Top 4 Types of Fat-Soluble Vitamins

The following points highlight the top four types of fat-soluble vitamins. The types are: 1. Vitamin 2. Vitamin D 3. Vitamin E (Tocopherols) 4. Vitamin K.

Fat-Soluble Vitamins: Type # 1. Vitamin A:

Chemistry:

a. Vitamin A₁ aldehyde (retinal) is derived from β-carotene by cleavage at the mid­point of polyene chain connecting the β-ionone rings.

b. The biosynthesis of vitamin A is likely a di-oxygenase reaction in which molecular oxygen reacts with the two central carbon atoms of β-carotene followed by the cleav­age of the central double bond of β-carotene to produce 2 moles of vitamin A₁ al­dehyde (retinal). The aldehyde is then re­duced by retinene reductase depending on NADH to yield vitamin A alcohol (retinol). The reaction is shown below.

c. The potency of vitamin A₂ (3-dehydroretinol) is 40% that of vitamin A₁ and it dif­fers from A₁ structurally by the presence of an additional double bond between carbon 3 and 4 of the β-ionone ring.

d. Retinol exists, as an ester with higher fatty acids, in the liver, kidney, lung and fat depots.

e. The plant pigments, carotenes or carotenoids, synthesized by all plants except parasites and saprophytes are said to be pro-vitamin A. In the human diet, vitamin A is derived from the preformed vitamin (retinol) and the pro-vitamin carotenoids, β-carotene has the highest vitamin A ac­tivity and is the most abundant in human diets.

β-carotene is an antioxidant and effective at low oxygen concentration but vitamin E which is effective at higher oxygen con­centration. The antioxidant property of these two lipid-soluble vitamins may well account for their possible anticancer ac­tivity.

f. Carotenes are only active as a vitamin pre­cursor when it is converted to retinol. This conversion takes place in the intestinal wall in rats, pigs, goats, rabbits, sheep and chickens although liver also participates; but in man, it takes place in the liver only.

Retinol is transported to the blood as retinol-binding protein (retinol attached to α₁-globulin). Whereas, the carotenes are transported with the lipoproteins.

g. A small fraction of retinal is oxidized to retinoic acid:

Absorption:

a. The dietary intake of vitamin A in the form of vitamin A esters are hydrolysed in the lumen of the intestine by the enzyme li­pase in presence of bile salts and fats. To­copherol prevents the oxidative destruc­tion of the vitamin.

b. The vitamin and the carotene are taken up by the intestinal mucosa where the vita­min is esterified and carotene is first con­verted to retinal and then to retinol by reti­nol dehydrogenase which is then esteri­fied mostly with palmitic acid.

c. These esters—together with some un­changed retinal and carotenoids which are not precursors of vitamin A—are absorbed and enter the intestinal lymphatic’s and eventually the circulation, in chylomi­crons.

d. In the blood, the vitamin esters are at­tached to β-lipoproteins and are then taken up by the liver (Kupffer ceils) which con­tains almost all the body store.

e. The vitamin is then released as retinol- binding protein for use elsewhere, e.g., in the retinal rods.

f. Since retinol dehydrogenase is present in the liver serum, retinal can be converted to retinol.

g. The impaired absorption of dietary fat (e.g., obstructive jaundice, chronic pancreati­tis) leads to the impaired absorption of vi­tamin A in the absence of pancreatic en­zymes (impaired hydrolysis of vitamin A esters) and in celiac disease or other con­ditions.

h. In subjects with liver damage, the capac­ity for storage and formation of vitamin A is impaired and its concentration in the blood is also decreased.

Storage:

a. 95 per cent of vitamin A in the form of esters is stored in the liver. The hepatic storage increases with age. The quantity stored in the liver varies in different spe­cies but the storage capacity in man is rela­tively large.

b. A small amount of it is also present in other tissues, e.g., lactating breast, adrenals, lung, intestine.

Sources:

a. Plant Sources:

All pigmented (particularly yellow) vegetables and fruits (e.g., sweet potatoes, carrots, pumpkins, papayas, to­matoes, apricots and peaches) and the leafy green vegetables which supply pro­-vitamin A (carotene) in the diet. Cereals also contain carotene.

b. Animal Sources:

Preformed vitamin A (retinol) is supplied by foods of animal origin; they are liver, milk, butter, eggs, kidney, the fat of muscle, meats, and fish liver oil which is very rich in the vitamin.

Daily Requirements:

Normal Concentration in Blood:

0.15 to 0.60 µg/dL

Physiological Functions:

a. Role in Vision:

Wald and Morton gave more emphasis on the specific role of vi­tamin A in physiological mechanism of vision.

Retina contains two types of receptor cells:

(a) Cones—which are specialized for colour and detail vision in bright light.

(b) Rods—which are specialized for visual activity in dim light (night vi­sion).

Photolysis of rhodopsin closes sodium channels in rod membrane through either a release of Ca⁺⁺ into cytosol or a hydro- lytic fall in the cytosolic cyclic GMP level. This results in lowering the permeability (membrane) to Na causing hyperpolarization of rod membrane and changes its conformation through 5° and initiates the visual signal from the rod.

The basic fac­tors stimulating the rods are:

(i) Cis-trans isomerization

(ii) Conformational changes in the rho­dopsin due to cGMP.

Visual activity of rod cells is dependent on their content of photosensitive pig­ment called “rhodopsin” which is a con­jugated protein. It contains opsin as its apoprotein and retinene as its prosthetic group. Retinene or retinal present in rhodopsin is 11-cis retinal. The aldehyde group of 11-cis retinal is bound to -NH₂ group of lysine of opsin. Rhodopsin has a light absorbing property due to polyene group of 11 -cis retinal.

When the light falls on rhodopsin it splits into opsin and all trans retinal in a series of event like bathorhodopsin → lumirho- dopsin → metarhodopsin 1 → metarho­dopsin II.

All trans retinal is inactive in synthesis of rhodopsin, it has to be con­verted to 11-cis retinal in following ways:

(a) All trans retinal may be isomerized to its 11-cis isomer in presence of blue light but in the eye this isomerization is not significant.

(b) The all trans retinol from blood can be converted to all trans retinal by retinene reductase by making use of NAD⁺ and all trans retinal then can be isomerized to its cis-isomer.

(c) All trans retinol from blood can be first isomerized to 11-cis-retinol. All 11-cis-retinol then can be converted to 11 -cis retinal by retinol dehydro­genase in presence of coenzyme NADP⁺.

Thus the visual process involves continual removal of the active retinol from blood into retina.

b. Vitamin A helps in maintaining the integ­rity of epithelial tissues as epithelial lay­ers of skin, respiratory mucosa, oesopha­gus and genitourinary tract.

c. It helps in the preservation of the struc­tural integrity and the normal permeabil­ity of the cell membrane as well as the membrane of the sub-cellular organelles such as mitochondria, lysosome etc.

d. It accelerates the normal formation of bones and teeth.

e. Retinoic acid is found to be more involved in glycoprotein synthesis probably form­ing its phosphate which acts as carrier of oligosaccharides in glycoprotein synthe­sis. Thus, vitamin A is involved in the development and maintenance of ground substances in collagen tissues.

f. Vitamin A is involved in the synthesis of chondroitin sulphate.

g. When retinol is taken up into cellular reti­nol binding protein, it is transported around the cell and binds to nuclear pro­tein and involves in gene expression. Thus, vitamin A behaves similar to steroid hor­mone.

Retinol, Retinal & Retinoic acid:

a. Retinol and Retinal are interconverted in the presence of NAD or NADP-requiring dehydrogenases or reductases present in many tissues.

b. Retinoic acid once formed from retinal cannot be converted back to retinal or to retinol.

c. Retinoic acid can support growth and dif­ferentiation but cannot replace retinal in its role in vision or retinol in its support of the reproductive system.

Retinol acts as a steroid hormone:

Retinol being taken up into CRBP is trans­ported around the cell and binds to nuclear pro­teins where it is involved in the control of the ex­pression of certain genes. Thus, vitamin A behaves similarly to steroid hormones.

Retinal is a component of Rhodopsin:

Rhodopsin occurring in the rod cells of the retina are responsible for vision in poor light. II- Cisretinal, an isomer of all-trans-retinal, is specially bound to the visual protein opsin to form rhodopsin. Rhodopsin on exposure to light dissociates into all-trans-retinal and opsin. This reaction is induced by a calcium ion channel in the membrane of the rod cell.

Retinoic acid participates in Glycoprotein synthesis:

Retinoyl phosphate functions as a carrier of oligosaccharides across the lipid layer of the cell by way of an enzymatic trans cis-isomerization. Thus, retinoic acid is involved in glycoprotein syn­thesis, since a deficiency of vitamin A results in the accumulation of abnormally low molecular weight oligosaccharide-lipid intermediates of glycoprotein synthesis.

Deficiency of Vitamin A:

a. Xerophthalmia:

Thickening and loss of transparency of the bulbar conjunctiva with yellowish pigmentation. The keratinization of ocular tissue progresses to blindness in the late result of vitamin A deficiency.

b. Follicular conjunctivitis:

c. Keratomalacia:

Softening of the cornea, in advanced cases with ulceration and necrosis. Defective vision due to keratinization of epithelium of cornea.

d. Night Blindness (Nyctalopia):

This is one of the earliest signals of vitamin A defi­ciency which is impairment of dark adap­tation. Some retinal liberated by rhodopsin is not available for resynthesize and must be replaced by synthesizing fresh 11-cis-retinal from retinol.

For this all trans-retinol is collected from blood and dehydrogenated and isomerized. So, continual sup­ply of retinol is essential for normal visual function. Retinol deficiency depresses the resynthesize of rhodopsin and interferes with the function of rods resulting in night blindness.

e. Follicular hyperkeratosis of the skin.

f. Keratinizing metaplasia of epithelium of nose, respiratory mucosa, oesophagus and genitourinary tract.

g. Formation of renal calculi (Urolithiasis).

Hypervitaminosis:

a. Acute symptoms are developed on the in­gestion of very large amounts of vitamin A. These include drowsiness, sluggish­ness, severe headache, vomiting and peel­ing of the skin about the mouth and else­where. In infants and young children, there may be a sudden rise of intracranial pres­sure.

b. Continued intake of excessive amounts, especially in children, produces roughen­ing of the skin, irritability, coarsening and falling of the hair, anorexia, loss of weight, headache, hyperesthesia, occasionally anemia, and leukopenia.

c. Serum level of vitamin A, lipid and acid phosphatase are elevated. All the symptoms vanish on withdrawal of vitamin A.

Coenzyme Activities:

Vitamin A has no coenzyme activities.

Determination of Vitamin A:

Colorimetric determination utilizes the Carr- Price reaction, in which a blue colour is obtained when a solution of antimony trichloride in chloro­form is added to the vitamin-containing mixture. This is used to determine the vitamin A content of blood plasma.

Effects:

Vitamin A in excess intake causes toxicity.

Management:

(a) On diagnosis in the deficiency of vitamin A a single large dose of 60 mg retinol as palmitate or acetate (200,000 I.U.) should be given orally. The oral dose should be repeated the next day and again prior to discharge.

(b) 5 mg retinol palmitate should be given by intramuscular injection if there is vom­iting or severe diarrhoea in addition to the deficiency of vitamin A.

(c) Antibiotics are of value in case of second­ary bacterial infection.

(d) Local treatment of the eye will be required only if there is the presence of dis-organisation and in this case the services of an ophthalmic surgeon is essential.

Toxicity:

(a) Acute overdose leads to nausea and head­ache, increased intracranial pressure and skin desquamation.

(b) Chronic high doses can cause liver dam­age and hyperostosis.

Fat-Soluble Vitamins: Type # 2. Vitamin D:

The vitamins D are a group of compounds. All are sterols occurring chiefly in animal organisms. Pro-vitamins D possess the property of curing or preventing rickets when subjected to long- wave ultraviolet light (about 265 nm).

Vitamin D is a steroid hormone. It is represented by a group of steroids that occur mainly in animals but also in plants and yeasts. They give rise to a hormone known as calcitriol by various metabolic changes. Calcitriol has a role in calcium and phos­phate metabolism.

Chemistry:

a. Ergosterol occurs in plants and 7-de-hydro-cholesterol in animals. Ergosterol is unsaturated and contains an extra methyl group in its side chain than 7-dehydrocholesterol. Ultraviolet irradiation from sunlight cleaves B ring of both com­pounds. Ergocalciferol (Vit. D₂) is formed in plants and cholecalciferol (Vit D₃) is formed in exposed skin. Both vitamins are of equal potency giving rise to D₂ calcitriol and D₃ calcitriol.

b. The most important D vitamins are D₂ (ac­tivated ergosterol) or ergocalciferol or viosterol and D₃ (activated 7-dehydrocholesterol, cholecalciferol) on the basis of nutrition.

c. Provitamin D₂ (ergosterol) occurs in the plant kingdom; whereas vitamin D₃ oc­curs in fish liver oil in nature.

d. The structure of vitamin D₂ is the same as that of D₃ except that the side chain on position 17 is that of cholesterol.

e. Pro-vitamin D₃ are synthesized in the body of man and other mammals. This is then activated in the skin by sunlight or ultra­violet rays and carried to various organs in the body for utilization or storage in the liver.

f. The D vitamins are more stable than vita­min A and are not lost by ordinary cook­ing and preserving processes.

Formation of Calcitriol:

The biologically active form of vit. D is calcitriol (synthesized in liver and kidney) :

Calcitriol (1, 25 dihydroxy cholecalciferol)

Synthesis of calcitriol:

Absorption and Storage:

a. The D vitamins are readily absorbed in the small intestines.

b. Since they are fat-soluble their absorption is enhanced by factors which favour fat absorption such as sufficient quantity of bile salts.

c. After absorption, the vitamin is stored largely in the liver, kidneys, intestines, adrenals and bones.

d. A small amount is excreted in the bile but is partly reabsorbed in the intestine. No amount is eliminated in the urine.

Sources:

Daily Requirements:

Normal Concentration in Blood:

Physiological Functions:

a. Intestinal absorption of calcium and phos­phate:

Vitamin D binds to the chromatin of target tissue and expresses the genes for calcium binding protein as well as Ca⁺⁺ -ATP ase in intestinal cells. This in­creases the Ca⁺⁺ absorption by actively transporting Ca⁺⁺ across the plasma mem­brane against electrochemical gradient.

b. Mineralization of Bones:

The synthesis of Ca⁺⁺ -binding protein (osteocalcin) and alkaline phosphatase increase Ca⁺⁺ and phosphate ions in the bone and enhances the mineralization of bone.

c. Vitamin D stimulates the transcription of mRNA for calcium-binding protein.

d. It increases the excretion of phosphate by kidney and decreases the concentration of serum phosphate.

e. It decreases the pH in the lower intestinal tract.

f. It increases the citrate level of blood, bone, kidney and heart tissues and also the excretion of citric acid.

g. It stimulates the activity of phytase which catalyzes the hydrolysis of phytic acid in intestine.

h. It helps in the development and growth of bone.

Deficiency of Vitamin D:

In absence of it, instead of growth occurring normally, the osteoblast proliferation does not take place in a regular manner and there is no vasculari­zation and mineralization of bones. As a result, ir­regularity is at the zone of calcification. The carti­lage cells do not degenerate and ends of the long bones become bulky and soft.

Bow legs and knock knees occur due to defi­ciency of it. The ankles, knees, wrists, elbows are swollen due to swelling of epiphyseal cartilages. The ribs give beaded appearance and chest gives pigeon breast appearance.

Vitamin D deficiency produces rickets in chil­dren and osteomalacia in adult.

a. There are two types of rickets:

(i) Type I:

Deficiency of lα-hydroxylase and as a result no conversion of 25(OH)D₃ to 1,25(OH)₂D₃.

(ii) Type II:

Autosomal recessive disor­der where there is a single amino acid change in one of the zinc fingers of the DNA binding sites for receptors.

b. Osteomalacia:

In fully grown bones in adults, there is a type of defect in miner­alization of osteoid tissue termed osteo­malacia. Vitamin D deficiency occurs due to absorption defect and less synthesis defect.

c. Renal Osteodystrophy:

When renal pa­renchyma is lost, it is unable to form calcitriol and calcium absorption is impaired.

Hypocalcemia leads to increase in PTH (par­athyroid hormone) which acts on bone to increase Ca⁺⁺. This condition is known as Renal osteodys­trophy.

Causes of deficiency of vitamin D:

i. Dietary insufficiency or insufficient ex­posure to sunlight.

ii. Gastrointestinal disorder.

iii. Chronic obstructive jaundice.

iv. Prolonged treatment with anticonvulsant drugs.

Hypervitaminosis D:

Extremely large amounts (500 to 1,000 times the normal requirements) cause hypervitaminosis D:

i. The early symptoms are anorexia, thirst, constipation and polyuria, followed later by nausea, vomiting and diarrhoea. Hyperphosphatemia also occurs.

ii. Increased urinary excretion of calcium and phosphate may lead to urinary lithiasis, and the hypercalcemia and hyperphos­phatemia may lead to metastatic calcifi­cation. The kidney, arteries, muscles and gastric mucosa are mainly involved. The development of renal failure leads to death.

Coenzyme activities—No coenzyme activi­ties.

William Syndrome:

i. Infants with hypercalcemia, hypervitami­nosis D, aortic stenosis and mental retar­dation (congenital).

ii. Hyperparathyroidism.

iii. Over dosage of vitamin D.

Management:

According to WHO the recommended oral daily intake in case of deficiency of vitamin D is as follows:

Toxicity:

(a) Large oral doses cause hypercalcemia with the symptoms of nausea, vomiting, constipation, drowsiness and signs of renal failure; metastatic calcification in the ar­teries, kidneys and other tissues.

(b) Renal damage may occur before clinical sings of toxicity and patients on large doses of vitamin D should have their se­rum calcium level checked regularly at an interval of three months and if serum cal­cium level is found to be above 10.5 mg/ 100 ml, it is an early indication of over-dosage.

Fat-Soluble Vitamins: Type # 3. Vitamin E (Tocopherols):

Chemistry:

a. Vitamin E refers to a group of compounds known as tocopherols.

b. Four tocopherols namely α-, β-, γ- and δ- have been isolated. β- and γ-tocopherols have two methyl groups in the aromatic nucleus whereas α-tocopherol has three methyl groups in the aromatic nucleus and δ- has only one methyl group.

c. Tocopherols are soluble in fat solvents and destroyed in an alkaline medium. The vi­tamin activity is destroyed by oxidation.

d. The tocopherols are largely methyl deriva­tives of the parent compound tocol; they are yellow oily substances.

e. Some tocopherols are derivatives of tocotrienol which contains three double bonds in the aliphatic side chain and is, therefore, terpenoid in structure.

Absorption and Storage:

a. It is absorbed in the intestine in the pres­ence of bile salts.

b. It is stored in the liver (mitochondria; microsomes) and fatty tissues.

c. It is present in high concentration in the adrenals, the pituitary, the uterus and the testes.

Sources:

Good Sources:

Eggs, meat, liver, fish, chicken, oatmeal, corn oil and cotton seed oil.

Daily Requirements:

Adults: 25-30 mg.

Normal Concentration in Blood:

10 mg/I.

Free Radical:

a. A free raical is an atom or molecule that has one or more impaired electrons. Its ten­dency to acquire an electron from other substances makes it highly reactive.

b. A free radical with an impaired electron may take away hydrogen from a methyl­ene group of polyunsaturated fatty acid and convert it into peroxyl free radical of polyunsaturated fatty acid which binds with O₂ to give a fatty acid peroxyl radi­cal.

This then changes into fatty acid hydro-peroxide by accepting hydrogen from methylene group of another polyun­saturated fatty acid, converting it into an­other free radical of fatty acid. Thus, the free radical peroxidates the unsaturated fatty acids of the cell membranes, mito­chondrial membranes etc.

c. Free radicals like OH^–, superoxide anion O₂⁻ are formed during the action of some oxidoreductases such as microsomal NADPH oxidase.

d. When oxygen is reduced to water by cy­tochrome oxidase, 4 electrons are required. Electrons can be gained one at a time by univalent reduction. The individual mol­ecules in univalent reaction are highly reactive and potentially damaging the tis­sues.

e. Other Sources:

Xanthine oxidase gener­ates superoxide. Cyclooxygenase and lipooxygenase produce hydroxyl and peroxyl radicals.

Superoxide may also be produced during the metabolism of xenobiotics by cytochrome P450 etc.:

f. Superoxide Anion is Produced:

(i) When Fe⁺⁺ is oxidised to Fe⁺⁺⁺.

(ii) By the action of drugs e.g., primaquine.

(iii) By peroxidation or anti-oxidation of membrane lipids.

Physiological Function:

a. Removal of free radicals

(i) Vitamin E appears to be the first line of defense against peroxidation of polyunsaturated fatty acids contained in cellular and subcellular membrane phospholipids.

(ii) The phospholipids of mitochondria, endoplasmic reticulum, plasma mem­branes possess affinities for α-tocopherol and the vitamin E appears to concentrate at these sites.

(iii) The tocopherol acts as antioxidant breaking free radical chain reactions as a result of their ability to transfer a phenolic hydrogen to a peroxyl free radical of a per-oxidized polyunsatu­rated fatty acid.

(iv) The phenoxy free radical formed may react with vitamin C to regenerate tocopherol or it reacts with a further peroxyl free radical so that the chromane ring and the side chain are oxidized to the non-free radical prod­uct:

(v) This oxidation product is conjugated with glucuronic acid and excreted in the bile. If it reacts in this manner, tocopherol is not recycled after car­rying out its function but must be re­placed totally to continue its biologi­cal role in the cell.

(vi) Antioxidant action of tocopherol is effective at high oxygen concentra­tion.

b. Antioxidant action of vitamin E along- with other factors prevent the per-oxidative effect of O₃, H₂O₂ and NO₂, on respiratory membrane and prevent their damage.

c. Vitamin E prevents the per-oxidative changes in membranes of mitochondria and helps in maintaining the smooth trans­location of phosphate ions into mitochon­dria. So the oxidative phosphorylation is enhanced.

d. It prevents the hepatic necrosis produced by the lack of sulphur containing amino acids in dietary proteins.

e. It prevents development of cerebral disor­der.

f. Selenium and Vitamin E act Synergistically:

(a) Selenium is required for normal pan­creatic function which is necessary for the digestion and absorption of lipids including vitamin E.

(b) As a component of glutathione per­oxidase, selenium helps to destroy peroxides and thereby reduces the peroxidation of polyunsaturated fatty acids of lipid membrane. This dimin­ished peroxidation greatly reduces the vitamin E requirement for the maintenance of membrane integrity.

(c) Glucose-6-phosphate .dehydrogenase test is required before the application of primaquine because primaquine has a capacity to produce superoxide anion (O₂⁻) and to damage the cell membrane of RBC or decrease the life span of erythrocyte by increasing the rate of oxidation of hemoglobin to methemoglobin.

In the HMP shunt, when glucoses-phos­phate is converted to 6-phosphogluconolactone in presence of glucoses-phos­phate dehydrogenase, there is a formation of NADPH + H⁺.

In the erythrocyte, NADPH is required for the reduction of oxidized glutathione to reduced glutathione catalysed by glutath­ione reductase. Reduced glutathione re­moves H₂O₂ from the erythrocyte (H₂O₂ is formed by the combination of O₂ and H⁺) in a reaction catalysed by glutathione peroxidase (containing selenium).

In absence of glucose-6-phosphate dehy­drogenase, NADPH is not formed and re­duction of oxidized glutathione to re­duced glutathione does not occur, so re­moval of H₂O₂ from the erythrocyte be­comes impossible. As a result, accumula­tion of H₂O₂ may decrease the lifespan of erythrocyte.

So, glucose-6-phosphate dehydrogenase test is a must before application of pri­maquine.

Deficiency Manifestations:

a. Increased susceptibility of erythrocytes to hemolysis by hydrogen peroxide and de­crease in the erythrocyte lifespan in hu­man adult males.

b. Anemia, edema and skin changes are ob­served in infants when fed unsaturated oils.

c. Decreased erythrocyte lifespan, hemolysis, creatinuria and ceriod deposi­tion in malabsorption syndromes in chil­dren.

d. Smaller testis and permanent sterility in male rats.

e. Resorption of foetus in female rats.

f. Increased oxygen consumption by skel­etal muscle.

g. Hepatic necrosis.

h. Anemia occurs in pregnant and lactating women and in newborn infants due to the deficiency of vitamin E.

i. Its deficiency causes neurologic disorder.

j. Vitamin E deficiency causes muscular dystrophy leading to the increased oxida­tion of polyunsaturated fatty acids in the muscle with a consequent rise in O₂ con­sumption and peroxide production which causes an increase in hydrolase activity producing muscular dystrophy and exhib­iting increased respiration.

k. Production of nocturnal muscle cramp.

l. Its deficiency causes fibrocystic breast dis­ease and atherosclerosis.

Coenzyme Activities:

No coenzyme activities.

Disorder:

Vitamin E is destroyed by commercial cook­ing and food processing including deep-freezing.

Toxicity:

Few adverse effects of vitamin E have been reported even up to 80 times the recommended in­take.

Fat-Soluble Vitamins: Type # 4. Vitamin K:

Dam (1935) named it vitamin K since it is a koagulation-vitamin. Dam, Karrer and co-workers (1939) isolated pure vitamin K₁. In the same year, Doisy and co-workers isolated pure vitamin K₂.

Chemistry:

a. The several substances (natural and syn­thetic) with vitamin K (anti-hemorrhagic) activity are naphthoquinones.

b. Two naturally occurring vitamins K have been identified. Vitamin K was isolated originally from alfalfa and vitamin K₂ was originally isolated from putrid fish meal. Menadione is the most important of the synthetic vitamins K.

c. The natural vitamins K are “fat-soluble” vitamins. The synthetic vitamins K are lacking the long hydrocarbon chain and hence are soluble in water to some extent.

d. Vitamin K₁ possesses a phytyl radical on position 3 which occurs in plants and vi­tamin K₂ (menaquinone, farnoquinone) possesses a difarnesyl radical which oc­curs in bacteria.

Absorption and Storage:

a. Being fat-soluble, its absorption is en­hanced by sufficient amount of bile salts mainly in the jejunum by way of lymphatic’s.

b. Absorption is diminished by large amounts of liquid petroleum.

c. Its absorption is interrupted leading to hemorrhage in jaundice and other liver diseases when the bile secretion is scanty.

d. It is present in blood stream in significant amounts.

e. Liver stores appreciable amounts.

f. All tissues contain small amounts of vita­min K.

g. The feces contain large amounts of it which is produced by the bacterial flora, e.g., E. coli.

Daily Requirements:

The average diet contains adequate amounts of vitamin K₁ and K₂ being synthesized by bacteria in the intestine. So the vitamin K deficiency has not been reported in healthy individuals except in newborn infants fed on mother’s milk when moth­er’s diet has low vitamin K content.

Physiological Functions:

a. Vitamin K catalyzes the synthesis of pro­thrombin by the liver after transcription from information carried on messenger RNA.

b. It reduces the prothrombin time.

c. It. regulates the synthesis of plasma clot­ting factors (factors VII, IX and X).

Vit K. is first converted to its hydroquinone form in liver microsomes by dehydroge­nase using NADPH. K-hydroquinone acts as a coenzyme for carboxylase and con­verts γc-glutamate to γ-carboxyglutamate with the help of CO₂. Hydroquinone may change to 2, 3 epoxide which is reduced back to quinone by microsomal epoxide reductase. Dicoumarol is found to inhibit epoxide reductase.

γ-carboxyglutamate residues now provide calcium binding sites in N-terminal por­tion. This brings together activated factor and accelerin close to the phospholipid membrane of platelets. This enhances blood coagulation.

d. Vitamin K₁ is an essential component of the phosphorylation processes involved in photosynthesis in green plants. It is also involved in oxidative phosphorylation in animal tissues.

e. Vitamin K is involved in the maintenance of normal levels of blood clotting factors II, VII, IX and X, all of which are synthe­sized in the liver initially as inactive pre­cursor proteins.

f. Vitamin K acts as cofactor of the carboxy­lase that forms γ-carboxyglutamate residues in precursor proteins.

g. Vitamin K is used therapeutically as an antidote to poisoning by dicoumarol-type drugs. The quinone forms of vitamin K will bypass the inhibited epoxide reduct­ase and provide a potential source of the active hydroquinone form of vitamin K.

h. Vitamin K acts as a cofactor of carboxy­lase.

i. Vitamin K is required for absorption of fat.

Deficiency Manifestation:

a. The deficiency of Vit. K leads to a lower­ing of prothrombin level and increased clotting time of blood. This may lead to hemorrhagic conditions.

b. Vitamin K deficiency causes hemorrhagic disease of the newborn.

c. Vitamin K deficiency is caused by fat mal­absorption which may be associated with pancreatic dysfunction, biliary disease, atrophy of the intestinal mucosa or any cause of steatorrhea.

d. Sterilization of the large intestine by anti­biotics can result in deficiency when di­etary intake is limited.

e. Short circuiting of the bowel as a result of surgery may also cause deficiency which may not respond even to large doses of vitamin K. Water-soluble form of vitamin K (vitamin K₃) is alone useful in such cases.

Hypervitaminosis K:

The parenteral administration of too large doses of vitamin K (e.g., 30 mg/day for 3 days) to infants has been shown to produce hyperbilirubi­nemia in some cases.

Coenzyme activities—No coenzyme activi­ties.

Management:

(i) Vitamin K₁ is given routinely to newborn babies to prevent hemorrhagic disease of the newborn.

(ii) Since dietary vitamin K is not absorbed in obstructive jaundice it is very important to administer the vitamin before biliary surgery.

(iii) Warfarin and related anticoagulants act by antagonizing vitamin K.