Vitamins Azita Hekmatdoost, MD, PhD. (1) organic compounds distinct from fats, carbohydrates, and proteins, (2) natural components of foods; usually present.

Vitamins

Azita Hekmatdoost, MD, PhD

(1) organic compounds distinct from fats, carbohydrates, and proteins,

(2) natural components of foods; usually present in minute amounts,

(3) not synthesized by the body in amounts adequate to meet normal physiologic needs,

(4) essential, also usually in minute amounts, for normal physiologic function (i.e., maintenance, growth, development, and reproduction),

(5) cause a specific deficiency syndrome by their absence or insufficienry.

Functions

(l) membrane stabilizers,

(2) hydrogen (H+) and electron donors

and acceptors,

(3) hormones,

(4) coenzymes.

Fat soluble vitamins (A, D, E, K)

Water soluble vitamins (B, C, Folate)

FAT SOLUBLE VITAMINS ( A,D,E,K)

SOLUBLE IN FAT INTEGRAL PARTS OF CELL MEMBRANES ABSORBED WITH LIPIDS (PANCREATIN JUICE, BILE )

EXCRETED (FECAL AND BILE ) STORED IN VARIOUS BODY TISSUES ( TOXCITY )

TRANSPORTED by Lymph

Vitamin A (Retinoids)

Three preformed compounds:

the alcohol (retinol),

the aldehyde (retinal or Retinaldehyde),

the acid (retinoic acid)

• Stored retinol is often esterified to a fatty

acid (usually palmitate) and is called retinyl-palmitate.

These retinyl esters are also usually found complexed with proteins in foods.

These active forms of vitamin A exist in only animal products.

Carotenoids

plants contain a group of compounds known

collectively as carotenoids, which can yield retinoids when metabolized in the body.

Although several hundred carotenoids exist in foods naturally as antioxidants, only a

few have significant vitamin A activity.

B-Carotene

The most important of these is B-carotene. The amount of vitamin A available from dietary

carotenoids depends on how well they are absorbed and how efficiently they are converted to retinol.

Absorption varies greatly (from 5% to 50%) and is affected by other dietary factors such as the digestibility of the proteins complexed with the carotenoids and the level and type of fat in the diet. (Fat-soluble vitamins need fat for proper absorption).

Dietary b-carotene is present at relatively high levels in carrots and yellow and green leafy vegetables; b-cryptoxanthin is found in oranges, and papaya, red belly pepper, watermellone.

In general, the all-trans form of each carotenoid is more abundant and has greater stability as compared with carotenoids containing one or more cis bonds.

Digestion

Absorption

Transport

By contrast to the retinoids, the carotenoids are transported by various plasma lipoproteins.

No specific cytosolic binding proteins or nuclear receptors have yet been found for carotenoids.

Retinoid-Binding Proteins (RBP)

(a)confer aqueous solubility to lipophilic retinoids,

(b)serve as chaperones that guide the transport and metabolism of specific retinoids,

(c) mediate certain retinoid functions.

RBP

Hepatic RBP synthesis depends on adequate protein. Therefore, blood levels of retinol can be affected by protein deficiency as well as by chronic vitamin A deficiency.

Thus children with protein-calorie malnutrition typically have low circulating retinol levels that may not respond to vitamin A supplementation unless the protein deficiency is also corrected.

The retinol-RBP-TTR complex delivers retinol to other tissues via cell surface receptors. Retinol is transferred from RBP to CRBP with the subsequent release of Apo RBP into binding protein and TTR to the blood

Apo RBP is eventually metabolized and excreted by the kidney. In addition to CRBP, cellular retinoic acid-binding proteins (CRABPs) bind retinoic acid in the cell and serve to control retinoic acid concentrations similar to the way CRBP controls retinol concentrations.

Metabolism

In addition to being esterified for storage, the transport form of retinol can also be oxidized into retinal and then into retinoic acid or conjugated into retinyl glucuronide or retinyl phosphate.

After retinoic acid is formed, it is converted to forms that are readily excreted. Chain-shortened and oxidized forms of vitamin A are excreted in the urine; intact forms are excreted in the bile and feces.

storage

vitamin A in the body is stored in the liver, although other tissues such as the adipose tissue, lungs, and kidneys also store retinyl esters in specialized cells called stellate cells.

This storage capacity buffers the effects of highly variable patterns of vitamin A intake and is particularly important during periods of low intake when a person is at risk for developing a deficiency.

Functions

• vision • normal cell differentiation• cell surface function (e.g., cell recognition)• growth and development• immune functions• reproduction.

visionlight

Gene expression

Glycoprotein synthesis

In a series of reactions, retinol forms retinyl-phosphomannose and then transfers the mannose to the glycoprotein. Glycoproteins are important for normal cell surface functions such as cell aggregation and cell recognition.

This role in glycoprotein synthesis may also account for the importance of vitamin A in cell

growth because it may increase glycoprotein synthesis for cell receptors that respond to growth factors.

Vitamin A activity

1 Retinol Activity Equivalent (RAE)

1 mcg retinol

12 mcg B carotene

3.33 IU vitamin A activity

5000IU=1500RAE=1500mcg retinol

Recommended Dietary Allowances for vitamin A

Age Children Men  Women

 Pregnancy

 Lactation

Ages 1-3 300 mcg or 1000 IU*

Ages 4-8 400 mcg or 1333 IU

Ages 9-13 600 mcg or 2000 IU

  x x x

Ages 14-18

  900 mcg or3000 IU

700 mcg or 2330 IU

750 mcg or 2500 IU

1200 mcg or 4000 IU

Ages 19 +

  900 mcg or3000 IU

700 mcg or 2330 IU

770 mcg or 2565 IU

1300 mcg or 4335 IU

Deficiency

Primary deficiencies of vitamin A result from inadequate intakes of preformed vitamin A or provitamin A carotenoids.

Secondary deficiencies can result from malabsorption caused by insufficient dietary fat, biliary or pancreatic insuffrciency, impaired transport from abetalipoproteinemia, liver disease, protein-energy malnutrition, or zinc deficiency.

DeficiencyNight blindness or nyctalopia

Defect in embryonic development

Impaired spermatogenesis

Spontaneous abortion

Anemia

Impaire immunocompetence

Reduction in T cells

Keratinization of mucus

Xerophthalmia

Follicular Hyperkeratosis

follicular-hyperkeratosis

Treatment

• Acute vitamin A deficiency is treated with large doses of vitamin A given orally.

• When the deficiency is part of concomitant protein-energy malnutrition, the malnutrition must be treated too.

• The symptoms relieve by the same order they appeared.

Toxicity

Persistent, large doses of vitamin A (more than 100 times the required amount) overcome the capacity of the liver to store the vitamin and can produce intoxication and eventually lead to liver disease.

• Acute hypervitaminosis A can be induced by single doses of retinol greater than 200 mg (200,000 RAEs) in adults or greater than 100 mg (100,000 RAIs) in children.

• Chronic hypervitaminosis A can result from chronic intakes (usually from misuse of supplements) greater than at least 10 times the AI (i.e., 4000 RAEs/day for an infant or 7000 RAEs/day for an adult).

• Dramatic stories in the literature describe reddening and exfoliation of the skin of Arctic explorers and fishermen who feasted on polar bear or halibut liver.

Toxicity• Serum vitamin of 75-2000 RAE/100cc• Cheilosis• Bone pain and fragility• Hydrocephalus and vomiting (infants and children)• Dry fissured skin• Brittle nails• Hair loss (alopecia)• Gingivitis• Anorexia, nausea, vomiting, headache• Irritability• Fatigue• Hepatomegaly and abnormal liver function• Ascites and portal hypertension

pregnant women are advised against exceeding 3000

RAEs/day of vitamin A.

Carotenoids Toxicity

Hypercarotenodermia can be differentiated

from jaundice in that the former affects only the skin, leaving the sclera (white) of the eye clear.

Hypercarotenodermia is reversible if excessive carotene intake is decreased.

However, high doses of B-carotene have been implicated as playing a role in some types of lung cancer especially in smokers!

Vitamin D

Calciferol

Vitamin D is known as the sunshine vitamin because modest exposure to sunlight is usually sufficient for most people to produce their own vitamin D using ultraviolet light and cholesterol in the skin. Because the vitamin can be produced in the body, has specific target tissues, and does not have to be supplied in the diet, it better meets the definition of a hormone rather than a vitamin and usually acts as a steroid hormone.

Absorption, Transport, Storage

Passive diffusion

D-binding protein (Transcalciferin)

50% efficiency

Little vitamin D is stored in the liver.

Metabolism

Predominant circulating form

calcitriol

Function

Gut

• Active transport of ca • Synthesis of calbindin protein• Opening voltage-gated ca channels• Acid phosphatase activity

Bone

• Osteoclast activity• Osteoclast numbers and differentiation

Kidney

Renal Tubular reabsorpsion of ca and p

Calcitriol plays roles that are not well understood in cell differentiation, proliferation, and growth in many tissues, including skin, muscles, pancreas, nerves, parathyroid gland, and immune system.

For example, as mentioned previously,

it stimulates differentiation of intestinal epithelial cells and osteoblasts; however, it seems to inhibit cell proliferation and growth.

Dietary Reference Intakes

vitamins D2 and D3 have equivalent biologic activities

One IU of vitamin D3 equals 0.025 mcg of vitamin D3,

and I mcg of vitamin D3 equals 40 IU of vitamin D3

AI: 10 mcg/day(400IU) for adults age 5 years and older and increases even more to 15 mcg/day( 600IU) for adults 71 years and older.

The UL for vitamin D for infants is 25 mcg/day (1000 IU) and for children and adults, 50 mcg/day (2000 IU).

Supplemental vitamin D is appropriate for individuals consistently shielded from sunlight, such as those who are housebound, live in northern latitudes or areas with high atmospheric pollution, wear clothing that completely covers the body, or work at night and stay indoors during the day.

Grant and Holick (2005) have noted that the current requirements are set based on protection against bone disease, but because of evidence of the protective effect of vitamin D against cancer, multiple sclerosis, and type I diabetes mellitus, these requirements may be revised upward (Hathcock et al., 2007).

Sources

• Herring, fresh, raw, 1 oz 6.6 mcg• Salmon, cooked. I oz 3.5mcg• Milk, cow's, fortified, I cup 2.5mcg• Sardinesc, anned,I oz 2.1mcg• Liver, chicken, cooked, 3 oz 1.1mcg• Shrimp, canned, I oz 0.7mcg• Egg yolk 0.6mcg• Milk, human, I cup 0-0.6mcg• Liver, calf, cooked, 3 oz 0.4mcg

DRI

• Infants and young children 5 mcg/day• Older children and adolescents 5 mcg/day• Adults 5-15 mcg/day• Pregnant 5mcg/day• Lactating 5mcg/day

Deficiency

Vitamin D deficiency manifests as rickets in children and growing animals and as osteomalacia in adults.

the high prevalence of inadequate vitamin D intake on a global basis, regardless of age or health status has been noted.

It is recommended that a level of 30 ng/ml be considered as the minimum level of serum 25-hydroxy vitamin D indicating deficiency.

Rickets

impaired mineralization of growing bones. It is the result not only of deprivation of vitamin D, but of deficiencies of calcium and phosphorus.

Rickets is characterized by structural abnormalities of the weight bearing bones (e.g., tibia, ribs, humerus, radius, ulna) and is associated with accompanying bone pain, muscular tenderness, and hypocalcemic tetany.

Soft, rachitic bones cannot withstand ordinary stresses and strains' resulting in bowed legs, “knock knees," beaded ribs (the rachitic rosary), pigeon breast, and frontal bossing of the skull.

Radiography reveals enlarged epiphyseal growth plates manifested as enlarged wrists and ankles resulting from their failure to mineralize and continue growth.

Patients have increased plasma and serum levels of alkaline phosphatase, which is released by the affected osteoblasts.

Rickets can also develop in children with chronic problems of lipid malabsorption and in those undergoing long-term anticonvulsant therapy (which reduces the circulating levels of 1,25-dihydroxyvitamin D3)

Osteomalacia

Osteomalacia develops in adults whose epiphyseal closures make that portion of the bone resistant to vitamin D deficiency. Therefore the disease involves generalized reductions in bone density and the presence of pseudofractures, especially of the spine, femur, and humerus. Patients experience muscular weakness and bone tenderness and have a greater risk of fractures, particularly of the wrist and pelvis.

Osteoporosis

Osteoporosis is associated with aging; it is thought to be a multifactorial disease involving impaired vitamin D metabolism and function associated with low or decreasing estrogen levels

Vit D3 and osteoporosis

Two large studies involving the chronic use of 1,25-dihydroxy vitamin D3 by women showed significant delay of the onset (and some reversal) of the signs and symptoms of osteoporosis. However, another study concluded that neither calcium nor vitamin D supplements alone are sufficient treatment for individuals with osteoporosis but are useful in conjunction with hormone replacement therapy in early postmenopausal women.

Toxicity• Excessive calcification of bone• Kidney stones• Metastatic calcification of soft tissues kidney, heart, lung,• and tympanic membrane)• Hypercalcemia• Headache• Weakness• Nausea and vomiting• Constipation• Polyuria• Polydipsia

Vitamin E

ضد) E ( TOCOPHEROL) ويتامين فاكتور يانازايي(

1922درسال شدند عقيم نر حيوانات

A,B,C,D باروري قدرت كاهش ماده RAT داشتند حيوانات

گياهي سالم روغن

گندم از : 1938 جوانه شد ا روغن فرمرل ستخراجشدن یعيتميايي شی

عملكرد : اساس بر نامگذاري درابتداTKOKOS PHERO = TO BRING FORTH

باروري قدرت

Vitamin E

• tocopherols • the related but much less biologically active

compounds, the tocotrienols

The vitamers of each series are named according to the position and number of methyl groups on their ring systems.

The most important of these is a-tocopherol in the natural D-isomer form.

توكوفرول صد 100 آلفا درتوكوفرول صد 40 بتا در

توكوفرول گ صد 30-10 اما در

توكوفرول درصد 1 دلتاتوكوترينول صد 30 الفا در

بيولوژيكي ليت فعا صد در بودن متفاوت علتمشتقات 8همه از تعداد كرومانول- 6تركيب از فقط و بوده

هاي گروه گيري قرار محل حلقه متيل و ساختمان BENZENدرهستند . متفاوت

ويتامرها بيولوژيكي فعاليت صد درتوكوفرول صد 100 آلفا در

توكوفرول صد 40 بتا درتوكوفرول گ صد 30-10 اما در

توكوفرول درصد 1 دلتاتوكوترينول صد 30 الفا در

Absorption

Vitamin E is absorbed in the upper small intestine by micelle-dependent diffusion, and, like the other fat-soluble vitamins, its use depends on the presence of dietary fat and adequate biliary and pancreatic function.

The esterified forms of vitamin E found in supplements (which are more stable) can only be absorbed after hydrolysis by esterases at the duodenal mucosa.

The absorption of vitamin E is highly variable, and efficiencies range from 20% to 70%.

Transport

Absorbed vitamin E is incorporated in to chylomicrons and transported into the general circulation via lymph.

Vitamin E delivered to the liver is incorporated into VLDLs using a transport protein specific for vitamin E.

In the plasma tocopherol is also partitioned in to LDLs and high-density lipoproteins HDLs, where it may protect the lipoproteins from oxidation.

Cellular uptake• Receptor-mediated process ( in which LDLs deliver the

vitamin into the cell), or as a process mediated by LP as vitamin E is released from chylomicrons and LDLs by the action of LP.

• Within the cell, intracellular transport of the tocopherol requires an intracellular tocopherol-binding protein (TBP).

• In most nonadipose cells vitamin E is located almost exclusively in membranes from which it can be mobilized;

• In adipose tissues it is partitioned primarily in the bulk lipid phase from which it is not readily mobilized.

متابوليسمE ويتامين

( Eويتامين ها ) ويتامر از انواعغذا

از . روده جذب قدرتدرصد 70-20غذا

فعال غير انتشار بصورت مقداري جذباز مستقيم

وريد *طريقجذب باب

لنف

به متصل

هاي ليپوپروتئين ,LDL, HDL.,V LD Lالسما(پها ار ( يتروسيت

چربي( بافتها نسج )90( كبد، صد اندامهاي در ، قلب عضالت، كليه فوق مثل، توليد

دف عطريق كمي مدفوع، صفرااز مقدار و

در متابوليتها ) 1ادرار ( از و صد در پوست

محل بيشترين

در ويتامين تراكمغشائ

ها سلولهاوارگانلجائيكه ( است

زاد آديكالهاي رااست ) زياد

خون

Turn Over

erythrocytes, liver, and spleen

heart, muscle, and spinal cord

brain

Metabolism

It is oxidized into the biologically inactive tocopheryl quinone, which can be reduced to tocopheryl hydroquinone.

Glucuronic acid conjugates of the hydroquinone are secreted in the bile, making excretion in the feces the major route of elimination of the vitamin.

With usual intakes of vitamin E, a very small portion is excreted in the urine as water-soluble, side-chain metabolites (tocopheronic acid and tocopheronolactone).

Functions

The most important lipid-soluble antioxidant in the cell

vitamin E is now understood to be an important component of the cellular antioxidant defense system, which involves other enzymes (e.g., superoxide dismutases [SODs], glutathione peroxidases [GSHPxs], glutathione reductase [GR], catalase, thioredoxin reductase [TR]) and nonenzymatic factors (e.g., glutathione, uric acid), many of which depend on other essential nutrients. For example, the expressions of the GSH-Px and TR depend on adequate selenium status; the expressions of the SODs depend on adequate copper, zinc, and manganese statuses; and the activity of GR depends on adequate riboflavin status. Therefore the antioxidant function of vitamin E can be affected by the levels of many other nutrients.

This antioxidant function suggests that vitamin E and related nutrients may collectively be important in protecting the body against and treating conditions related to oxidative stress such as aging, arthritis, cancer, cardiovascular disease, cataracts, diabetes, infection, and some cases of Alzheimer's disease.

Recent evidence has indicated that vitamin E also functions in regulation of cell signaling processes and gene expression, particularly of drug metabolizing enzyme.

Dietary Reference Intakes

Vitamin E is quantified in terms of a-tocopherol quivalents (a-TEs)

1 mg of R,R,R-a-tocopherol is defined as I a-TE, and 1 mg of the synthetic all-rac-a-tocopherol is defined as 0.5 a-TE.

An IU of vitamin E is equal to 0.67 mg of RRR-a-tocopherol and 1 mg of all-rac-a-tocopherol.

The need for vitamin E depends in part on the amount of PUFAs consumed

For Americans typical intakes are about 0.4 mg a-TE/mg of PUFA

Sources

Because tocopherols and tocotrienols are synthesized only by plants, plant products-especially the oils-are the best sources of them, with α- and γ-tocopherols being the predominant forms in most common foods.

Sources• Raisin bran, 1 cup 13.50 mg• Almonds, I oz 7.33mg• Sunflower oil, I tbsp 5.59mg• Mixed nuts I oz 3.10mg• Canola oil, I tbsp 2.39mg• Asparagus, I cup 2.16mg• Peanut oil, I tbsp 2.12mg• Corn oil, 1 tbsp 1.94mg• Olive oil, 1 tbsp 1.94mg• Apricots, canned, sweetened, ½ cup 1.55mg• Margarine, I tbsp 1.27mg

DRI

• Infants 4-5mg/d• Young children 6-7mg/d• Older children and adolescents 11-15mg/d• Adults 15mg/d• Pregnant 15mg/d• Lactating 19mg/d

stability

The free alcohol forms of vitamin E (e.g., tocopherols) are fairly stable but can be destroyed by oxidation.

Vitamin E esters (e.g., tocopheryl acetate) are very stable even in oxidizing conditions.

Because the vitamers E are insoluble in water, they are not lost by cooking in water but can be destroyed by deep-fat frying.

Deficiency

neuromuscular, vascular and reproductive

systems

In the neuromuscular system, vitamin E deficiency, which may take 5 to 10 years to develop, manifests clinically as loss of deep tendon reflexes impaired vibratory and position sensation, changes in balance and coordination, muscle weakness, and visual disturbance. Symptoms in humans are uncommon and have occurred only in those with lipid malabsorption (e.g., biliary atresia, exocrine pancreatic insufficiency) or lipid transport abnormalities (e.g., abetalipoproteinemia)

Toxicity

Vitamin E is one of the least toxic of the vitamins. Humans and animals seem to be able to tolerate relatively high intakes-at least 100 times the nutritional requirement.

The UL for vitamin E in adults is 1000 mg/day.

However, in very high dose, vitamin E can decrease the body's ability to use other fat-soluble vitamins.

Vitamin K

In addition to playing an essential role in blood clotting, scientists now know that vitamin K plays a role in bone formation and regulation of multiple enzyme systems

Naturally occurring forms of vitamin K are the phylloquinones (the vitamin K1 series), which are synthesized by green plants, and the menaquinones (the vitamin K2 series), which are synthesized by bacteria. Both of these natural forms have a 2-methyl1-1,4-napthoquinone ring and alkylated side chains.

The synthetic compound menadione (vitamin K3) has no side chain but can be alkylated in the liver to produce menaquinones. Menadione is twice as potent biologically as the naturally occurring forms vitamins K1 and K2.

Absorption

The phylloquinones (K1) are absorbed by an energy-dependent process in the small intestine.

However, the menaquinones (K2) and menadione (K3) are absorbed in the small intestine and colon by passive diffusion. Like the other fat soluble vitamins, absorption depends on a minimum amount of dietary fat and on bile salts and pancreatic juices.

Transport

Absorbed vitamers K are incorporated into chylomicrons in the lymph and taken to the liver where they are incorporated into VLDLs and subsequently delivered to the peripheral tissues by LDLs.

storage

Vitamin K is found in low concentrations in many tissues, where it is localized in cellular membranes.

Because of the metabolism of the vitamin, tissues show mixtures of vitamers K even when a single form is consumed. Most tissues contain phylloquinones and menaquinones

Metabolism

Phylloquinones can be converted to menaquinones by successive bacterial dealkylation and realkylation before absorption.

Side-chain shortening and oxidation produce metabolites that are excreted in the feces via the bile, frequently as glucuronic acid conjugates, and catabolize phylloquinones and menaquinones.

Menadione is metabolized more rapidly; it is excreted primarily in the urine as a phosphate, sulfate, or glucuronide derivative.

FunctionsVitamin K is essential for the posttranslational carboxylation

of glutamic acid residues in proteins to form carboxyglutamate. the residues bind calcium. In the process of generating residues, vitamin K is oxidized (i.e., donates a hydrogen) to an epoxide. It is restored to its hydroquinone form by the enzyme expoxide reductase. This process is known as the vitamin K cycle. The vitamin K cycle can be disrupted by inhibitors of the regeneration of reduced vitamin K, including coumarin-type drugs such as warfarin and dicumarol (which is the basis for their anticoagulant activities).

Four plasma-clotting GLA proteins have been identified, including thrombin, which is necessary for the conversion of fibrinogen to fibrin in blood clotting.

at least three proteins found in calcified tissues (including osteocalcin).

at least one protein found in calcified atherosclerotic tissue (atherocalcin).

Vit k may play a role in the regulation of multiple enzymes involved in sphingolipid metabolism in the brain as well as other enzyme systems.

The mechanisms of action may be related to a vitamin K role in carboxylation of glutamic acid residues, but other mechanisms may be involved.

DRI

The DRIs for vitamin K are given as AIs, and no UL has been determined.

Sources

• Spinach, frozen, cooked I cup 1027mcg• Broccoli, cooked, I cup 220mcg• Asparagus, cooked, 1 cup 144mcg• Cabbage, cooked, I cup 73mcg• Green beans, raw, I cup 47mcg• Carrot, raw, 1 cup 14mcg• Lettuce, iceberg, I cup 13mcg

DRIs

Infants 2.0-2.5 mcg/day

Young children 30-55 mcg/day

adolescents 60-75 mcg/day

Adults 90-120mcg/day

Pregnant 75-90mcg/day

Lactating 75-90mcg/day

stability

Vitamin K is fairly stable; it is not destroyed by ordinary cooking methods, nor is it lost in cooking water.

However, it is sensitive to light and alkalis.

Deficiency

hemorrhage, which in severe cases can cause fatal anemia.

Vitamin K deficiencies are rare among humans but have been associated with lipid malabsorption, destruction of intestinal flora in those receiving chronic antibiotic therapy, and liver disease.

Newborn infants, particularly those who are premature or exclusively breast-fed, are susceptible to hypoprothrombinemia during the first few days of life as the result of poor placental transfer of vitamin K and failure to establish a vitamin K-producing intestinal microflora.

Toxicity

Neither the phylloquinones nor the menaquinones have shown any adverse effects by any route of administration.

However, menadione can be toxic. excessive doses have produced hemolytic anemia in rats and severe jaundice in infants.