Fatsoluble Vitamins

FATSOLUBLE VITAMINS

VITAMIN A

Chemistry And Source

Vitamin A occurs in nature in several forms. Retinol (Vit. A1) is an unsaturated alcohol containing an ‘ionone’ ring. Marine fish (cod, shark, halibut) liver oils are rich sources. Appreciable amounts are present in egg yolk, milk and butter.

Dehydroretinol (Vit A2) is present in fresh water fishes. Carotenoids are pigments found in green plants (carrot, turnip, spinach), β Carotene is the most important carotenoid. It is inactive as such, one molecule splits to provide two molecules of retinol. Man on normal diet gets half of his vit A as retinol esters and half from carotenoids.

1 μ g of retinol = 3.3 IU of vit. A activity

It is now called 1 Retinol Equivalent = 6 μg of dietary carotene (because of incomplete utilization of the provitamin).

Absorption And Fate

Retinyl palmitate, the chief retinyl ester in diet, is hydrolysed in intestines to retinol which is absorbed by carrier transport and reesterified. Aided by bile, it passes into lacteals. Absorption is normally complete, but not in steatorrhoea, bile deficiency and from protein poor diet. Retinol ester circulates in chylomicrons and is stored in liver cells. Free retinol released by hepatocytes combines with retinol binding protein (RBP a plasma globulin) and is transported to the target cells. On entering them, it gets bound to the cellular retinol binding protein (CRBP). Small amount is conjugated  with  glucuronic  acid, excreted in bile, undergoes  enterohepatic

circulation. Minute quantities of water soluble metabolites are excreted in urine and faeces.

In contrast to retinol, only 30% of dietary β carotene is absorbed. It is split into two molecules of retinal in the intestinal wall; only half of this is reduced to retinol and utilized.

Physiological Role And Actions

Visual Cycle

Retinal generated by reversible oxidation of retinol is a component of the light sensitive pigment Rhodopsin which is synthesized by rods during dark adaptation. This pigment gets bleached and split into its components by dim light and in the process generates a nerve impulse through a Gprotein called Transducin. Retinal so released is reutilized. A similar pigment (Iodopsin) is synthesized in the cones— responsible for vision in bright light, colour vision and primary dark adaptation. In vit. A deficiency rods are affected more than cones; irreversible structural changes with permanent night blindness occur if the deprivation is long-term.

Epithelial Tissue

Vit. A promotes differentiation and maintains structural integrity of epithelia all over the body. It also promotes mucus secretion, inhibits keratinization and improves resistance to infection. It appears to have the ability to retard development of malignancies of epithelial structures. Vit A is also required for bone growth.

Reproduction

Retinol is needed for maintenance of spermatogenesis and foetal development.

Immunity

Increased susceptibility to infection occurs in vit A deficiency. Physiological amount of vit A appears to be required for proper antibody response, normal lymphocyte proliferation and killer cell function.

Deficiency Symptoms

Since vit. A is stored in liver, deficiency symptoms appear only after long-term deprivation, but vit A deficiency is quite prevalent, especially among infants and children in developing countries. Manifestations are:

Xerosis (dryness) of eye, ‘Bitot’s spots’, keratomalacia (softening of cornea), corneal opacities, night blindness (nyctalopia) progressing to total blindness.

Dry and rough skin with papules (phrynoderma), hyperkeratinization, atrophy of sweat glands.

Keratinization of bronchopulmonary epithelium, increased susceptibility to infection.

Unhealthy gastrointestinal mucosa, diarrhoea.

Increased tendency to urinary stone formation due to shedding of ureteric epithelial lining which acts as a nidus.

Sterility due to faulty spermatogenesis, abortions, foetal malformations.

Growth retardation, impairment of special senses.

Therapeutic Uses

Prophylaxis of vit A deficiency during infancy, pregnancy, lactation, hepatobiliary diseases, steatorrhoea: 3000–5000 IU/day.

Treatment of established vit A deficiency: 50,000–100,000 IU i.m or orally for 1–3 days followed by intermittent supplemental doses.

Skin diseases like acne, psoriasis, ichthyosis. Retinoic acid (see below) and 2nd or 3rd generation retinoids are used.

Interactions

Vit E promotes storage and utilization of retinol and decreases its toxicity.

Regular use of liquid paraffin by carrying through with it vit A can result in deficiency.

Long-term oral neomycin induces steatorrhoea and interferes with vit A absorption.

Hypervitaminosis A

Regular ingestion of gross excess of retinol (100,000 IU daily for months) has produced toxicity—nausea, vomiting, itching, erythema, dermatitis, exfoliation, hair loss, bone and joint pains, loss of appetite, irritability, bleeding, increased intracranial tension and chronic liver disease. Excess retinol is also teratogenic in animals and man. Daily intake should not exceed 20,000 IU.

Acute poisoning has been described after consumption of polar bear liver which contains 30,000 IU/g vit A. Single massive ingestion (> one million IU) produces intense headache, drowsiness, irritability, rise in intracranial tension, vomiting, liver enlargement and shedding of skin. Due to saturation of RBP, excess retinol esters circulate in the free state or loosely associated with lipoprotein. These have surfactant property which damages tissues.

Treatment consists of stopping further ingestion, supportive measures, and vit E which promotes storage of retinol in tissues and speeds recovery. Most signs regress in a week, some persist for months. Excess intake of carotenoids does not produce hypervitaminosis A, because conversion to retinol has a ceiling.

Retinoic Acid (vit A acid)

Retinoic acid has vit A activity in epithelial tissues and promotes growth, but is inactive in eye and reproductive organs. Alltrans retinoic acid (Tretinoin) is used topically, while 13cis retinoic acid (Isotretinoin) is given orally for acne (see Ch. No. 64). Unlike retinol, it is not stored but rapidly metabolized and excreted in bile and urine.

The cellular retinoic acid binding protein (CRABP) is different from CRBP, is present in skin and other tissues but not in retina—this may be the reason for the inability of retinoic acid to participate in visual cycle.

Retinoid Receptors

Retinol and retinoic acid act through nuclear retinoid receptors which function in a manner analogous to the steroid receptors: activation results in modulation of protein synthesis. In the target cells (epithelial, gonadal, fibroblast) synthesis of certain proteins is enhanced while that of other proteins is depressed—accounting for the structural and functional changes. Two distinct families of retinoid receptors, viz. Retinoic acid receptors (RARs) and Retinoid X receptors (RXRs) have been identified with differing affinities for different retinoids.

VITAMIN E

Chemistry And Source

A number of tocopherols, of which α tocopherol is the most abundant and potent, have vit E activity. The d-isomer is more potent than l-isomer. Wheat germ oil is the richest source, others are cereals, nuts, spinach and egg yolk.

1 mg of d α-tocopherol is called α-tocopherol equivalent = 1.49 IU of vit E.

The daily requirement of vit. E is estimated at 10 mg. It is increased by high intake of polyunsaturated fats.

Absorption And Fate

Vit. E is absorbed from intestine through lymph with the help of bile; it circulates in plasma in association with βlipoprotein, is stored in tissues and excreted slowly in bile and urine as metabolites.

Physiological Role And Actions

Vit E acts as antioxidant, protecting unsaturated lipids in cell membranes, coenzyme Q, etc. from free radical oxidation damage and curbing generation of toxic peroxidation products. Feeding animals with polyunsaturated fats increases vit E requirement, while antioxidants like cystein, methionine, selenium, chromenols prevent some vit E deficiency symptoms in animals. However, vit E might be having some more specific action or a structural role in biological membranes, because other deficiency symptoms are not relieved by these unrelated antioxidants.

Deficiency Symptoms

Experimental vit E deficiency in animals produces recurrent abortion, degenerative changes in spinal cord, skeletal muscles and heart, and haemolytic anaemia. No clearcut vit E deficiency syndrome has been described in humans, but vit E deficiency has been implicated in certain neuromuscular diseases in children, neurological defects in hepatobiliary disease and some cases of haemolytic anaemia.

Therapeutic Uses

1. Primary vit E deficiency does not occur clinically. Supplemental doses (10–30 mg/ day) may be given to patients at risk (see above).

2. G6PD deficiency—prolonged treatment with 100 mg/day increases survival time of erythrocytes.

3. Acanthocytosis—100 mg /week i.m: normalizes oxidative fragility of erythrocytes.

4. The risk of retrolental fibroplasia in premature infants exposed to high oxygen concentrations can be reduced by 100 mg/kg/day oral vitamin E.

5.  Alongwith vit A to enhance its absorption and storage, and in hypervitaminosis A to reduce its toxicity.

6. Large doses (400–600 mg/day) have been reported to afford symptomatic improvement in intermittent claudication, fibrocystic breast disease and nocturnal muscle cramps.

For its antioxidant property, vit E has been promoted for recurrent abortion, sterility, menopausal syndrome, toxaemia of pregnancy, atherosclerosis, ischaemic heart disease, cancer prevention, several skin diseases, prevention of neurodegenerative disorders, postherpetic neuralgia, scleroderma and many other conditions, but without convincing evidence of benefit.

Toxicity

Even large doses of vit E for long periods have not produced any significant toxicity, but creatinuria and impaired wound healing have been reported; abdominal cramps, loose motions and lethargy have been described as side effects of vit. E.

Vit E can interfere with iron therapy.