WATER-SOLUBLE AND FAT-SOLUBLE VITAMINS

Vitamins are among the nutrients found to be essential for life. Unlike other classes of nutrients, vitamins serve no structural function nor do they provide significant energy. Their various uses tend to be highly specific. Common food forms of most vitamins require some metabolic activation into a functional (active) form. Although vitamins share these general characteristics, they show few close chemical or functional similarities. For example, some vitamins function as coenzymes, others function as antioxidants, and two vitamins, A and D, function as hormones.

Fourteen substances are now generally recognized as vitamins. Vitamins are frequently described according to their solubility; they may be either fat-soluble or watersoluble. This method of classification dates back to the history of their discovery as labeled by McCollum as “fatsoluble A” and “water-soluble B.”

Other sections in this encyclopedia describe the chemistry, biochemistry, and physiology of the vitamins. This article provides additional information that is focused on dietary requirements, upper levels (to avoid toxicity from supplementation), and food sources.

Water-Soluble Vitamins

Thiamin. Thiamin was the first vitamin to be identified. In modern times, thiamin deficiency is seen most commonly in association with chronic alcoholism. Only a small percentage of large doses are absorbed, and elevated serum levels result in its active urinary excretion. After an oral dose of the vitamin, peak excretion occurs in about two hours (Davis et al., 1984). Total body thiamin content in adults is approximately 30 milligrams with a half-life of 9 to 18 days (Ariaey-Nejad et al., 1970).

The recommended dietary allowance (RDA) for thiamin in adult women is 1.1 mg/day and in adult men it is 1.2 mg/day. The RDA for pregnancy and lactation is 1.4 mg/day (FNB, 1998). It should be noted that increased needs exist in persons being treated with hemodialysis or peritoneal dialysis, individuals with malabsorption syndrome, women carrying more than one fetus, and women nursing more than one infant.

There are no reports of adverse effects from the consumption of excess thiamin consumed in food or supplements. No upper level (UL) can be set due to the lack of reported findings associated with adverse effects. Supplements that contain up to 50 mg/day are available over-the-counter with no reported problems.

Food sources from which most of thiamin in the United States is derived include enriched, fortified, or whole-grain products, such as bread, bread products, mixed foods that contain grain, and ready-to-eat cereals. Foods that are especially rich in thiamin include yeast, lean pork, and legumes. Thiamin is absent from fats, oils, and refined sugars. Milk, milk products, seafood, fruits, and vegetables are not good sources.

Riboflavin. The second vitamin discovered was named vitamin B₂ or riboflavin. Most dietary riboflavin is consumed as a complex of food protein. Signs of riboflavin deficiency are sore throat, redness, and edema of the throat and oral mucous membranes, cheilosis (cracking of the skin around the mouth), and glossitis (red tongue). Vitamin B₂ deficiency most often occurs in combination with other nutrient deficiencies. The B vitamins are quite interrelated; for example, niacin requires riboflavin for its formation from the amino acid tryptophan, and vitamin B₆ requires riboflavin for conversion to the active coenzyme form (McCormick, 1989).

The RDA for riboflavin has been set at 1.3 mg/day for men and 1.1 mg/day for women through age seventy years and older. For pregnancy, the RDA for riboflavin is set at 1.4 mg/day and it is 1.6 mg/day for lactation (FNB, 1998).

When riboflavin is absorbed in excess, very little is stored in the body tissues. Excess is excreted via the urine, and the amount varies with intake, metabolic events, and age (McCormick and Greene, 1994). No adverse effects associated with riboflavin consumption from food or supplements have been reported. No adverse effects were reported from a single dose of up to 60 milligrams and 11.6 milligrams of riboflavin given as a single intravenous (IV) dose (Zempleni et al., 1996).

The greatest contribution of riboflavin from the diet comes from milk and milk drinks, followed by bread products and fortified cereals. Especially good food sources of riboflavin are eggs, lean meats, milk, broccoli, and enriched breads and cereals. Recall that riboflavin loss occurs when it is exposed to light, so store milk in opaque containers or away from the light.

Niacin. The term “niacin” refers to nicotinamide and nicotinic acid. The coenzymes, the active form of niacin in the body, are synthesized in all tissues of the body. The amount of niacin in the body is the result of absorbed nicotinic acid and nicotinamide, as well as conversion of the amino acid tryptophan (60 milligrams of tryptophan = 1 milligram of niacin; Horwitt et al., 1981). Excess niacin is excreted through the urine.

Pellagra is the classical manifestation of niacin deficiency. Pellagra has been seen in areas where corn (low in niacin and tryptophan) is the dietary staple. Enrichment and fortification of grain has virtually eliminated pellagra from the United States and Europe.

The RDA for adult men is 16 mg/day of niacin equivalents, and the RDA for women aged nineteen to over seventy is 14 mg/day. In pregnant women the RDA is 18 mg/day of niacin equivalents and in lactating women it is 17 mg/day (FNB, 1998).

Niacin, given as nicotinic acid in doses from 4 to 6 g/day, is one of the oldest drugs used in the treatment of hyperlipidemia, which consists of elevated blood levels of triglycerides and cholesterol. Niacin lowers low-density lipoprotein (LDL) cholesterol and triglyceride concentration. This therapeutic effect is not seen with nicotinamide. Nicotinic acid in therapeutic doses can cause flushing and headache in some people. These side effects are not harmful.

An upper limit for niacin was set at 35 mg/day for adults, if the niacin is obtained from supplements, not foods. Individuals who take over-the-counter niacin to “self-medicate” may exceed the UL on a chronic basis. The UL is not intended to apply to those receiving niacin under medical supervision.

Dietary intake of niacin comes mainly from mixed dishes containing meat, poultry, or fish, followed by enriched and whole-grain breads, and fortified cereals. Significant amounts of niacin are found in red meat, liver, legumes, milk, eggs, alfalfa, cereal grains, yeast, and fish.

Vitamin B_6. Vitamin B₆ is a coenzyme for more than 100 enzymes involved in the metabolism of amino acids, glycogen, and nerve tissues (FNB, 1998). Microcytic anemia, reflecting decreased hemoglobin synthesis, can be seen in deficiency states. The interaction of vitamin B₆ and folate (another B vitamin discussed below) has been shown to reduce the plasma concentrations of homocysteine and decrease the incidence of cardiovascular disease (CVD) risk (Rimm et al., 1998). Subjects with the highest intake of folate and vitamin B₆ had a twofold reduction in CVD as compared to the group with the lowest intake.

In the 1970s there was quite a bit of discussion about the status of vitamin B₆ in women using oral contraceptives. This was probably an artifact of hormonal stimulation of tryptophan catabolism rather than vitamin B₆ deficiency. At the time these studies were conducted, estrogen concentrations were three to five times higher in contraceptive agents than they are today.

The RDA for vitamin B₆ is 1.3 mg/day for adult men and women up to age fifty years. The RDA for people over fifty years of age is 1.7 mg/day for men and 1.5 mg/day for women. For pregnant women the RDA is set at 1.9 mg/day and for lactating women, 2.0 mg/day (FNB, 1998).

No adverse effects have been associated with intakes of vitamin B ₆ from food. However, large doses of pyridoxine used to treat carpal tunnel syndrome and premenstrual syndrome have been associated with sensory neuropathy (Schaumburg and Berger, 1988). These findings were noted with dosages from 2 to 6 g/day. It appears that the risk of developing sensory neuropathy decreases quite rapidly at dosages below 1 g/day. Thus, the UL for adults is set at 100 mg/day of vitamin B₆ as pyridoxine.

Food sources of vitamin B₆ include fortified, ready-to-eat cereals; mixed foods with meat, fish, or poultry as the main ingredient: white potatoes, starchy vegetables, and noncitrus fruits. Vitamin B₆ is widely distributed in foods; good sources are meats, whole-grain products, vegetables, and nuts.

Folate. Folate is a B vitamin that exists in many chemical forms (Wagner, 1996). Folic acid, the most stable form of folate, occurs rarely in food, but is the form used in supplements and fortified food products. Folate coenzymes are involved in numerous reactions that involve DNA synthesis, purine synthesis, and amino acid metabolism. The most well known is the conversion of homocysteine to methionine. It is this reaction that reduces the concentration of homocysteine in the plasma, and may lower the risk of cardiovascular disease (Rasmussen et al., 1996).

The metabolic interrelationship between folate and vitamin B₁₂ may explain why a single deficiency of either vitamin leads to the same hematological changes. In either folate or vitamin B₁₂ deficiency, megaloblastic changes occur in the bone marrow and other replicating cells.

Pregnant women are at risk for developing folate deficiency because of the heightened demands imposed by increased synthesis of DNA. Low folate status is associated with poor pregnancy outcome, low birth weight, and fetal growth retardation (Scholl and Johnson, 2000). Because of the possible incidence of neural tube defects (NTDs) during the preconception period (that is, just before and during the first 28 days of conception), the Food and Nutrition Board recommends that women who are capable of becoming pregnant should consume 400

Recommendations for intake of folate are dependent on variation in bioavailability. Supplemental folate is nearly 100 percent absorbed, while absorption of folate found in foods is only about 50 percent. Fortified foods approach the level of bioavailability of folate found in supplements. This has led to the term Dietary Folate Equivalents or DFEs. Thus, dietary recommendations for folate intake are based on “folate equivalents.” 

No adverse effects have been associated with the consumption of normal folate-fortified foods. However, the risk of neurological effects that result from vitamin B₁₂ deficiency that are masked with high doses of folate caused the FNB to set a UL. The UL for adults, nineteen years and older, is set at 1,000

Folates are found in nearly all natural foods. Protracted cooking or processing may destroy folate. Foods with the highest folate content include yeast, liver, other organ meats, fresh green vegetables, and some fruits (oranges, for example). Most of the dietary intake of folate in the United States comes from fortified ready-to-eat breakfast cereals followed by a variety of beans and peas, fresh and dried. As of 1 January 1998, all enriched cereal grains, pasta, flour, and rice are required to be fortified with folate at 1.4 mg/kg of grain.

Vitamin B_12. Cyanocobalamin is the compound we call vitamin B₁₂. This is the only vitamin B₁₂ preparation used in supplements. An adequate supply of vitamin B₁₂ is essential for normal blood formation and neurological function. The absorption of vitamin B₁₂ is dependent on several physiological steps. In the stomach, food-bound vitamin B₁₂ is dissociated from proteins in the presence of stomach acid. Vitamin B₁₂ then binds with protein and in the intestine the vitamin B₁₂ binds with intrinsic factor for absorption. If there is a lack of sufficient acid in the stomach or intrinsic factor in the intestine, malabsorption occurs and the resulting condition caused is pernicious anemia.

The anemia of vitamin B₁₂ deficiency (completely reversed by addition of B₁₂) is indistinguishable from that seen with folate deficiency. Because up to 30 percent of people older than fifty are estimated to have atrophic gastritis with low stomach acid secretion, older adults may have decreased absorption of B₁₂ from foods. Thus, it is recommended that most of the vitamin B₁₂ consumed by adults greater than fifty-one years of age be obtained from fortified foods or supplements.

The RDA of vitamin B₁₂ for men and women is 2.4 12 intake from food or supplements. After reviewing the literature, the FNB found insufficient evidence for determining a UL.

Vitamin B₁₂ is present in all forms of animal tissues. It is not present in plants and thus does not occur in fruits or vegetables. Because a generous intake of animal foods is customary in the United States, B₁₂ intake from foods is usually adequate. People who avoid eating animal products may obtain most of their requirement through fortified foods.

Vitamin C. Ascorbic acid (the chemical name for vitamin C) is a potent antioxidant in animals and plants. Vitamin C is important in the synthesis of collagen. Some evidence indicates that vitamin C reduces virus activity by inhibiting viral replication (Johnston, 2001). Many anecdotal reports support a role for vitamin C supplementation to reduce the severity of cold symptoms.

Some epidemiological evidence indicates that supplemental vitamin C protects against risk for myocardial infarction. However, large-scale epidemiological studies do not suggest a benefit of vitamin C supplementation on cardiovascular health risks (Kushi et al., 1996).

Non-heme iron absorption from food is enhanced two-to threefold in the presence of 25 to 75 mg of vitamin C, presumably because of the ascorbate-induced reduction of ferric iron to ferrous iron, which is less likely to form insoluble complexes in the intestine. However, vitamin C has no effect on increasing iron absorption from heme iron (Johnston, 2001). Unlike most animal species, humans lack the ability to synthesize ascorbic acid; thus, the diet is the sole source for this vitamin.

The current requirement of vitamin C is 90 mg/day for adult men and 75 mg/day for adult women. During pregnancy the RDA is 85 mg/day, and 120 mg/day during lactation. The UL for vitamin C was set at 2 g/day (FNB, 2000). This level was set as a guideline for people using dietary supplements and was based on reports of gastrointestinal symptoms reported when too much vitamin C was taken.

Almost 90 percent of vitamin C in the diet comes from fruits and vegetables, with citrus fruits, tomatoes, tomato juice, and potatoes being the major contributors. It is also added to some processed foods as an antioxidant.

Pantothenic acid. Pantothenic acid was named after the Greek, meaning “from everywhere,” because it is so widespread in foods. Pantothenic acid is essential in the diet because of the inability of animals and humans to synthesize the pantoic acid moiety of the vitamin. Pantothenic acid plays a primary role in many metabolic processes, such as oxidative metabolism, cell membrane formation, cholesterol and bile salt production, energy storage, and activation of some hormones (Miller et al., 2001).

Pantothenic acid deficiency in humans is rare because of its ubiquitous distribution in foods. Many health claims are made regarding the role of pantothenic acid in ameliorating rheumatoid arthritis, lowering cholesterol, enhancing athletic performance, and preventing graying of hair (Miller et al., 2001). However, sufficient information is lacking at this time and so firm recommendations may not be made. No reports of adverse effects of oral pantothenic acid in humans have been reported.

The Food and Nutrition Board (1998) established an adequate intake level (AI) for pantothenic acid of 5.0 mg/day for adult men and women, 6.0 mg/day during pregnancy, and 7.0 mg/day during lactation. As mentioned above, pantothenic acid is found in a wide variety of both plant and animal foods. Because of its thermal lability and susceptibility to oxidation, significant amounts are lost during processing. Rich food sources include chicken, beef, liver, and other organ meats, whole grains, potatoes, and tomato products.

Biotin. In mammals, biotin serves as a coenzyme for reactions that control such important functions as fatty acid metabolism and gluconeogenesis. Biotin is recycled upon degradation of enzymes to which it is bound. Biotin from pharmaceutical sources is 100 percent bioavailable. Deficiency is rare but has been seen in patients on parenteral nutrition without biotin supplementation (Zempleni and Mock, 1999). Lipoic acid and biotin have structural similarities, thus competition potentially exists for intestinal or cellular uptake. This may be of concern in settings where large doses of lipoic acid are administered or taken as supplements (Zempleni et al., 1997).

The Food and Nutrition Board established an AI for biotin due to insufficient data to set an RDA. Adult men and women have an AI of 30

Biotin is distributed widely in natural foods. Those rich in biotin include egg yolk, liver, and some vegetables. It is estimated that individuals in the United States consume between 35 and 70

Choline. Choline has been considered a nonessential nutrient because humans can synthesize sufficient quantities. However, when hepatic function is compromised, hepatic choline synthesis is decreased and thus choline is now considered “conditionally” essential. In a 1998 report from the Food and Nutrition Board, choline is considered an essential nutrient (FNB, 1998). The Food and Nutrition Board noted that additional studies on the essentiality for human nutrition are needed. Specifically, the 1998 Food and Nutrition Board study suggested that graded doses of choline intake be studied regarding their effects on organ function, plasma cholesterol, and homocysteine levels.

Choline functions as a precursor for phospholipids and acetylcholine, and betaine. The AI for adult men was set at 550 mg/day and for women at 425 mg/day. For pregnancy, the AI was increased to 450 mg/day and during lactation, to 550 mg/day (FNB, 1998). Due to reports of hypotension (low blood pressure) from excess intake, a UL was set at 3.5 g/day for persons nineteen years and older. Choline and choline-containing lipids, mainly phosphatidylcholine, are abundant in foods of both plant and animal origin. Rich sources include muscle and organ meats and eggs. To date there are no nationally representative estimates of choline intake from food or supplements.

Fat-Soluble Vitamins

Vitamin A. The active forms of vitamin A participate in three essential functions: visual perception, cellular differentiation, and immune function. A number of food sources are available for vitamin A. Preformed vitamin A is abundant in animal foods and provitamin A carotenoids are abundant in dark-colored fruits and vegetables. With a 2001 report from the Food and Nutrition Board (FNB 2001), there has been recognition of a change in equivalency values of various carotenoids to vitamin A. Retinol activity equivalents (RAEs) for dietary provitamin A carotenoids—beta-carotene, alpha-carotene, and betacryptoxanthin—have been set at 12, 24, and 24 A number of factors affect the bioavailability of carotenoids (Castenmiller and West, 1998). Percent absorption

decreases as the amount of dietary carotenoids increases, and the relative carotene concentration absorbed increases when consumed with oil or associated with plant matrix material. That is part of the plant vitamin source, not separated out as a supplement. The presence of dietary fat stimulates the secretion of bile acids and improves the absorption of carotenoids.

Recommended dietary allowance for men is 900

Based on the literature review, the FNB used liver abnormalities as the critical adverse effect for setting the UL for adults. Issues of carcinogenicity were considered for women of childbearing age. The UL varies slightly with age between 2,800 and 3,000

The richest sources of vitamin A are fish oils, liver, and other organ meats. Whole milk, butter, and fortified margarine and low-fat milks are also rich in the vitamin. In the United States carrots, fortified spreads, and dairy products are the leading contributors of vitamin A to the diet.

Vitamin D. Vitamin D is essential for life in higher animals. It is one of the most important regulators of calcium homeostasis and was historically considered the “anitrachitic” factor. The biological effects of vitamin D are achieved only by its hormonal metabolites, including two key kidney-produced metabolites: 1,25(OH)₂ vitamin D and 24,25(OH) vitamin D. In addition to its role in calcium metabolism, research has identified that vitamin D plays an important role in cell differentiation and growth of keratinocytes and cancer cells and has shown that it participates in the process of parathyroid hormone and insulin secretion (Bouillon et al. 1995).

Vitamin D₃, the naturally occurring form of the vitamin, is produced from the provitamin, 7-dehydrocholesterol, found in the skin under the stimulation of ultraviolet (UV) irradiation or UV light. Vitamin D₂ is a synthetic form of vitamin D that is produced by irradiation of the plant steroid ergosterol. A requirement for vitamin D has never been precisely defined because vitamin D is produced in the skin after exposure to sunlight. Therefore, humans do not have a requirement for vitamin D when sufficient sunlight is available. The fact that humans wear clothes, live in cities where tall buildings block the sunlight, use synthetic sunscreens that block UV rays, and live in geographical regions of the world that do not receive adequate sunlight contributes to the inability of the skin to synthesize sufficient vitamin D (Holick, 1995). Exposure to the sun sufficient for humans to obtain enough UV radiation to synthesize adequate vitamin D can be as little as three weekly exposures of the face and hands to ambient sunlight for 20 minutes (Adams et al., 1982).

A substantial proportion of the U.S. population is exposed to suboptimal levels of sunlight during the winter months. Under these conditions, vitamin D becomes a true vitamin and must be supplied regularly in the diet. The Food and Nutrition Board recommend an AI or adequate intake of vitamin D at 200 IU/day (5

To prevent life-threatening hypercalcemia, an upper level (UL) for vitamin D has been set at 2,000 IU/day (50 2 vitamin D for treatment of hypoparathyroidism, vitamin D–resistant rickets, renal osteodystrophy, osteoporosis, and psoriasis opens the door for potential toxicity because this form of the vitamin is much more toxic and the body’s metabolic controls are bypassed. When this medication is being used, careful monitoring of plasma calcium concentrations is required.

Salt-water fish are good unfortified sources of vitamin D. Small quantities are derived from eggs, beef, butter, and vegetable oils. Fortification of milk, butter, margarine, cereals, and chocolate mixes help in meeting the dietary requirements. Excessive amounts of vitamin D are not available in usual dietary sources. However, excessive amounts can be obtained through supplements that result in high plasma levels of 25(OH) vitamin D.

Vitamin E. Vitamin E (also called tocopherol) is found in cell membranes and fat depots. Because of their chemical structure, there are eight stereoisomers of each of the tocopherols. In addition to each of the stereoisomers, each occur in alpha, beta, gamma, and delta forms (FNB, 2000).

Its most recognized function is to protect polyunsaturated fatty acids (PUFA) from oxidation. PUFAs are particularly sensitive to oxidative damage, and the protective role of vitamin E is supported by a similar antioxidant protection from vitamin C and selenium. One tocopherol molecule can protect 100 or more PUFA molecules from autoxidative damage (Pryor, 2001).

The various forms of vitamin E have different biological activity, with the natural source isomer—R,R,R,-alpha-tocopherol—being the most active. In supplements you may see this isomer called by its former name, d-alpha-tocopherol. Synthetic vitamin E is called all-rac-alpha-tocopherol or dl-alpha-tocopherol in supplements. Biological activities of vitamin E are given in the older international units (IU) or alpha-tocopherol equivalents (alpha-TE). Because of the many forms of vitamin E in plants and available synthetically, the relative activities of each form is complex. Current evidence indicates that vitamin E from natural sources has approximately twice the bioactivity in humans that the all-rac (synthetic) vitamin does (Burton et al., 1998).

Based on the literature review, FNB used hemorrhagic (bleeding) effects for the criteria to set the UL. For adults nineteen years and older the UL is 1,000 mg (2,326 mol)/day of any form of supplementary alpha-tocopherol. There is no evidence of adverse effects from intake of vitamin E naturally occurring in foods.

The RDA for vitamin E is 15 mg/day of naturally occurring alpha-tocopherol for adults above nineteen years of age (FNB, 2000). During pregnancy 15 mg/day is recommended and 19 mg/day for lactation.

The tocopherol content of foods varies widely depending on storage, processing, and preparation. The best sources of vitamin E are the common vegetable oils and products made from them. However, most of the tocopherols may be removed in processing. Wheat germ and walnuts also have high amounts of tocopherols.

Vitamin K. Vitamin K was named after the first letter of the German word Koagulation. For many years blood coagulation was assumed to be the sole physiological role for vitamin K. We now know that vitamin K plays an essential role in the synthesis of proteins including prothrombin and the bone-forming protein, osteocalcin (Vermeer et. al., 1995).

Dietary vitamin K absorption is enhanced by dietary fat and is dependent on bile and pancreatic enzymes. The human gut contains large amount of bacterially produced vitamin K, but its contribution to the maintenance of vitamin K status has been difficult to assess (Suttie, 1995). The vitamin K produced by bacteria in the gut is less biologically active even though it is stored in the liver and present in blood. Current understanding supports the view that this vitamin K source may partially satisfy the human requirement but that the contribution is much less than previously thought.

The drug warfarin, widely prescribed as an anticoagulant, functions through inhibition of vitamin K. As a result, alterations in vitamin K intake can influence the efficacy of warfarin. The effective dose of warfarin varies from individual to individual, as does the dietary intake of vitamin K. The best solution appears to be to establish the necessary dose of warfarin and urge patients to maintain a constant intake of foods high in vitamin K in their diets. Only a small number of food items contribute substantially to the dietary vitamin K.

The recommended intake is based on an AI or adequate intake of 120

Collards, spinach, and salad greens are high in vitamin K. Broccoli, Brussels sprouts, cabbage, and Bib lettuce contain about two-thirds as much, and other green vegetables contain even less. Vitamin K is also found in plant oils and margarine, with soybean and canola oils having the highest amounts. U.S. food intake surveys indicate that spinach, collards, broccoli, and iceberg lettuce are the major contributors of vitamin K in the diet.