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This is the most important functional aspect of vitamin E.

• Removal of free radicals: Vitamin E is involved in removal of free radicals and prevents their peroxida- tive effects on unsaturated lipids of membranes and thus helps maintain the integrity of cell membrane. Vitamin E prevents peroxidation. Vit E (α-tocopherol) reacts with the lipid peroxide radicals formed by peroxidation of polyunsaturated fatty acids before they can establish a chain reaction, acting as free radical trapping antioxidant.

The tocopheroxy-free radical (Toc.O•_{) product,} formed in the process, is relatively unreactive and ultimately forms non-radical compounds. Usually the tocopheroxyl radical is reduced back to α-tocopherol again by reaction with vitamin C from plasma or reduced glutathione (G-SH) (Fig. 12.5).

2. Role in Reproduction in Rats

Vitamin E helps in maintaining seminiferous epithelium intact. However, its deficiency leads to

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irreversible degenerative changes leading to permanent sterility. Motility of sperms is lost and spermatogenesis is impaired.

In female rats the ovary is unaffected by vitamine E deficiency, but the foetus does not develop normally, dying in utero undergoing resorption.

3. Other Functions

• Tocopherol derivative tocopheranolactone may be involved in synthesis of coenzyme Q or ubiquinone.

• Vitamin E may have some role in nucleic acid synthesis.

Deficiency of Vitamin E

• Muscular dystrophy: Vitamin E deficiency leads to the increased oxidation of polyunsaturated fatty acids in the muscle with a consequent rise in O2 consumption and peroxide production, peroxides may then cause an increase in intracellular hydrolase activity by affecting the lysosomal membranes. Those hydrolases may then catalyse such breakdowns in muscle and produce muscular dystrophy. The muscle creatine is low and creatinuria occurs.

• Hemolytic anemia: Low tocopherol diet may produce low plasma tocopherol, increased susceptibility to hemolysis due to peroxides and dialuric acid. This could be the reason of hemolytic or macrocytic anemia. Extensive oedema, reticulocytosis, thrombo- cytosis and thrombus formation in blood vessels, increased susceptibility of the RBC to hemolysing effects of peroxides and dialuric acid is observed. These symptoms are often aggravated by diets rich in essential fatty acids. Clinical cases of vitamin E deficiency may be found in lipoproteinemia and in

diseases like sprue, obstructive jaundice, pancreatitis, and steatorrhoea.

• Dietary hepatic necrosis: Diets low in cystine and rich in polyunsaturated fatty acids can cause hepatic necrosis. Fall in acetate utilisation and in respiration of necrotic liver is more effectively cured or prevented by tocopherols. Vitamin E and Factor 3, a selenite compound are complementary to one another in preventing hepatic necrosis or muscular dystrophies (Refer Selenium metabolism).

Clinical and therapeutic uses: Recently, vitamin E has been used in following diseases (Refer box below): • Nocturnal muscle cramps (NMC)

• Intermittent claudication (IC) • Fibrocystic breast disease (FBD) • Atherosclerosis

VITAMIN K

Chemistry: All vitamin K forms are the naphthoquinone derivatives. It is closely related to a compound pthiocol, a constituent of tubercle bacilli with slight vitamin K activity.

Vitamins K₁ and K₂are the two naturally occurring forms

of vitamin K that have been identified. The third form vitamin K3 is the synthetic analogue.

Therapeutic Uses of vitamin E

Disease Mechanism of action of Vitamin E

1. Nocturnal muscle cramp (NMC) The precise mechanism not known. By virtue of its antioxidant property, vit. E prevents oxidation of certain radicals and ensures better utilisation of oxygen in muscle tissue, thereby improving muscle metabolism.

2. Intermittent claudication (IC) Same as above. In addition:

• A decrease in circulating lactate level and increase in pyruvate level noted after therapy

• Improvement in blood supply due to opening of new vessels, improving circulation 3. Fibrocystic breast disease (FBD) Precise mechanism of action in FBD remains obscure

It has been suggested that vit. E probably acts by correcting the deranged progesterone/estrogen ratio in women of FBD

4. Atherosclerosis Beneficial effects of vit. E in atherosclerosis are due to:

• Inhibits the formation of lipid peroxides and restores PG-I₂ synthesis • Inhibits platelets aggregation

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Types of Vitamin K 1. Vitamin K1

It is phylloquinone or phytonadione isolated from alfalfa leaves. Also called Mephyton.

Thus vitamin K1 is 2 methyl, 3 phytyl-1,4 naphtho- quinone. It is a light yellow oil.

2. Vitamin K2

Also known as farnoquinone, it was isolated from putrid fish meal synthesised by bacteria and has a longer difarnesyl chain attached at position 3. Vitamin K2 (farnoquinone) is 2 methyl-3-difarnesyl-1,4 naphthoquinone. It is also a yellow oil.

3. Vitamin K3

Vitamin K3 is 2 methyl, 1, 4 naphthoquinone without any side chain or OH group (Also known as menadione), is the synthetic analogue of vitamin K. It is three times more potent than natural varieties. It is water-soluble and can be given parenterally. Its activity is related to the presence of methyl group at position 2. Other two forms are Menadiol and Menadioldiacetate.

Dietary sources and daily requirement: Both vitamin K1 and K2 are mainly found in plants and synthesised by bacteria respectively. Vitamin K1 is present chiefly in green leafy vegetables, such as alfalfa, spinach, cauliflower, cabbage, soyabeans, tomatoes.

Vitamin K2 also called Menaquinones is a product of metabolism of most bacteria including the normal intestinal bacteria of most higher animal species. Menaquinones (K2) are absorbed from gut to some extent

but it is not clear to what extent they are biologically active as it is possible to induce signs of vit K deficiency simply by feeding a phylloquinone (K1) deficient diet, without inhibiting intestinal bacterial action.

Absorption and excretion: It is absorbed from the small intestine in presence of bile salts. It is not stored to any appreciable extent. It can cross the placental barrier and is available to the foetus. Vitamin K is not excreted in the urine or bile. Faeces contain large quantities. This may be of bacterial origin. It may also represent actual excretion by the intestinal mucosa.

FUNCTIONS OF VITAMIN K 1. Blood Coagulation

The main function of vitamin K is the promotion of blood coagulation by helping in the post- transcriptional modifications of blood factors such as prothrombin, and factors II, VII, IX, X. Vitamin K is first converted to its hydroquinone form in liver microsomes by dehydrogenase using NADPH. It then functions as coenzyme for carboxylase. It uses CO2 to be incorporated as an additional –COOH group at the γ-C of a specific glutamate of these coagulation proteins. This converts the glutamate residues into γγγγγ-carboxyglutamate. Hydroquinone may change to 2, 3 epoxide which is reduced back to quinone by microsomal epoxide reductase. Dicumarol is found to inhibit epoxide reductase.

All the first ten glutamate residues of prothrombin are first carboxylated by vitamin K. The γ-carboxy- glutamate residues now provide calcium binding sites in the N-terminal portion. This brings together activa- ted factor and accelerin close to the phospholipid membrane of platelets. This enhances blood coagula- tion manifold.

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2. Calcium Binding Proteins

Vitamin K similarly is found to carboxylate specific glutamate residues of calcium binding proteins of bones, spleen, placenta and kidneys. This enhances the capacity of these proteins to deposit calcium in the tissues concerned.

3. Role in Oxidative Phosphorylation

Vitamin K is a necessary cofactor in oxidative phosphorylation being associated with mitochondrial lipids. UV irradiation of isolated mitochondria destroys their vitamin K content and ultimately their ability for oxidative phosphorylation. The normal process of oxidative phosporylation is restored when vitamin K is added to them. Further dicumarol, an antagonist of vitamin K, is known to act as uncoupler of oxidative phosphorylation.

DEFICIENCY OF VITAMIN K

Deficiency of vitamin K is very rare, since most common foods contain this vitamin. In addition, intestinal flora of microorganisms also synthesise vitamin K. However, a deficiency may occur as a result of:

• Prolonged use of antibiotics and sulfa drugs: This sup- presses the growth of vitamin K2 producing bacteria thus making vitamin K2 not available.

• Malabsorption and biliary tract obstruction: Sprue, steatorrhoea and coeliac disease can lead sometimes to vitamin K deficiency. Vitamin K being a fat soluble vitamin, is absorbed with the help of bile salts. The biliary obstruction impairs the delivery of bile hence vitamin K is not able to get absorbed.

• Spoilt Sweet-clover hay: When consumed by cattle, causes a bleeding disease. In such cases fall in O2 consumption, poor oxidative phosphorylation, low prothrombin, proconvertin and stuart factor activities are observed. Spoilt sweet-clover hay contains dicu- marol-vitamin K antagonist.

• Short circuiting of the bowel: As a result of surgery short-circuiting of the bowel may also foster deficiency which may not respond even to large oral doses of vitamin K. Water-soluble form of vitamin K, i.e. vitamin K3 alone is useful in such cases.

• In immediate post-natal infants: Hypoprothrom- binemia and bleeding in many tissues occurs in

vitamin K deficiency. Relatively small amounts of vitamin K are obtained from the mother through placental membranes and also because the intestinal microflora has not yet been established, this leads to vitamin K deficiency and its consequent effects. If prothrombin is significantly low this may result in hemorrhagic disease of the newborn.

Note: Hypoprothrombinemia can be prevented by administering vitamin K to the mother before parturition or by giving the infant a small dose of vitamin K.

WATER-SOLUBLE VITAMINS