all Royal Navy crewmen starting in 1796.

Common Cold

Effects on prevention, duration, and severity of the common cold have been the focus of separate studies on vitamin C.

According to Cochrane research, taking vitamin C on a daily basis did not prevent the common cold when taking at least 200 mg/day. There was no benefit to prevention observed when analysis was limited to trials using at least 1000 mg/day.

On the other hand, taking vitamin C regularly did shorten colds by 14% in kids and 8% in adults on average. It also made them less severe. According to a subset of adult trials, supplementation cut the frequency of colds in half for marathon runners, skiers, and soldiers serving in subarctic environments.

Another group of studies examined therapeutic use, which meant that vitamin C was not started until patients showed symptoms of a cold. Vitamin C had no effect on the severity or duration of these.

According to a previous review, vitamin C did not shorten the duration of colds or lessen their intensity. According to the Cochrane review’s authors,

Regular vitamin C supplementation is not warranted, as evidenced by the fact that it has not been able to lower the prevalence of colds in the general population.

Vitamin C has been found in regular supplementation trials to shorten cold duration; however, this finding has not been confirmed in the limited therapeutic trials that have been conducted.

However, considering the low cost and safety of vitamin C, together with its constant effect on cold duration and intensity in regular supplementation studies, it would be worth testing if therapeutic vitamin C is helpful for individuals with common colds.

High amounts of vitamin C are quickly absorbed during infections, distribute easily into immune cells, and have antibacterial and natural killer cell properties. These results point to a significant function of vitamin C in immune system regulation.

The European Food Safety Authority discovered a causal association between vitamin C intake from food and the ability of people and children under three years old to have a healthy immune system.

According to a number of studies, vitamin C has particular antiviral properties that cause viruses’ RNA, DNA, or assembly to become inactive.

COVID-19

As of early 2021, there were 50 completed or continuing COVID-19 clinical trials using vitamin C as a therapy, according to ClinicalTrials.gov. In October 2021, a meta-analysis comprising six published trials was released.

Intravenous or oral treatments were administered. The dosage was between 50 mg/kg and 24 g per day. Mortality, length of stay in hospital, length of stay in intensive care, and requirement for ventilation were the reported outcomes.

The Conclusion: “The current meta-analysis demonstrated that when compared to either placebo or standard therapy, vitamin C delivery had no influence on significant health outcomes in patients infected with COVID-19.

Sub-group analysis also showed that it had no appreciable benefit in these individuals, regardless of dosage, mode of administration, or severity of the condition.

Therefore, more extensive prospective randomized studies are required to Analyze the impact of administering vitamin C separately to people who are depleted and those who are replete in the nutrient.

More US FDA warning letters about vitamin C than any other substance for COVID-19 prevention and/or treatment were sent out between March and July 2020.

The National Institutes of Health (NIH) COVID-19 Treatment Guidelines as of April 2021 said that “there is not enough information to advocate the use of vitamin C for COVID-19 preventive or treatment, either in favor of or against it.

Cancer

There is no proof that taking a vitamin C supplement lowers the risk of lung cancer in healthy individuals or those who are more vulnerable because they smoke or have been exposed to asbestos.

Prostate cancer risk was not affected, according to a second meta-analysis. The impact of vitamin C supplementation on colorectal cancer risk was assessed by two meta-analyses. One discovered a tenuous correlation between vitamin C intake and lowered risk, while the other discovered no impact from supplementation.

Supplementing with vitamin C may prevent breast cancer, however, a 2011 meta-analysis found little evidence to support this theory.

However, a subsequent study found that vitamin C may improve the chances of survival for people who have already been diagnosed with breast cancer.

A 2015 meta-analysis revealed that high-dose vitamin C had no anticancer impact or improvement in quality-of-life metrics C. Trials using intravenous and oral vitamin C were included in this study.

Cardiovascular Disease

An independent study conducted in 2017 on 15,445 people did not find any indication that vitamin C lowers the risk of cardiovascular disease.

These findings corroborated a 2013 study (which did not give a subset analysis for studies that employed vitamin C alone) that concluded there was no evidence that antioxidant vitamin supplementation lowers the risk of myocardial infarction, stroke, cardiovascular mortality, or all-cause mortality.

However, a different 2013 review discovered a link between a decreased risk of stroke and elevated circulating or dietary vitamin C levels.

When consumed at dosages larger than 500 mg per day, vitamin C has been shown in a 2014 review to have a favorable effect on endothelial dysfunction.

The inner surface of blood arteries is lined with a layer of cells called the endothelium.

Brain Function

In comparison to those with normal cognition, those suffering from cognitive impairment, such as dementia and Alzheimer’s disease, have reduced vitamin C concentrations, according to a 2017 comprehensive review.

However, the mini-mental state examination, which is merely a broad measure of cognition, was used in the cognitive testing, showing a generally low-quality study evaluating the possible impact of vitamin C on cognition in both normal and impaired individuals.

An assessment of the nutritional status of individuals with Alzheimer’s disease found that in addition to low blood levels of vitamin B12, vitamin E, and folate, there was also low plasma vitamin C.

Iron Deficiency

Lower iron absorption is one of the reasons for iron deficiency anemia. Iron-containing foods or supplements can be better absorbed if vitamin C is also consumed.

The variety of foods that are suited for this is limited by the instability of vitamin C during heating and/or storage. The decreased ferrous form of iron, which is more soluble and readily absorbed, is maintained with the aid of vitamin C.

Topical Application to Prevent Signs of Skin Aging

Vitamin C is found in human skin and helps prevent UV-induced photoaging, including photocarcinogenesis, by promoting collagen synthesis and reducing its breakdown.

This information is frequently used to support the marketing of vitamin C as a topical “serum” ingredient for the treatment or prevention of wrinkles, melasma (dark pigmented areas), and aging of the facial skin.

Its antioxidant properties are thought to be responsible for scavenging free radicals produced by exposure to sunshine, air pollution, or regular metabolic activities. It is unclear if topical therapy is more effective than oral ingestion.

The clinical trial literature is characterized as inadequate to substantiate health claims in two reviews published in 2023; one explanation offered was that “all the studies employed vitamin C in conjunction with other substances or therapeutic pathways, making it more difficult to draw precise findings about the effectiveness of vitamin C.

A thorough review found that few clinical trials fulfilled the requirements for design. It revealed noticeably lighter skin and smoother, less wrinkled skin, but it also said that more research is necessary.

Other Diseases

Contradictory findings have been found in studies looking at how vitamin C intake affects the risk of Alzheimer’s disease. For any potential advantage, maintaining a healthy dietary intake is likely more crucial than taking supplements.

Research conducted in 2010 concluded that vitamin C supplementation had no place in the management of rheumatoid arthritis. Age-related cataracts cannot be prevented or have their course slowed down by vitamin C supplements.

Low consumption and low serum levels were linked to a higher rate of periodontal disease progression, according to a comprehensive study..

Side Effects

As a water-soluble vitamin, excesses in food are not absorbed and blood excesses are quickly eliminated in the urine, making vitamin C notably less harmful in the short term. If consumed more than two or three grams at a time, especially when empty, indigestion may result.

Taking calcium and sodium ascorbate, which are forms of vitamin C, may lessen this effect. Large doses have also been linked to other symptoms like diarrhea, cramping in the abdomen, and nausea.

The osmotic impact of unabsorbed vitamin C traveling through the colon is responsible for these effects. Theoretically, a high vitamin C diet could result in increased iron absorption.

An overview of studies on supplements in healthy participants did not mention this issue, but it did leave open the potential that people with inherited Hemochromatosis may suffer as a result.

The conventional medical establishment has long held the view that vitamin C raises the risk of kidney stones. “Reports of kidney stone formation associated with excess ascorbic acid intake are limited to individuals with renal disease”.

One large, multi-year trial did report a nearly two-fold increase in kidney stones in men who regularly consumed a vitamin C supplement.

However, reviews state that “data from epidemiological studies do not support an association between excess ascorbic acid intake and kidney stone formation in apparently healthy individuals”.

Diet

Recommended Levels

Several national organizations have established guidelines for adults’ recommended vitamin C intake.

• 40 milligrams daily: India Hyderabad’s National Institute of Nutrition
• 300 mg per week or 45 mg per day: World Health Organization
• The European Commission’s Council on Nutrition Labeling recommends 80 mg per day.
• 75 mg per day for women and 90 mg per day for men: Health Canada 2007
• National Academy of Sciences of the United States: 90 mg/day for men and 75 mg/day for women.
• Japan National Institute of Health and Nutrition: 100 mg/day
• The European Food Safety Authority recommends 110 mg for men and 95 mg for women each day.

The North American Dietary Reference Intake’s chapter on vitamin C was revised in 2000. The new information established a tolerable upper intake level (UL) of 2,000 mg/day for adults and provided the Recommended Dietary Allowance (RDA) of 90 mg/day for adult men and 75 mg/day for adult women.

US vitamin C recommendations (mg per day)
RDA (children ages 1–3 years)	15
RDA (children ages 4–8 years)	25
RDA (children ages 9-13 years)	45
RDA (girls ages 14–18 years)	65
RDA (boys ages 14–18 years)	75
RDA (adult female)	75
RDA (adult male)	90
RDA (pregnancy)	85
RDA (lactation)	120
UL (adult female)	2000
UL (adult male)	2000

The table (right) displays the ULs for adults as well as the RDAs for children in the US and Canada, as well as for women who are pregnant or nursing.

Higher guidelines were issued by the EFSA for the European Union for both adults and children: 20 mg for younger children, 30 mg for older children, 45 mg for older adults, 70 mg for older adults, 100 mg for older males, 15–17 mg for older females, and 70 mg for younger children. 100 mg daily during pregnancy; and 155 mg daily during nursing.

In contrast, India’s recommendations are substantially lower: 40 mg per day for adults and children up to age 1, 60 mg per day during pregnancy, and 80 mg per day during lactation. Clearly, nations cannot agree on anything.

Serum vitamin C levels are lower in cigarette smokers and secondhand smoke exposure victims than in non-smokers. It is believed that smoking damages the lungs and depletes this vitamin, which is an antioxidant.

Although it did not formally set a higher RDA for smokers, the U.S. Institute of Medicine assessed that smokers require 35 mg more vitamin C per day than nonsmokers.

A meta-analysis revealed a negative correlation between vitamin C intake and lung cancer, but it also said that additional study was necessary to support this finding.

The biannual National Health and Nutrition Examination Survey (NHANES) is a program run by the U.S. National Center for Health Statistics that evaluates the health and nutritional status of adults and children in the country.

What We Eat in America reports on a few of the findings. According to the 2013–2014 survey, women ingested 75.1 mg/d on average and males consumed 83.3 mg/d on average for people 20 years of age and older.

This indicates that over half of men and half of women do not get the recommended daily allowance of vitamin C.

According to the same poll, over 30% of adults said they took dietary supplements containing vitamin C or multivitamin/mineral supplements including vitamin C, with these individuals consuming between 300 and 400 mg/d overall.

Tolerable Upper Intake Level

The Tolerable Upper Intake Level (UL) for adults was established by the Institute of Medicine of the U.S. National Academy of Sciences in 2000 at 2,000 mg/day.

The dosage was selected because over 3,000 mg/day of the supplement had been associated with gastrointestinal problems, including diarrhea, in human trials.

Since this was the Lowest-seen-deleterious-Effect Level (LOAEL), larger intakes were seen to cause additional deleterious effects. The lower the ULs get for younger and younger kids.

The Japan National Institute of Health and Nutrition in 2010 and the European Food Safety Authority (EFSA) in 2006 both noted the disruptions at that dose level, but both agencies concluded that there was insufficient data to establish a vitamin C upper limit of concern.

Food Labelin

To comply with U.S. regulations for food and dietary supplement labeling, the quantity in a serving is stated as a percentage of Daily Value (%DV). As of May 27, 2016, 100% of the Daily Value for vitamin C was amended to 90 mg to align with the RDA.

Previously, the value was 60 mg. Reference Daily Intake provides a table with the current and old adult daily values.

Labels must list energy, protein, fat, saturated fat, carbs, sugars, and salt in accordance with EU rules.

If nutrients are present in substantial quantities, they may be shown voluntarily. Amounts are expressed as a percentage of Reference Intakes (RIs) rather than Daily Values. In 2011, a 100% RI of 80 mg was established for vitamin C.

Sources

Fruits and vegetables are the best natural sources of vitamin C, while it can also be found in other meals. The most popular dietary supplement is a vitamin.

Plant source

See Staple Food § Nutrition for the vitamin C content of eleven typical staple foods, including corn, rice, and wheat.

Plant foods are generally a rich source of vitamin C, but how much is in a food depends on a number of factors, including the type of plant, soil type, climate, time since harvest, storage conditions, and preparation technique.

Citrus grown organically might have more vitamin C than citrus grown traditionally. The relative abundance in several raw plant sources is displayed in the approximate table that follows. Cooking typically results in a decrease in vitamin C content.

Since some plants were examined while they were still fresh, and others were dried, which resulted in artificially elevated concentrations of specific components like vitamin C, the results could differ and make comparisons challenging.

The amount per 100 grams of the edible part is stated in milligrams of the vegetable or fruit.

Raw plant source	Amount (mg / 100g)
Kakadu plum	1000–5300
Camu Camu	2800
Acerola	1677
Indian gooseberry	445
Rosehip	426
Common sea-buckthorn	400
Guava	228
Blackcurrant	200
Yellow bell pepper/capsicum	183
Red bell pepper/capsicum	128
Kale	120
Broccoli	90
Kiwifruit	90

Raw plant source	Amount (mg / 100g)
Green bell pepper/capsicum	80
Brussels sprouts	80
Loganberry, redcurrant	80
Cloudberry, elderberry	60
Strawberry	60
Papaya	60
Orange, lemon	53
Cauliflower	48
Pineapple	48
Cantaloupe	40
Passion fruit, raspberry	30
Grapefruit, lime	30
Cabbage, spinach	30

Raw plant source	Amount (mg / 100g)
Mango	28
Blackberry, cassava	21
Potato	20
Honeydew melon	20
Tomato	14
Cranberry	13
Blueberry, grape	10
Apricot, plum, watermelon	10
Avocado	8.8
Onion	7.4
Cherry, peach	7
Apple	6
Carrot, asparagus	6

Animal Sources

Foods derived from animals don’t contain as much vitamin C as those derived from plants, and what little they do have is mostly destroyed by cooking. For instance, the concentration of chicken liver is 17.9 mg/100 g when it is raw, but just 2.7 mg/100 g when it is fried.

But smoked foods like beef sticks still contain some vitamin C. Human breast milk contains 5.0 mg of vitamin C per 100 g. A single infant formula sample that was examined had 6.1 mg/100 g. Even though cow’s milk only has 1.0 mg per 100 g, pasteurization eliminates it with heat. If goat’s milk isn’t pasteurized, it has 1.3 mg/100 g.

Irrespective of their cooking state, chicken eggs lack vitamin C.

Food Preparation

Under some circumstances, vitamin C undergoes a chemical breakdown, which frequently happens while food is being cooked. The amount of vitamin C in different food items decreases with time in direct proportion to the storage temperature.

Cooking can cause vegetables to lose about 60% of their vitamin C content, probably as a result of enhanced enzymatic degradation. Extended cooking periods could intensify this result.

Leaching, which moves vitamin C to the cooking water that is decanted but not consumed, is another way that vitamin C is lost from food. When heating or storing, broccoli may keep more vitamin C than other vegetables.

Supplements

Dietary supplements containing vitamin C can be found as a crystalline powder, pills, capsules, drink mix packets, multi-vitamin/mineral formulations, and antioxidant formulations. Certain fruit juices and juice drinks also include vitamin C.

The amount of each tablet and capsule varies from 25 mg to 1500 mg. The three supplement ingredients that are most frequently utilized are calcium, salt, and ascorbic acid.

Additionally, vitamin C molecules can be integrated into liposomes or bind to the fatty acid palmitate to form ascorbyl palmitate.

Food Fortification

In 2014, the Meals to Which Vitamins, Mineral Nutrients, and Amino Acids May or Must be Added advice paper was created by the Canadian Food Inspection Agency to assess the impact of fortifying meals with ascorbate.

There were descriptions of both required and optional fortification for different food groups. Fruit-flavored drinks, mixes, and concentrates; meals for a low-energy diet; meal replacement products; and evaporated milk were among the items categorized for mandated vitamin C fortification.

Food Additive

Commonly added to a variety of foods, including canned fruits, ascorbic acid, and several of its salts and esters are used primarily to inhibit oxidation and enzymatic browning.

It could be applied as a flour treatment agent for baking bread. They are designated E numbers since they are food additives, and the European Food Safety Authority is in charge of approving and assessing their safety. The following E numbers are pertinent:

1 E 300 ascorbic acid (licensed for use in the United States, Canada, Australia, and New Zealand as a food additive)
2 E 301 Sodium Ascorbate (accepted in the United Kingdom, the United States, Canada, Australia, and New Zealand) as a food additive
3 As a permitted food additive in the United Kingdom, the United States, Canada, Australia, and New Zealand is E 302 calcium ascorbate.
4 E 303 potassium ascorbate is not permitted in the UK, US, or Canada but is permitted in Australia and New Zealand.
5Ascorbyl palmitate, one of the E 304 fatty acid esters of ascorbic acid that are permitted for use as food additives in the United Kingdom, the United States, Canada, Australia, and New Zealand

Despite being ineffective in humans, the stereoisomers of vitamin C have a comparable impact when consumed in food. Erythorbic acid and its sodium counterpart are among them.

Pharmacology

Ascorbate, or vitamin C, is a nutrient that the body uses for many physiological processes. It is an electron donor and an enzyme substrate or cofactor.

These include tyrosine synthesis and catabolism, collagen, carnitine, and neurotransmitter production, as well as microsome metabolism.

Ascorbate functions as a reducing agent during biosynthesis, helping to maintain the reduced states of iron and copper atoms by giving electrons and preventing oxidation.

Enzymes For Which Vitamin C is A Cofactor Include:

Prolyl-3-hydroxylases, prolyl-4-hydroxylases, and lysyl hydroxylases are the three groups of enzymes needed for the hydroxylation of proline and lysine during the collagen manufacturing process.

Prolyl hydroxylase and lysyl hydroxylase, which both require vitamin C as a cofactor, are responsible for these processes, which add hydroxyl groups to the amino acids proline or lysine in the collagen molecule. Prolyl hydroxylase and lysyl hydroxylase oxidize from Fe2+ to Fe3+ and reduce from Fe3+ to Fe2+, respectively, while vitamin C plays this job as a cofactor.

Because hydroxylation enables the collagen molecule to take on its triple helix form, vitamin C is necessary for the growth and upkeep of cartilage, blood vessels, and scar tissue.

Carnitine production requires two enzymes: a-butyrobetaine hydroxylase and e-N-trimethyl-L-lysine hydroxylase. Transporting fatty acids into mitochondria for ATP synthesis requires carnitine.

Proline dioxygenase enzymes that are induced by hypoxia (isoforms: EGLN1, EGLN2, and EGLN3)

Dopamine beta-hydroxylase is involved in the process by which dopamine is converted to norepinephrine.

By eliminating the glyoxylate residue from peptide hormones’ c-terminal glycine residues, peptididylglycine alpha-amidating monooxygenase amidated peptide hormones. Peptide hormone activity and stability are increased as a result.

Absorption, metabolism, and excretion

The National Institutes of Health in the United States [In humans] “At moderate doses of 30–180 mg/day, approximately 70–90% of vitamin C is absorbed. However, absorption drops to less than 50% at doses greater than 1,000 mg/day.”

Large amounts of sugar in the colon can impede absorption because it is carried through the intestine by both glucose-sensitive and glucose-insensitive processes.

The body absorbs ascorbic acid by both simple diffusion and active transport. The two transporter proteins needed for active absorption are known as sodium-dependent active transporters (SVCTs) and hexose transporters (GLUTs).

Ascorbate in its reduced form is imported across plasma membranes by SVCT1 and SVCT2. The glucose transporters GLUT1 and GLUT3 exclusively move the vitamin C form known as dehydroascorbic acid (DHA).

Under normal circumstances, cells quickly convert dehydroascorbic acid to ascorbate, resulting in a low concentration of dehydroascorbic acid in plasma and tissues, despite the fact that it is absorbed more quickly than ascorbate.

Except for red blood cells, which lose their SVCT proteins as they mature, SVCTs seem to be the body’s primary mechanism for transporting vitamin C.

With rare exceptions, the concentration of ascorbic acid in cellular synthesizers of vitamin C (such as rats) and non-synthesizers (such as humans) is significantly higher than that of plasma, which is typically 50 micromoles/liter (µmol/L).

Muscle has 200–300 µmol/L of ascorbic acid, while the pituitary and adrenal glands can have up to 2,000 µmol/L. There may be additional, as-yet-unknown uses for ascorbic acid because its recognized enzymatic activities do not call for such high concentrations.

Because of the high concentration of organ material, plasma vitamin C is not a reliable measure of overall health, and individuals may differ in how long it takes for deficient symptoms to appear when eating a diet extremely low in vitamin C.

Urine can be used for ascorbic acid excretion. In humans, the kidneys reabsorb vitamin C instead of excreting it when dietary intake is minimal. This salvage procedure postpones the onset of the deficit.

The excess quantities flow freely into the urine and re-absorption only decreases when plasma concentrations reach 1.4 mg/dL or higher.

Moreover, ascorbic acid oxidizes to dehydroascorbate (DHA) and subsequently non-reversibly to 2,3-diketogulonate and oxalate from that molecule.

Urine also excretes these three chemicals. Because humans are superior to guinea pigs in their ability to convert DHA back to ascorbate, vitamin C deficiency develops considerably later in life.

Chemistry

When the term “vitamin C” is used, it always refers to ascorbic acid’s l-enantiomer and its oxidized forms, like dehydroascorbate (DHA). Thus, in the nutritional literature, “ascorbate” and “ascorbic acid” refer to l-ascorbate and l-ascorbic acid, respectively, unless otherwise noted.

A weak sugar acid that is structurally similar to glucose is ascorbic. Ascorbic acid is only present in low pH environments in biological systems; in solutions with a pH higher than 5, it is mostly found as ascorbate, an ionized form.

Unless otherwise noted, all of these compounds are interchangeably referred to as vitamin C since they all possess vitamin C action.

Several analytical techniques have been developed to detect ascorbic acid. For instance, the amount of sample needed to decolorize a dichlorophenolindophenol (DCPIP) solution can be used to determine the vitamin C content in food samples, such as fruit juice.

The results can then be calibrated by comparing them to a known concentration of vitamin C.

Testing

There are easy tests available to determine the vitamin C content of serum and urine. These more accurately represent current food consumption than overall body composition.

Serum concentrations have been found to exhibit a circadian cycle or to be influenced by short-term dietary changes; in contrast, the content of cells or tissues is more stable and provides a more comprehensive picture of the ascorbate availability across the entire body.

However, few hospital laboratories have the necessary tools and expertise to perform such in-depth examinations.

Synthesis

The majority of plants and animals can produce vitamin C by converting monosaccharides to the nutrient through a series of enzyme-driven processes. It is the stereoisomer, erythorbic acid, that is produced by yeasts instead of l-ascorbic acid.

Mannose or galactose is converted to ascorbic acid in plants to carry out synthesis. Glucose serves as the beginning ingredient in animals.

Glycogen is taken out of glycogen in certain animals (such as perching birds and mammals) whose livers produce ascorbate; this process is dependent on glycogenolysis.

The enzyme l-gulonolactone oxidase (GULO), which catalyzes the final step in biosynthesis, is severely mutated and non-functional in humans and in animals that are unable to manufacture vitamin C.

Animal synthesis

There is some data regarding the serum vitamin C concentrations that are maintained in vitamin C-synthesising animal species.

A study involving multiple dog breeds found an average of 35.9 µmol/L. Ranges of 100–110, 265–270, and 160–350 µmol/L were recorded in reports on goats, sheep, and cattle, respectively.

In vertebrates, the production of UDP-glucuronic acid initiates the biosynthesis of ascorbic acid. The enzyme UDP-glucose 6-dehydrogenase catalyzes two oxidations of UDP-glucose, which results in the formation of UDP-glucuronic acid.

NAD+ is the co-factor that UDP-glucose 6-dehydrogenase uses as an electron acceptor. A UMP is removed by the transferase UDP-glucuronate pyrophosphorylase, and the last phosphate, which is d-glucuronic acid, is removed by glucuronokinase and cofactor ADP.

l-gulonic acid is produced when this compound’s aldehyde group is converted to primary alcohol by the enzyme glucuronate reductase and the cofactor NADPH.

The next step is the production of lactones between the hydroxyl group on C4 and the carbonyl group on C1, using the hydrolase gluconolactonase.

The enzyme L-gulonolactone oxidase, which is nonfunctional in humans and other Haplorrhini monkeys (see Unitary pseudogenes), then catalyzes the reaction of l-gulonolactone with oxygen. and the FAD+ cofactor.

2-Oxogulonolactone (2-keto-gulonolactone) is the product of this process. It naturally enolates to generate ascorbic acid.

A number of animals, including tarsiers and simians, who together comprise one of the two primary primate suborders, Haplorrhini, are incapable of synthesizing vitamin C. Humans are members of this category.

The other, more rudimentary primates, known as strepsirrhines, are capable of producing vitamin C. Most bat species and those belonging to the rodent family Caviidae, which includes capybaras and guinea pigs, do not undergo synthesis; however, other rodent species, such as rats and mice, do.

Ascorbic acid is produced in the kidneys of reptiles and older bird orders. The majority of mammals and recent orders of birds produce ascorbic acid in their livers. Not all species of passerine birds synthesize, and those that do not are not related.

It has been suggested that birds lost the ability to synthesize on multiple occasions. Specifically, in at least two cases, the ability to produce vitamin C is thought to have been lost and subsequently regained.

Approximately 96% of fish that still exist today are incapable of synthesizing vitamin C.

Vitamin C cannot be synthesized by the majority of examined bat groups (order Chiroptera), including the main insect and fruit-eating bat families.

Out of the six investigated bat families, gulonolactone oxidase was found in traces in just one of the 34 species of bats. At least two bat species—the insectivorous Hippocidestes armiger and the frugivorous Rousettus leschenaultii—retain (or regain) the capacity to produce vitamin C.

By recycling oxidized vitamin C, several of these species—including humans—are able to get by on the lesser amounts that are provided by their meals.

Most simian animals eat the vitamin in doses 10–20 times higher than what governments suggest for humans, measured in milligrams per kilogram of body weight. Much of the debate surrounding the current suggested dietary allowances stems from this disparity.

Arguments that humans are excellent at preserving dietary vitamin C and can maintain blood levels of vitamin C equivalent to those of simians on a significantly lesser dietary intake—possibly through recycling oxidized vitamin C—oppose this.

Evolution of Animal Synthesis

Ascorbic acid is a potent reducing agent that can quickly scavenge a variety of reactive oxygen species (ROS) and is a frequent enzymatic cofactor in mammals utilized in the formation of collagen.

It is remarkable that the capacity to synthesize ascorbate has not always been retained given its important activities. It is actually true that most bats, anthropoid monkeys, teleost fish, Cavia porcellus (guinea pigs), and many passerine birds have all individually lost the capacity to produce vitamin C internally in the liver or kidney.

When ascorbic acid auxotrophs underwent genomic investigation, the mutations causing loss of function in the gene encoding L-guano-?-lactone oxidase were identified as the cause of the alteration in every enzyme responsible for the last action of the ascorbic acid pathway.

Genetic drift could be the cause of the recurring loss of the capacity to synthesize vitamin C; if the diet had been high in nutrients, natural selection would not have worked to retain it.

Since the simians’ loss of vitamin C synthesis occurred shortly after the emergence of the first primates, it is believed that the loss of vitamin C synthesis in these animals may have occurred much earlier in evolutionary history than the emergence of humans or even apes.

This is because the early primates split into two major suborders: the non-tarsier prosimians, or Strepsirrhini, and the Haplorrhini, which cannot make vitamin C “nosed” primates), who continued to be able to synthesize vitamin C.

Molecular clock dating indicates that these two suborder primate branches split off between 63 and 60 million years ago.

The infraorder Tarsiiformes split off from the other haplorrhines about three to five million years ago (58 million years ago), which is only a little time afterward from an evolutionary standpoint.

The only family of tarsiers that remains is Tarsiidae. Given that tarsiers are likewise incapable of producing vitamin C, it follows that the mutation has previously taken place and that it happened sometime between these two marker points, which are 63 and 58 million years ago.

It has also been observed that the loss of ascorbate synthesis is strikingly similar to the loss of uric acid breakdown capacity, which is another trait shared by primates. Both ascorbate and uric acid are potent reducing agents.

This has led to the hypothesis that uric acid has replaced some of ascorbate’s activities in higher primates.

Plant Synthesis

Plants have a wide variety of ascorbic acid production routes. The majority of these processes originate from byproducts of other pathways, such as glycolysis. For example, one pathway goes through the plant cell wall polymers.

The primary substrate in the plant ascorbic acid production pathway appears to be l-galactose. The enzyme l-galactose dehydrogenase combines with l-galactose to produce l-gluconolactone, which is the consequence of the lactone ring opening and reforming with lactone between the hydroxyl group on C4 and the carbonyl on C1.

Ascorbic acid is then produced when l-galactonolactone combines with the mitochondrial flavoenzyme l-galactonolactone dehydrogenase.

L-ascorbic acid inhibits spinach’s l-galactose dehydrogenase enzyme in a negative way. A well-established process of iron reduction, ascorbic acid outflow by dicot plant embryos is a necessary step for iron uptake.

Ascorbic acid is synthesized by all plants. In addition to being an antioxidant and regenerator of other antioxidants, ascorbic acid is a cofactor for enzymes involved in photosynthesis and the manufacture of plant hormones.

Plants make vitamin C through a variety of processes. The primary pathway begins with simple sugars like glucose, fructose, or mannose and moves on to ascorbic acid, L-galactose, and L-galactonolactone.

Because ascorbic acid inhibits enzymes in the production pathway, feedback regulation is in place. Because of the diurnal pattern of this process, the expression of enzymes increases in the morning to facilitate biosynthesis later in the day when the intensity of midday sunlight necessitates high amounts of ascorbic acid.

Certain plant components may have their own minor routes, which can either begin with inositol and proceed via L-galactonic acid to L-galactonolactone to reach ascorbic acid, or they can be the same as the vertebrate system (which includes the GLO enzyme).

Industrial Synthesis

There are two primary processes that convert glucose to vitamin C. Developed in the 1930s, the Reichstein process follows a full chemical pathway after a single pre-fermentation.

Additional fermentation is used in the current two-step fermentation method, which was first developed in China in the 1960s, to partially replace the later chemical processes. Sorbitol is the initial material in both the Reichstein process and contemporary two-step fermentation procedures, which use fermentation to change it into sorbose.

In order to avoid using an additional intermediary, the current two-step fermentation procedure subsequently transforms sorbose into 2-keto-l-gulonic acid (KGA) through a second fermentation stage. About 60% of the vitamin C produced by both methods comes from the glucose diet.

Ascorbic acid, also known as vitamin C, is one of China’s most popular exports, accounting for around 95% of global supply in 2017 and bringing in a total of US$880 million in revenue.

The price of vitamin C increased threefold to US$12 per kg in 2016 alone as a result of pressure on the Chinese industry to stop burning coal, which is often used to manufacture the vitamin.

History

The medicinal properties of citrus fruits were recognized during Vasco da Gama’s journey in 1497. Later, the Portuguese planted vegetables and fruit plants in Saint Helena, an Asian port of call that provided food for passing ships.

On occasion, authorities advised plant food to ward against scurvy during lengthy maritime trips. In his 1617 book The Surgeon’s Mate, John Woodall, the first surgeon employed by the British East India Company, suggested using lemon juice both as a preventive and therapeutic measure.

The Dutch author Johann Bachstrom expressed the solid belief in 1734 that”scurvy is solely owing to a total abstinence from fresh vegetable food, and greens.” For a long time, the main cause of death for sailors on lengthy sea trips was scurvy.

As Jonathan Lamb puts it, “In 1499, Vasco da Gama lost 116 of his crew of 170; In 1520, Magellan lost 208 out of 230;…all mainly to scurvy.”James Lind, a ship physician in the Royal Navy, made the first attempt to provide a scientific explanation for the etiology of this illness.

In May 1747, while at sea, Lind conducted one of the earliest controlled experiments in history by giving some crew members two oranges and one lemon each day in addition to their regular rations, while others continued on cider, vinegar, sulfuric acid, or seawater. Citrus fruits prevented the sickness, according to the research. In 1753, Lind published his research in his Treatise on Scurvy.

While it was easier to store fresh fruit in juice form, the vitamin content was lost when it was cooked, particularly in copper kettles. The British Navy didn’t start using lemon juice as a normal issue at sea until 1796. Instead, lime juice was given to ships in the West Indies in 1845, and by 1860, the Royal Navy was using lime juice exclusively,

which is how the British were dubbed “limey” in the United States. Having previously taken his troops to the Hawaiian Islands without losing a single man to scurvy, Captain James Cook had shown the benefits of having “Sour Krout” on board. The British Admiralty gave him a medal for this.

In the eighteenth and nineteenth centuries, foods that were known to stave off scurvy were referred to be antiscorbutics. Lemons, limes, oranges, sauerkraut, cabbage, malt, and portable soup were among these items.

Vilhjalmur Stefansson, a Canadian Arctic anthropologist, demonstrated in 1928 that the Inuit eat a diet high in raw meat to prevent scurvy.

Subsequent research on the traditional food diets of Northern Canadian Dene, Inuit, Métis, and Yukon First Nations revealed that their average daily consumption of vitamin C was 52–62 mg, which is comparable to the Estimated Average Requirement.

Discovery

The first vitamin to be manufactured, vitamin C was found in 1912, isolated in 1928, and produced again in 1933. Soon after, Tadeus Reichstein developed what is now known as the Reichstein technique to successfully synthesize the vitamin in large quantities.

This allowed vitamin C to be produced in large quantities at a low cost. Hoffmann-La Roche started selling synthetic vitamin C as a dietary supplement in 1934 after receiving a trademark for it under the name Redoxon.

In 1907, Norwegian doctors Axel Holst and Theodor Frølich fed guinea pigs their test diet of grains and flour in order to study shipboard beriberi.

To their surprise, scurvy developed in place of beriberi, providing a model for laboratory animals that would help identify the antiscorbutic factor. Fortunately, this species does not produce vitamin C on its own as mice and rats do.

Casimir Funk, a Polish biochemist, created the notion of vitamins in 1912. It was believed that the anti-scorbutic factor was one of these. This was known as “water-soluble C” in 1928, even though its chemical makeup was unknown.

The anti-scorbutic factor was found between 1928 and 1932 by the Hungarian team led by Albert Szent-Györgyi and Joseph L. Svirbely, and the American team led by Charles Glen King.

Hexuronic acid was extracted from the adrenal glands of animals by Szent-Györgyi, who hypothesized that it was the antiscorbutic factor. Giving Svirbely the remainder of his adrenal-derived hexuronic acid in late 1931, Szent-Györgyi suggested that it might be the anti-scorbutic factor.

This was demonstrated by King’s laboratory in the spring of 1932, but the results were not attributed to Szent-Györgyi when they were published. A savage argument about priority resulted from this.

Walter Norman Haworth was born in 1933. determined the vitamin’s chemical identity to be l-hexuronic acid in 1933 and demonstrated this by synthesis. Because of its ability to prevent scurvy, Haworth and Szent-Györgyi suggested renaming L-hexuronic acid as ascorbic acid, or chemically as l-ascorbic acid.

The word’s derivation comes from Latin, where “a-” denotes afar or off from, and “-scorbic” comes from the Medieval Latin scorbuticus, which refers to scurvy. It is related to Old Norse skyrbjugr, French scorbut, Dutch scheurbuik, and Low German scharbock.

Szent-Györgyi received the 1937 Nobel Prize in Medicine in part because of this discovery, while Haworth shared the 1937 Nobel Prize in Chemistry.

J. J. Burns demonstrated in 1957 that certain mammals are prone to scurvy because their livers are deficient in the final enzyme in the chain of four that creates vitamin C, l-gulonolactone oxidase.

Irwin Stone, an American biochemist, was the first to use vitamin C as a food preservative. Later on, he came up with the theory that the l-gulonolactone oxidase coding gene is mutated in humans.

Large doses

The term “vitamin C mega dosage” refers to the ingestion or injection of vitamin C at dosages that are either higher or equivalent to those generated by the livers of mammals that possess the ability to manufacture vitamin C.

This was supported by an argument (albeit not the phrase itself) that Linus Pauling described in a 1970 article. In short, he believed that in order to make up for the fact that humans cannot produce vitamin C, they should consume at least 2,300 mg per day in order to maintain good health.

The suggested consumption range also included gorillas, a non-synthesizing close relative of humans. Serum ascorbic acid concentrations rise with increased intake until they peak at roughly 190 to 200 micromoles per liter (µmol/L), which provides a second justification for high intake.

greater than 1,250 milligrams. As previously mentioned, the usual plasma concentration is around 50 µmol/L, therefore the government’s recommended range of 40 to 110 mg/day represents ‘normal’, or around 25% of what is possible when oral consumption falls within the suggested megadose range.

In 1970, Pauling made the idea of using high doses of vitamin C to treat and prevent colds more well-known. A few years later, he hypothesized that vitamin C could prevent cardiovascular disease and treat late-stage cancer by giving 10 grams of the vitamin intravenously for 10 days at first, and then orally.

Other proponents of ascorbic acid megadosing include scientist Irwin Stone, as well as the contentious Matthias Rath and Patrick Holford, who have both been charged with making unproven therapy claims for HIV/AIDS and cancer.

Megadoses of vitamin C have mostly been debunked. There isn’t any scientific proof that taking large amounts of vitamin C can prevent or treat cancer, the common cold, or other illnesses.

Benefits are not exclusive to the mega-dose range; they are not greater at supplement intakes exceeding 1,000 mg/day when compared to intakes between 200 and 1,000 mg/day.

Forty years after Pauling’s groundbreaking work, the notion that massive doses of intravenous ascorbic acid can be utilized to treat late-stage cancer is still regarded as unproven and in need of further high-quality study. Still, individual doctors continue to provide intravenous ascorbic acid to thousands of cancer patients despite the absence of proof.

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