Water soluble vitamins

Thiamin, riboflavin, niacin, vitamin B6, pantothenic acid,

biotin, folic acid, vitamin B12, and vitamin C

Thiamin

Thiamin plays essential roles in carbohydrate metabolism and neural function.

The vitamin must be activated by phosphorylation into thiamin triphosphate (TTP), or cocarboxylase, which serves as a coenzyme in energy metabolism and the synthesis of pentoses.

Absorption

Thiamin is absorbed from the proximal small intestine by active transport (in low doses) and passive diffusion (in high doses i.e >5 mg/day).

Active transport is inhibited by alcohol consumption, which interferes with transport of the vitamin, and by Folate deficiency, which interferes with the replication of enterocytes.

Transport, Storage

The activated TPP is carried to the liver by the portal circulation.

Most (approximately 90%) of circulating thiamin is carriedas TPP by erythrocytes, although small amounts existprimarily as free thiamin and thiamin monophosphate(TMP) bound chiefly to albumin. Uptake by cells of peripheral tissues occurs by passive

diffusion and active transport. Tissues retain thiamin as phosphate esters, most of whichare bound to proteins. Tissue levels of thiamin vary, with noAppreciable storage of the vitamin.

Metabolism

Thiamin is phosphorylated in many tissues by specific kinases in to the diphosphate and triphosphate esters. Each of these esters can be catabolized by a phosphorylase to yield TMP.

Small amounts of some 20 other excretory metabolites are also produced and excreted in the urine.

Function

The functional form of thiamin is TPP, which is a coenzyme for several dehydrogenase enzyrne complexes essential in the metabolism of pyruvate and other a-keto acids. Thiamin is essential for the oxidative decarboxylation of a-ketoacids, including the oxidative conversion of pyruvate to acetyl coenzyme A (acetyl CoA), which enters the tricarboxylic acid (TCA), or Krebs, cycle to generate energy. It is also required for the conversion of a-ketoglutarate and the 2-ketocarboxylates derived from the amino acids methionine, threonine, leucine, isoleucine, and valine. TPP also serves as the coenzyme for transketolase, which catalyzes 2-carbon fragment exchange reactions in the oxidation of glucose by the hexose monophosphate shunt.

DRI (0.2-1.4 mg/day, depending on age and gender)

• Thiamin is expressed quantitatively in terms of its mass, usually in milligrams. The DRIs for thiamin include AIs for infants and the newly defined RDA.

• In general, the RDA are based on levels of energy intake because of the direct role of thiamin in energy metabolism, whereas the AIs for infants are based on the thiamin levels typically found in human milk.

Sources

Thiamin is widely distributed in many foods, most of which contain only low concentrations.

The richest sources are yeasts and liver; however, cereal grains comprise the most important source of the vitamin in most human diets. Although whole grains are typically rich in thiamin, most of it is removed during milling and refining.

Plant foods contain thiamin predominantly in the free form, whereas almost all of the thiamin in animal products exists as the more efficiently used TPP.

Stability

Thiamin can be destroyed by heat, oxidation, and ionizing radiation, but it is stable when frozen.

Cooking losses of the vitamin tend to vary widely, depending on cooking time, pH, temperature, quantity of water used and discarded, and whether the water is chlorinated.

Thiamin can be destroyed by several sulfites added in processing; by thiamin-degrading enzymes (thiaminases) in raw fish, shellfish, and some bacteria; and by certain heat-stable factors in several plants (e.g., ferns, tea, betel nuts).

status

Erythrocyte transketolase activity,

Measuring blood or serum levels of thiamin, Measuring urinary thiamin excretion levels

Toxicity

Little information exists about the toxic potential of thiamin, although massive doses (i.e., 1000 times greater than nutritional needs) of the commercial form, thiamin hydrochloride, have suppressed the respiratory center, causing death.

Parenteral doses of thiamin at 100 times the recommended levels have produced headache, convulsions, muscular weakness, cardiac arrhythmia, and allergic reactions.

Riboflavin

Vitamin B2

Riboflavin is essential for the metabolism of carbohydrates, amino acids, and lipids and supports antioxidant protection. It carries out these functions as the coenzyme flavin adenine dinucleotide ( FAD) and flavin adenine mononucleotide ( FMN).

Because of its fundamental roles in metabolism, riboflavin deficiencies are first evident in tissues that have rapid cellular turn over such as the skin and epithelia.

Absorption

Riboflavin is absorbed in the free form by a carrier-mediated process in the proximal small intestine. Because most foods contain the vitamin in its coenzyme forms, FMN and FAD, absorption occurs only after the hydrolytic cleavage of free riboflavin from its various flavoprotein complexes by various phosphatases.

Riboflavin absorption is a carrier-mediated process that requires ATP.

Transport

Riboflavin is transported in the plasma as free riboflavin and FMN, both of which are mainly bound to plasma proteins, primarily albumin.

A specific riboflavin-binding protein (RfBP) has also been identified and is thought to function in the transplacental movement of the vitamin.

Riboflavin is transported in its free form into cells by a carrier-mediated process. It is then converted to FMN or FAD;

because both are primarily protein bound, it prevents their diffusion out of the cell and makes them resistant to catabolism.

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Storage

Although small amounts of the vitamin are found in the liver and kidney, it is not stored in any useful amount and therefore must be supplied in the diet regularly

Metabolism

Riboflavin is converted to its coenzyme forms by ATP-dependent phosphorylation to yield riboflavin-5-phosphate, or FMN, by the enzyme flavokinase.

Most FMN is then converted to FAD by FAD-pyrophosphorylase.

Both steps are regulated by the thyroid hormones, adrenocorticotropic hormone (ACTH) and aldosterone.

Excretion

Most excess riboflavin is excreted in the urine.

However, free riboflavin can be glycosylated in the liver, and the glycosylated metabolite excreted.

Riboflavin may also have a direct metabolic function. It can also be catabolized by oxidation, demethylation, and hydroxylation of its ring system to yield products that are excreted in the urine with free riboflavin.

Function

The flavin coenzymes FMN and FAD accept pairs of hydrogen atoms forming FMNH2 or FADH2. As such they can participate in either one- or two-electron redox reactions.

FMN and FAD serve as prosthetic groups of several flavoprotein enzymes that catalyze oxidation-reduction reactions in the cells and function as hydrogen carriers in the mitochondrial electron transport system.

FMN and FAD are also coenzymes of dehydrogenases (such as in the TCA cycle, that catalyze the initial oxidations of fatty acids and several intermediates in glucose metabolism.

FMN is also required for the conversion of pyridoxine (vitamin B6) to its functional form, pyridoxal phosphate.

FAD is also required for the biosynthesis of the vitamin niacin from the amino acid tryptophan.

In other cellular roles, mechanisms dependent on riboflavin and nicotinamide adenine dinucleotide phosphate NADPH seem to combat oxidative damage to the cell.

A cataract study suggests that nutritional supplements (including riboflavin) help to improve cataracts.

Powers (2003) reviewed the implications of riboflavin in human health and concluded that it was implicated in a number of disease states.

DRI(0.3-1.6m g/day depending on age and gender)

The DRIs for riboflavin include AIs for infants and newly defined RDA. In general, the RDAs are based on the amount required to maintain normal tissue reserves based on urinary excretion, red blood cell riboflavin contents, and erythrocyte glutathione reductase activity. Riboflavin requirements are higher during pregnancy and lactation so that they can meet the needs of increased tissue synthesis and the losses of riboflavin secreted in breast milk.

Sources

Riboflavin, measured in milligrams in foods, is widely distributed in foods in a form bound to proteins as FMN and FAD.

Rapidly growing, green leafy vegetables are rich in the vitamin; however, meats and dairy products are the most important contributors too.

More than half of the vitamin is lost when flour is milled;

stability

Riboflavin is stable when heated but can be readily destroyed by alkali and exposure to ultraviolet irradiation.

Very little of the vitamin is destroyed during the cooking and processing of foods; however because of its sensitivity to alkali, the practice of adding baking soda to soften dried peas or beans destroys much of their riboflavin content.

Wax-lined paper containers protect milk against riboflavin loss from exposure to sunlight.

Deficiency

Who are susceptible?

Phototherapy for infants with hyperbilirubinemia often leads to riboflavin deficiency (by photodestruction of the vitamin) if the therapy does not also include riboflavin supplementation.

Otherwise riboflavin deficiencies usually occur in combination with deficiencies of other water-soluble vitamins such as thiamin and niacin in those who are malnourished.

Status

Riboflavin status is measured by assessment of the activity of erythrocyte glutathione reductase.

This enzyme requires FAD and converts oxidized glutathione to reduced glutathione.

Toxicity

Riboflavin is not known to be toxic;

high oral doses are considered essentially nontoxic.

However, high doses are not beneficial.

Niacin

Vitamin B3

Niacin is the generic term for nicotinamide and nicotinic acid.

It functions as a component of the pyridine nucleotide coenzymes nicotinamide adenine dinucleotide NADP and NADPH, which are essential in all cells for energy production and metabolism.

Biosynthesis

Niacin can be synthesized from the essential amino acid tryptophan. Even though this process is not efficient, dietary tryptophan intake is important to the overall niacin status of the body.

Bioavailability

Niacin in many foods, particularly those from animal sources, consists mostly of the coenzyme forms NAD and NADPH, each of which must be digested to release the absorbed forms, nicotinamide (Nam) and nicotinic acid (NA).

Many foods derived from plants, particularly grains, contain niacin in covalently bound complexes with small peptides and carbohydrates that are not released during digestion. These forms, collectively referred to as niacytin, are not biologically available but can become bioavailable through alkaline hydrolysis.

Thus the Central American tradition of soaking maize in lime water before preparing tortillas effectively increases the bioavailability of niacin in what otherwise would be considered a low niacin food.

Absorption, Transport, Storage

Nam and NA are absorbed in the stomach and small intestine by carrier-mediated facilitated diffusion.

• Both are transported in the plasma in free solution, and each is taken up by most tissues through passive diffusion, although some tissues (e.g., erythrocytes, kidney, brain) also have a transport system for NA.

• Niacin is retained in tissues by being converted primarily to NAD but is also converted to NADPH.

Metabolism

The de novo synthesis of NAD and NADPH occurs from quinolinic acid, a metabolite of the indispensable amino acid tryptophan.

The conversion of tryptophan to niacin depends on such factors as the amount of tryptophan and niacin ingested and pyridoxine status; therefore the body must have adequate levels of riboflavin and to a lesser extent vitamin B6.

Humans are moderately efficient at this conversion; and 60 mg of tryptophan is considered equal to 1 mg of niacin.

NAD and NADPH can be produced from NA and Nam obtained from the diet.

Nam is deaminated to yield NA.Then two ribose phosphates are attached to the

nitrogen in the pyridine ring. Next, adenosine is attached to the ribose. Finally, an amino group is added to the acid group, forming an amide, yielding NAD.

NAD can be phosphorylated in the hexose monophosphate shunt to yield NADPH.

Function

The coenzyme NAD and NADPH are the most central electron carriers of cells, playing essential roles as cosubstrates of more than 200 enzymes involved in the metabolism of carbohydrates, fatty acids, and amino acids.

In general, NAD and NADPH facilitate hydrogen transport by two-electron transfers, which use the hydride ion (H+) as the carrier, but play very different roles in metabolism. The NAD-dependent reactions are involved in intracellular respiration (e.g., betaoxidation, TCA cycle function.

NADPH, on the other hand, is important for biosynthetic (e.g., fatty acid, sterol) pathways. Because of its fundamental role in metabolism, niacin may play an important role in mechanisms for DNA repair and gene stability and, therefore influence cancer risk.

DRI (2-18 mg/day)

Niacin is expressed in total milligrams of niacin or niacin equivalents NEs), which are calculated from the preformed niacin content plus l/60 of the tryptophan content.

Requirements are directly related to energy intake because of niacin's role in energy-producing reactions in metabolism. They are expressed as NEs from preformed niacin and tryptophan.

Sources

Significant amounts of niacin are found in many foods; lean meats, poultry, fish, peanuts, and yeasts are particularly rich sources.

Niacin exist predominantly as protein-bound NA in plant tissues and as Nam, NAD, and NADPH in animal tissues.

Milk and eggs contain small amounts of niacin, but they are excellent sources of tryptophan, giving them significant niacin equivalent contents.

Deficiency

Niacin deficiency symptoms initially include muscular weakness, anorexia, indigestion, and skin eruptions.

Severe deficiency of niacin leads to pellagra, which is characterized by dermatitis, dementia, and diarrhea ("the 3 Ds"); tremors; and sore tongue (or "beef tongue").

• The dermatologic changes are usually the most prominent. Skin that has been exposed to the sun develops cracked, pigmented, scaly dermatitis. Central nervous system involvement symptoms include confusion, disorientation, and neuritis. Digestive abnormalities cause irritation and inflammation of the mucous membranes of the mouth and the GI tract. Untreated pellagra can cause death (which is often referred to as "the fourth D").

Patients with pellagra can also show clinical signs of riboflavin deficiency, highlighting the metabolic interrelationships of these vitamins. Patients with pellagra are likely to have very poor diets that not only provide very little niacin but also lack protein and other nutrients.

Status

measurement of the urinary excretion of the methylated metabolites

methylnicotinomide

and methylpyridone carboxamide

Toxicity

In general, niacin toxicity is low. However, high doses of I to 2 g of NA three times per day-dosages that have been used in attempts to lower blood cholesterol concentrarions can have side effects.

The main side effect is a histamine release that causes flushing and may be harmful to those with asthma or peptic ulcer disease. (Nam does not have this effect.) High doses of niacin can also be toxic to the liver and risks are greater with time-released forms of the vitamin. Megavitamin use should be monitored carefully because high doses act as drugs, not nutritional supplements.

Pantothenic acid

Vitamin B5

Pantothenic acid is widely distributed in foods; cases of clinical deficiency are rare. The vitamin has critical roles in metabolism. It is an integral part of CoA, which is essential in energy production from the macronutrients, and acyl-carrier protein (ACP), which is used in synthesis reaction.

Absorption, Transport, Storage

Pantothenic acid exists in foods mostly as CoA and ACP.

Therefore absorption requires hydrolysis to phosphopantetheine and then conversion to pantothenic acid.

Pantothenic acid is absorbed by passive diffusion and active transport in the jejunum.

It is then transported in the free acid form in solution in the plasma and taken up by diffusion into erythrocytes, which carry most of the vitamin in the blood.

is taken up by cells of peripheral tissues by a sodium-dependent active transport process in some tissues and by facilitated diffusion in others.

Within the cell the vitamin is converted to CoA, which is its predominant form in most tissues, particularly the liver, adrenals, kidney,brain, heart, and testes.

Metabolism

All tissues are capable of synthesizing CoA from pantothenic acid.

This multienzyme process takes place in four steps. First pantothenica cid is phosphorylated to yield 4'-phosphopantothenic acid. Then it is condensed with cysteine to yield 4'-phosphopantothenoylcystein. Next phosphopantothenoylcysteine is decarboxylated to yield 4'-phosphopantetheine, which is finally converted to CoA.

ACP contains 4 '-phosphopantetheine that is transferred from CoA to bind to the Apo acetyl carrier protein forming ACP.

Excretion

The vitamin is excreted mainly in the urine as free pantothenic acid but also as 4 '-phosphopantothenate.

An appreciable amount (some 15% of the daily intake) is oxidized completely and excreted through the lungs as carbon dioxide.

FunctionsCoA and ACP function metabolically as carriers of

acyl groups. CoA is critical in the formation of acetyl CoA, which

condenses with oxaloacetate and enters the TCA cycle to release energy.

it is also the compound in the first steps of the synthesis of fatty acids or cholesterol or in the acetylation of alcohols,amines, and amino acids.

It also activates fatty acids before their incorporation into triglycerides and acts as an acyl donor for proteins.

ACP is a component of the multienzyme complex fatty acid synthetase, which is necessary for fatty acids synthesis.

DRI

1.7-7 mg/day, depending on age and gender

Sources

Pantothenic acid is present in all plant and animal tissues.

The most important sources in mixed diets are meats (particularly liver and heart); but mushrooms, avocados, broccoli, egg yolks, yeast, skim milk, and sweet potatoes are also good sources of the vitamin.

Stability

Pantothenic acid is fairly stable during ordinary cooking and storage, although the vitamin can be lost in frozen meats during thawing.

Because it is localized in the outer layers of grains, about half of the vitamin is lost in the milling of flour.

Deficiency

Pantothenic acid deficiency results in impairments in lipid synthesis and energy production. Because the vitamin is so widely distributed in foods, deficiencies are rare.

Pantothenic acid deficiency has been observed among severely malnourished humans. Symptoms include paresthesia in the toes and soles of the feet, burning sensations in the feet, depression, fatigue, insomnia, and weakness.

Toxicity

The toxicity of pantothenic acid is negligible. no adverse effects after ingestion of large doses of the vitamin have been reported in any species.

Massive doses( e.g., l0 g/day) administered to humans have produced only mild intestinal distress and diarrhea.