VITAMIN C

BACKGROUND METABOLISM DRI VITAMIN C AND EXERCISE Description Absorption / Bioavailability Current DRI Requirements Sources Transport Deficiency Oxidative Stress   Storage Toxicity Exercise Recovery Excretion   Physiological Role SUMMARY REFERENCES

A. Background

Description

Vitamin C, also referred to as ascorbic acid or ascorbate, belongs to the water-soluble class of vitamins. Humans are one of the few species who lack the enzyme to convert glucose to vitamin C (13). Ascorbic acid (AA) is an odorless, white solid having the chemical formula C6H8O6. The vitamin is easily oxidized to form dehydroascorbic acid (DHAA), and thus oxidation is readily reversible. Vitamin C is a generic name for all compounds that exhibit the same biologic activity as AA. Consequently, the term includes both AA and DHAA. The importance of vitamin C was first was discovered in 1747. During the 16th century numerous sea voyagers died due to the disease known as scurvy. James Lind found that men suffering from scurvy were cured when given oranges and lemons and he published his findings in the Treatise of the Scurvy in 1753. He developed a hypothesis based upon the results he observed; although his ideas were incorrect, he was the first person to understand the importance of what would later be called vitamin C. These findings were not widely accepted by the rest of the world and scurvy continued to lead to wide spread death throughout the 19th century (17). Finally, in 1907 scurvy was induced in lab animals and this opened a new opportunity to understand the disease. Around 1930 two scientists working independently isolated and published their findings on vitamin C. The men found that vitamin C prevented and treated scurvy. The term ascorbic acid was adopted to describe its ability to prevent scurvy. The vitamin was then synthesized in the laboratory during 1933 (5).

Sources

A wide variety of food exists that contains vitamin C. A well-balanced diet easily obtains the DRI for vitamin C. It is widely known by the general public today that the best sources of vitamin C are citrus fruits and their juices. Fruits with a high vitamin C content include, but are not limited to oranges, lemons, peaches, strawberries, bananas and grapefruit. A wide variety of other foods also contain sufficient quantities of vitamin C. Cabbage, broccoli, cauliflower, leaf lettuce, tomatoes, potatoes, and beans also have relatively high (7 mg/100 g to 163 mg/100g) vitamin C content (17).

B. Metabolism

Absorption and Bioavailability

Transport of vitamin C is a saturable and dose dependent process that occurs by active transport. At the intestine and cells AA is oxidized to DHAA, which is more quickly transported across the cell membrane. Once inside the tissue or intestinal epithelium the vitamin is reduced back to AA. | The degree of intestinal absorption decreases as intake of AA increases. Intakes of 1 to 1.5 grams results in 50% absorption, but at intakes over 12 grams only 16% of the vitamin is absorbed. In contrast, an intake of less than 20 mg, has a 98% absorption rate (13). Absorption of vitamin C is greater when several individual doses of vitamin C, in quantities less than one gram, are taken throughout the day rather than one megadose (17). Eighty to ninety-five percent of the vitamin C found in foods is absorbed (13). Furthermore, the bioavailability of synthetic and "natural" forms of the vitamin differ very little despite the claims made by manufacturers (13,17). Vitamin C absorption can be impaired by a number of factors. A single large dose saturates the enzyme kinetics for vitamin C, leading to excess AA in the intestinal lumen, which causes numerous gastrointestinal problems. Pectin and zinc also inhibit AA absorption, but this mechanism is not well understood. A high iron concentration in the gastrointestinal tract may cause oxidative destruction and in turn impair uptake (13).

Transport

Active transport is the main mechanism of vitamin C distribution within the body. Simple diffusion may occur in the mouth and stomach but accounts for only a very small percentage of uptake (13). Sodium-independent transport systems shuttle vitamin C across the basolateral membrane of the intestinal cells. In the plasma absorbed ascorbic and dehydroascorbate (DHAA) can either be transported freely or be bound to albumin. Ascorbate can also move into body cells and tissues (13). As previously mentioned DHAA is the primary form of vitamin C that crosses cellular membranes. The adrenal and pituitary glands, red blood cells, lymphocytes, and neutrophils all receive vitamin C in the form of DHAA (13,17).

Storage

Vitamin C is stored throughout body tissues and blood. Ascorbic acid content of blood components, fluid, and tissue varies widely on an individual basis. Tissue concentrations exceed those found in the plasma by three to ten times. Energy-driven transport pumps are responsible for the higher tissue concentrations of vitamin C versus the plasma. Both tissue and plasma levels of vitamin C are correlated to intake up to 90 mg / day (13). The total body pool of vitamin C has been estimated, using radiolabeled isotopes, to a maximum of 20 mg/kg body weight. This corresponds to a plasma AA concentration of 57 umol/L. Alternate techniques of measurement have estimated maximum total body AA stores to be 22 mg/kg (17). The pituitary glands, adrenal glands, and lens of the eye contain the highest vitamin C content (at least140umol/ 100 g wet weight) within the body (13,17). In contrast the saliva and plasma have the lowest AA content (17). Vitamin C content of cardiac tissue is between 28 and 85 ml/100g wet weight, while that in skeletal muscle is approximately 17 ml/100g wet weight (16). Other tissues with intermediate levels of vitamin C include the kidneys, brain, liver, lungs, and thyroid. The water-soluble properties of vitamin C prevent it from being stored in the adipose tissue of the body.

Excretion

The average half-life of AA is believed to be between 16 and 20 days (17). Its half-life is inversely related to intake. The water-soluble properties of vitamin C lead to urinary excretion of the vitamin. Metabolites of vitamin C including dehydroascorbate (DHAA), oxalic acid, 2-O-methyl ascorbate, and 2-ketoascorbitol are also excreted from the body via the urinary system (13,17). The kidneys play a major role in vitamin C excretion and retention. DHAA and AA can be reabsorbed by the kidney tubules as long as body pool levels are equal to or less than 1500 mg. Levels within the body that are 1500 mg or less will result in no urinary excretion of vitamin C (13). As levels increase above 1500 mg the reabsorption efficiency of the kidneys decreases. Thus, body pool levels from 1500 to 3000 mg relate to tissue saturation of the vitamin (13). Plasma ascorbate levels between 0.8 and 1.4 mg/dl are considered the renal threshold. Above these levels, vitamin C will be excreted rather than reabsorbed by the kidneys (13).

Physiological Role

Vitamin C has been studied for many years. It participates in numerous biochemical reactions, suggesting that vitamin C is important for every body process from bone formation to scar tissue repair (13). The only established role of the vitamin appears to be in curing or preventing scurvy. Vitamin C is the major water-soluble antioxidant within the body. The vitamin readily donates electrons to break the chain reaction of lipid peroxidation. The water-soluble properties of vitamin C allow for the quenching of free radicals before they reach the cellular membrane. Tocopherol and glutathione also rely on AA for regeneration back to their active isoforms. The relationship between AA and glutathione is unique. Vitamin C reduces glutathione back to the active form. Once reduced, glutathione will regenerate vitamin C from its DHAA or oxidized state. The prophylactic effects of vitamin C as an antioxidant during exercise, when free radical formation is high, will be discussed in future sections of this literature review. A well-known function of AA is the role it plays in hydroxylation reactions that are essential for the formation of collagen. Vitamin C is important in collagen formation as it allows for a tight cross-linking of the triple helix, thereby resulting in stabilization of the peptide. Evidence also suggests that AA may be involved in collagen gene expression. However, this mechanism is not well understood. Carnitine synthesis prefers to use vitamin C as the reducing agent (13). Carnitine facilitates the beta-oxidation of fat, through its role transporting long chain fatty acids from the cytoplasm into the mitochondrial matrix of cardiac and skeletal muscle. High concentrations of AA are found in adrenal and brain tissue where they are fairly resistant to AA depletion. Vitamin C is directly involved in the enzyme activity of two copper dependent mono-oxygenases, which are important in the formation of norepinephrine and serotonin (13,17). Furthermore, AA regulates the activity of some neurons within the brain. Some of these functions include neurotransmitter membrane receptor synthesis, and neurotransmitter dynamics. Indirectly, AA plays important regulatory roles throughout the entire body due to its involvement in the synthesis of hormones, hormone-releasing factors, and neurotransmitters (13). Animal models have also shown that AA is an important factor in development of the nervous system, specifically in the maturation of glial cells and myelin (17) Vitamin C is important to a host of numerous other functions within the body. The vitamin is an important aid in the absorption and conversion of iron to its storage form. Bile acid formation, and hence cholesterol degradation are highly dependent on AA. Some hypothesize that vitamin C may even have a hypocholesterolemic effect. This has been suggested because the enzyme needed for the first step in bile acid synthesis, cholesterol 7-alpha hydroxylase, is dependent upon the presence of vitamin C. Ascorbic acid may also has vasodilatory and anticlotting effects within the body by stimulating nitric oxide release. Physiological effects such as an antihistamine modified bronchial tone, and insulin responses have been linked to AA. The protection of neural and endothelial tissue, along with effects on cellular tone can also be attribute to vitamin C. Multiple other mechanisms of function for vitamin C have been proposed, but experimental results addressing these topics are variable. Possible other functions for vitamin C include regulation of cellular nucleotide concentrations, immune function, and the endocrine system. Vitamin C has been proposed by some to have pharmacological benefits in preventing cancer, infections, and the common cold. However, these benefits have yet to be reported in the scientific literature. The role of vitamin C in preventing cancer is controversial, but has been studied for cancers of the oral cavity, uterus, esophagus, bladder, and pancreas. The research is at best equivocal and more studies are needed to further address the role of vitamin C in preventing cancer.

C. Dietary Reference Intake (DRI)

Current DRI

The Recommended Daily Allowance (RDA) has been replaced by a DRI for vitamin C in the year 2000. In 1989 the RDA was established at 60 mg for adults. This level was believed to be sufficient enough to maintain body pool levels at 1500 mg and does not differ from that established in 1980. A RDA for smokers was established in 1989 at 100 mg/day. This greater RDA was established because smokers have a higher turnover rate of vitamin C versus non-smokers (13). The DRI does not differentiate the need between smokers and non-smokers. Dietary reference intakes for vitamin C have been established at 90 mg for men and 75 mg for women (28).

Deficiency

Between the 16th and 18th centuries numerous sea voyagers died mysterious deaths, but symptoms could be reversed with the consumption of citrus fruits. Dr. James Lind made this discovery in 1747 after the British Admiralty demanded that a cure for the disease be found. The disease was later termed scurvy and the cure ascorbic acid because of its antiscurvy properties (16). Today the disease still exists, but is rare in the United States. However, the symptoms and cure are well known. The disease is most commonly seen in people who have poor diets, cancers, are alcoholics, or have been institutionalized. The disease is more common in those who have cancer and those who are alcoholics due to the increased turnover rate of the vitamin.

Toxicity

The saturable kinetics of vitamin C make toxicity more likely when multiple large doses (~1gram) are consumed throughout a day versus one single dose. A common symptom of unabsorbed vitamin C left in the gastrointestinal tract is osmotic diarrhea (13). Vitamin C can be transformed in the body to oxalate, which is a common constituent of kidney stones. Doses up to 10 grams have shown to be associated with a higher prevalence of oxalate excretion, but the level does not fall outside of the normal range. As a precaution, people who are prone to kidney stones may want to avoid large doses (10 times the DRI or greater) of the vitamin (13). People who lack the control to regulate iron uptake should also avoid large doses of the vitamin. As stated earlier vitamin C enhances iron absorption which, can lead to toxicity of iron in some people. Furthermore, excess ascorbate in the urine and feces can falsify lab tests such as glucose in the urine and fecal occult blood test.

D. Vitamin C And Exercise

Effects of Exercise on Vitamin C Requirements

The evidence addressing the vitamin C requirement of athletes is abundant and contradictory. Multiple studies have found blood and plasma levels of vitamin C to be diminished in those who exercise. Keith (24) summarizes the findings of Namyslowski who published two papers addressing the requirement of ascorbate in exercising individuals. The second study concluded that blood vitamin C levels decreased in athletes ingesting 100 mg per day. A dietary intake of 300 mg/day maintained blood levels of the vitamin. This was some of the first evidence to suggest vitamin C needs are increased in those who exercise. Athletes receiving a one-gram vitamin C supplement showed increased work capacity at a heart rate of 170 beats per minute. Subjects served as self-controls and were given a placebo for two weeks and then vitamin C for two weeks. During vitamin C supplementation subjects repeatedly demonstrated decreased heart rates at all levels of work when compared with the placebo trial (16). However, treatments (placebo or vitamin) were given in succession. An alternate study by Telford et al. (35) provided evidence that supplementation for 7 to 8 months did not have any significant effect on blood levels of the vitamin. However, females were shown to have significantly higher levels of vitamin C in their blood versus the male population. Also, this study showed that plasma vitamin C levels could remain elevated for 24 hours after strenuous exercise (11,39). Vitamin C has shown favorable effects when used during heat acclimatization in humans. Two separate studies (26, 33) from the 1970s have both shown similar results. Plasma levels of ascorbic acid in thirteen male volunteers rose to a level fourfold higher in supplemented (250 mg or 500 mg) than unsupplemented subjects. The higher plasma levels of ascorbate were associated with reduced body temperature and sweat loss. These results support the hypothesis that vitamin C is beneficial to those trying to acclimatize themselves to heat (27). In a study done one year earlier the same results were found. However, it was determined that doses of 500 mg versus 250 mg result in no enhanced benefits in subjects acclimatizing to heat (33). The effects of vitamin C supplementation on anaerobic and aerobic work capacity were investigated by Keren and Epstein (26). Thirty-three healthy males partook in a 21-day training session that uses primarily involved mainly aerobic work. Measures of aerobic and anaerobic work capacity were then measured. Vitamin C supplementation provided no enhancement in either aerobic or anaerobic work. Many ultra long-distance runners experience upper respiratory tract infections. Peters et al. (30) addressed the possible role of vitamin C in preventing these infections. Symptoms of upper respiratory infection were monitored for 14 days after an ultramarathon (> 26.2 miles) in subjects receiving either placebo or vitamin C supplementation. Sixty-eight percent of the runners on the placebo reported the development of respiratory tract infections. In contrast only one-third of the vitamin C group reported the infections. The scientists concluded that vitamin C supplementation may actually be beneficial in helping prevent upper respiratory infections in ultramarathoners. Blood vitamin C levels greater than 0.6mg/100ml have been established as being adequate (41). Multiple studies have shown blood vitamin C levels of various athletes including runners (11,40) to be adequate. Concentrations of plasma AA have been reported to be significantly higher five minutes after a 21 km (13.1 mile) run than baseline values. The levels then fell 20% below pre-exercise values within 24 hours and remained depressed for 2 days (11). This may be due to a loss in plasma volume following exercise. Contradictory results were found by Rokitzki et al. (31) and Glesson et al. (11) who found that vitamin C was higher immediately after exercise. However, Rokitzki et al. (31) also noted that the levels remained high for 24 hours following a marathon. The fluctuating levels of vitamin C are likely controlled by the adrenal gland (11). In conclusion, a high probability exists that a large majority of athletes consume sufficient vitamin C in their diet. At the same time it is know that a diet lacking vitamin C will in turn inhibit performance (5). A daily intake between 100-300 mg of vitamin C may be warranted to meet the needs of all people who exercise (5). However, until an alternative RDI for athletes is established the recommended intake for vitamin C shall remain at 75 mg for women and 90 mg for men. Doses of 1500 milligrams or greater oversaturate the body pool and are excreted in the urine. Therefore, multiple large doses are not warranted. One must also be aware of the enzyme kinetics of vitamin C transport. Multiple small doses help prevent side effects and are advised for those choosing to consume large quantities or supplement with the vitamin. The previously mentioned levels are easily obtainable by substituting a well-balanced diet for a supplement. Clarkson summarizes (7) that athletes taking a multivitamin do not appear to obtain ergogenic benefits and likely do not need the supplementation (40). However, a small portion of those who exercise will lack an adequate vitamin C intake. Bazzarre et al. (3) have shown some bodybuilders have vitamin C intakes below 40 mg. Similar conclusions were found in basketball players (15), cyclists (25), and even Navy Seals (8). Currently it appears that the variety and adequacy of individual diets will determine if supplementation with vitamin C is needed

Prevention Of Oxidative Stress / Lipid Peroxidation

Vitamin C has the ability to sequester the singlet oxygen radical, stabilize the hydroxyl radical, and regenerate reduced vitamin E back to the active state. These functions work to halt peroxidation of cellular lipid memebranes (21). Despite these functions the studies involving AA and lipid peroxidation are disappointing at best. Vitamin C has been shown to induce a lower-frequency fatigue (indicates less muscle damage) when compared with those deficient in the vitamin (18). A second study found that vitamin C does control reactive oxidant species formed during exercise (32). If not controlled these species have the ability to react with cell membranes and damage them, initiating lipid peroxidation. In 1992 Kaminski et al. (21) examined the relationship between AA given to 19 subjects for three days before exercise (and seven after) and the muscle damage induced by two bouts of eccentric exercise that were 3 weeks apart. The authors concluded that AA reduced muscle damage, however they did not measure any indices of oxidative stress other than muscle soreness (21) Supplementation with two 500-gram dosages of vitamin C for one day is associated with a decreased shift from pre-exercise to post exercise prooxidant activity when compared to a placebo. The same dosage given over a two-week period did not elicit as great a change in peroxidation activity as a one-day supplementation provided (1). This difference may be related to the fact that a one-day dose of vitamin C, such as that used in this study, helped to regenerate other antioxidants in the body (i.e. Vitamin E). The authors hypothesize that a two-week period of vitamin C supplementation may replenish other antioxidants and then lead to prooxidant properties within the body (1), likely via the Fenton reaction. As shown here there is an obvious lack of research addressing antioxidants and exercise, particularly vitamin C. The existing preliminary data addressing vitamin C to-date seems promising, but also demonstrates the need for further research in this area.

Vitamin C And Exercise Recovery

Current research concerning vitamin C and exercise recovery is limited at best. A previously mentioned study found that vitamin C supplementation prevented muscle soreness (21). However, the aim of the study was not that of exercise recovery, but rather peroxidation of membranes. Vasankari et al. (39) performed one of the few studies addressing the role of vitamin C in exercise recovery. Conjugated dienes decreased by 11% after exercise in those individuals who ingested vitamin C versus those receiving a placebo. The design of this study should be noted as the subjects received one gram of vitamin C in supplement form immediately after a bout of exercise. However, these methods and results may be the basis for future research addressing vitamin C (and antioxidant) supplementation immediately after exercise. This author believes that vitamin C likely only aids in recovery if a person is deficient in the vitamin. The adrenal gland has been shown to regulate vitamin C release into the plasma (11). The significance of this has yet to be determined. However, it is likely that vitamin C does not directly function in muscle recovery because post-exercise values in the previous study (11) fell to values 20% below baseline within the first 24 hours of recovery. The possibility does exist that vitamin C may play an indirect role in exercise recovery. The vitamin has the ability to regenerate vitamin E. This means that any function vitamin E has within the body can also be linked back to vitamin C. The literature suggests that the role vitamin E plays in muscle recovery is limited and contradictory at this time. The relationship between vitamin E and muscle recovery is further addressed in a separate section. In summary, the role of vitamin C in exercise recovery is not known. The literature to date seems to imply that vitamin C probably has no direct significant role in muscle recovery from exercise, but may possibly play a significant indirect role in the process.

E. Summary / Current Recommendations

Depressed vitamin C levels can ultimately cause decreased performance. Vitamin C can regenerate other antioxidants and act as an antioxidant itself. Therefore the need for vitamin C is likely increased in those who exercise regularly. An intake of 100 to 500 mg seems to be sufficient to meet the needs of the exercising individual. This level can easily be obtained through a fruit and vegetable inclusive diet. As stated earlier these dosages would best be absorbed if taken in small quantities at multiple intervals. Some athletes will experience inadequate vitamin C intakes that are below the RDA. For this group of people increased vitamin C may be beneficial to performance. The abundance of vitamin C rich foods establishes that inadequate vitamin C levels should be increased via food sources, not by supplementation, if possible. The paucity of research investigating vitamin C and the prevention of oxidative damage makes interpretation difficult. This confusion has led to difficulty in formation of a clear-cut recommendation, so one will not be presented. Many studies have looked at the effects of combined vitamin C and E supplementation. These were not addressed in this literature review. Future research needs to investigate the role that vitamin C, alone, has in preventing or lessening oxidative stress. This too may be difficult as AA has the ability to regenerate vitamin E. Furthermore, research addressing the validity of acclimatization studies warrants further investigation.

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