VITAMINS

Vitamins, formerly known as ‘accessory food factors’, are present in many animal and vegetable foods. Their absence from the diet causes deficiency diseases such as scurvy, beri-beri, rickets and night blindness. The value of citrus juices in the treatment of scurvy was realized in the eighteenth century. Systematic feeding experiments began about 1873 and much work on the subject was done by Gowland Hopkins from 1906 to 1912. Fraser and Stanton established that beri-beri was produced in people living mainly on polished rice, who could be cured if ‘rice-polishings’, the outer part of the grain removed in making polished rice, were added to the diet. In 1911 Funk coined the name ‘vitamine’ now usually spelt vitamin, for the active fraction of rice-polishings.

The existence of vitamin A was proved in 1915 and other letters were applied to later vitamins discovered. Many vitamins have since been proved to be extremely complex mixtures, and one now speaks, for example, of the vitamin B complex, components of which can be referred to as B₁, B₂, etc., or by their chemical or other names. As the chemical nature of the vitamins has been discovered and vitamin complexes have been resolved into their constituents, there is an increasing tendency in the scientific and medical literature to discard the term ‘vitamin’ with its associated letter (and number) in favour of the chemical name for the material under consideration (see, for example, the BP monographs on Hydroxocobalamin, Riboflavine and Thiamine Hydrochloride). However, in the lay literature the original vitamin terminology persists and pharmacists need to be familiar with this. Some vitamins have as yet no proved role in the treatment of human diseases but others are valuable items of the materia medica. A large number of different pharmacopoeial and proprietary vitamin preparations are available but with a well-balanced diet the normal individual should require no vitamin supplementation (Table 31.1). However, people on a strict vegetarian diet who eat no eggs or dairy produce need a supplement of vitamin B₁₂; and alcoholics need vitamin B₁, which is required for the complete metabolism of ethanol. Other groups, such as narcotic drug users, whose diet is generally inadequate are also prone to vitamin deficiency. Need for vitamins is still great in many underdeveloped countries. Notwithstanding the above, the consumption by the general public of vitamin preparations is enormous and this is one of the larger areas of the pharmaceutical industry. Numerous publications on healthy foods and promotional leaflets ensure that these substances are universally recognized.

Table 31.1 Sources of vitamins.

Vitamin	Alternative names	Distribution
A (A₁, A₂)	Anti-infective or antixerophthalmic vitamin, retinol	Fish livers (cod, halibut, shark, etc.) and other animal fats. Plants contain proto-vitamin A, the vitamin precursors (e.g. α-, β- and γ-carotene) and cryptoxanthine; these are converted to vitamin A in liver
B₁	Aneurine, thiamine	Rice polishings, cereal germ, animal organs, yeast or prepared synthetically
B₂	Riboflavine	Widely distributed in both plants and animals; bacteria, yeasts and other fungi, cereal grains and many fruits
B₃	Niacin, nicotinic acid, nicotinamide, niacinamide, pellagra-preventing or PP vitamin	Milk, eggs, liver, yeast, malted barley, or may be prepared by fermentation
B₅	Pantothenic acid	Yeast, liver, red meat, chicken, milk, mushrooms, beans, bananas, nuts, avocados, potatoes
B₆	Pyridoxine, pyridoxine hydrochloride	Prepared synthetically but present in many foodstuffs, including yeast, liver, red meat, fish, yoghurt, bananas, cabbage, wholegrains
B₉	Folic acid, folacin, vitamin M	Yeast, liver, green plants, wholemeal bread, oranges, nuts
B₁₂	Cyanocobalamin, megaloblastic anaemia vitamin	From livers or from the metabolic products of microorganisms such as Streptomyces griseus
C	Ascorbic acid	Fruits, particularly citrus fruits, tomatoes, potatoes, capsicums; raw vegetables; or made synthetically
D₂	Antirachitic vitamin; calciferol, ergocalciferol	Calciferol is produced by irradiation of ergosterol
D₃	Cholecalciferol	Formed by irradiation of cholesterol. It is found in fish-liver oils (e.g. cod, halibut) and in human skin following exposure to sunlight
E	Tocopherols, alpha tocopheryl acetate	Embryos of cereals (wheat and maize germ oils); other vegetable oils (palm, olive, etc.); fresh vegetables, nuts, eggs, butter
H	Biotin (two forms), coenzyme R	Yeast, peanuts, chocolate, carrots, liver, kidney, eggs
K₁	Phytomenadione, coagulation factor, antihaemorrhagic vitamin	From plants (e.g. alfalfa, lucerne, tomatoes, etc.); or by synthesis. Abundant in the human intestine, where it is synthesized by intestinal bacteria
P	Permeability factor (significance now doubtful)	Flavonoids derived especially from Citrus, Ruta, Sophora and other genera
Ubiquinone 10	Ubidecanenone; coenzyme Q₁₀. Has been referred to as Vitamin Q₁₀	A coenzyme found in liver; also in other metabolic tissues of plants and animals

It will be noted in Table 31.1 that a number of gaps appear in the naming of the vitamins and this is because some substances once regarded as vitamins (e.g. vitamin F and a number of the B group) are of indefinite character or have been reclassified as essential nutritional factors.

Chemically, vitamins vary from very simple compounds to very complex ones. They belong to no one chemical type. Vitamin A has already been mentioned under ‘Diterpene compounds’; vitamin C has affinity with the sugars, being the enolic form of 3-oxo-L– gulofuranolactone; B₁₂, which first became official in 1963, has a very complex molecule. Several forms of vitamin D occur. Vitamin K₁ is 2-methyl-3-phytyl-1,4-naphthoquinone. As might be expected from these wide variations in structure, vitamins differ from one another in physical properties such as solubility. They have been traditionally classified according to their water-solubility and fat-solubility properties and this division is still useful. In the main, the water-soluble vitamins are non-toxic and can be consumed in large doses without harm; they also remain in the body for a relatively short time. Conversely, the fat-soluble vitamins are more toxic in large doses and are stored in the fatty reserves of organs of the body for long periods of time. The solubilities also determine the type of food products in which the two groups occur, e.g. fatty dairy products as opposed to plant juices.

FAT-SOLUBLE VITAMINS

Vitamin A (A₁; A₂)

Vitamin A is found as such only in the animal kingdom and is particularly abundant in fish-liver oils. The preparation of cod-liver oil is described below. Vitamin A occurs in three or more forms termed vitamers. Vitamin A₁, retinol (see Fig. 31.1), is an alcohol and retinal is its corresponding aldehyde. Vitamin A₂, dehydroretinal, has a second unsaturated bond in the ring system and also occurs as the aldehyde dehydroretinol. The carotenes (see Chapter 24) are C₄₀ compounds found in the plant kingdom and are converted to vitamin A in the small intestine and other organs. Although the formulae of the carotenes might suggest that each molecule would give rise to two molecules of vitamin A, the successive oxidations of the molecule in fact give rise to only one molecule of the vitamin. Infants and young children have only a limited capacity to effect this conversion and true carnivores (e.g. cats) and invertebrate animals are unable to utilize carotene in this respect.

Fig. 31.1 Structures of some fat-soluble vitamins.

Vitamin A is decomposed by exposure to light and may be assayed in fish-liver oils and other preparations by ultraviolet absorption and spectrophotometry.

Vitamin A is essential for the normal functioning of the body epithelia and the retina. Deficiency is indicated by night blindness and by a drying and crusting of the mucous membranes.

Vitamin D

The compounds comprising this group have antirachitic activity and are individually designated D₂–D₆; they are formed by the opening of ring B of a steroidal provitamin. Vitamin D₃ (cholecalciferol, see Fig. 31.1) is the only member to occur naturally in higher animals and is formed photochemically from 7-dehydro-cholesterol by the sun’s irradiation of the skin. Vitamin D₂ (calciferol, ergocalciferol) differs from D₃ in having an unsaturated side-chain. D₄, D₅ and D₆ are produced artificially by the irradiation of 22-dihydroergosterol, 7-dehydrositosterol and 2-dehydrostigmasterol respectively. These vitamins are relatively stable and preparations containing them are assayed (BP/EP) by liquid chromatography using, as a standard, a preparation of crystalline vitamin D₃.

Vitamin D regulates the calcium and phosphorus balance in the body by direct action on phosphorus metabolism. It promotes calcium absorption and is an essential factor in bone formation (a deficiency causes rickets). Excessive doses of the vitamin should be avoided.

Vitamin E

Contained in this group are a number of tocopherols, prefixed α-, β-, γ-, etc, which are of wide occurrence in plants, being particularly abundant in the germ oil of cereals. For the preparation of vitamin products the cereal embryos are conveniently separated during the manufacture of the appropriate starches; α- (see Fig. 31.1), β- and γ-tocopherols are among those found in the germ of wheat, barley and rye, whereas others are found in soya beans, ground nuts and maize. Oats contains some five different tocopherols. The various tocopherols differ in the methylation patterns of the ring system. Virgin Wheat-germ Oil and Refined Wheat-germ Oil are included in the BP/EP; also seven monographs based on derivatives of the racemic and RRR-α-tocopherols. These are evaluated by gas chromatography.

Discovered in 1922, vitamin E is a powerful antioxidant and has an important role in the preservation of the well-being of cells, for slowing their ageing effects and in counteracting the harmful aspects of toxins in the blood and lungs. It may assist protection of the cardiovascular system by preventing blood–lipid peroxidation with the subsequent formation of sticky deposits. Traditionally the vitamin has been associated with the improvement of fertility.

A normal diet supplies adequate amounts of the vitamin; deficiency leads to the destruction of red blood cells with resultant anaemia. It may be added to cod-liver oil (q.v.).

Vitamin K (phytomenadione, phylloquinone)

This vitamin occurs in several natural forms. Vitamin K₁ (Fig. 31.1) is found in many plant sources and has a C₂₀ side-chain with one unsaturated linkage. K₂, originally prepared from decaying fish, has a polyunsaturated isoprenoid side-chain which is of variable length. These compounds, termed menaquinones (MK), are produced by bacteria and, as an example, MK-8 refers to a menaquinone produced by Escherichia coli with 8 isoprene units and 40 carbon atoms in the side chain. (For the biogenesis of these compounds, see R. Bentley and R. Meganathan, J. Nat. Prod., 1983, 46, 44.) The formation of phylloquinone in green plants has received less attention; chorismic acid (q.v.) and 2-succinylbenzoic acid are probable intermediates. Similar compounds with vitamin K activity have been synthesized.

Vitamin K is a necessary factor in the blood-clotting process; it acts indirectly by activating those substances which are necessary for the conversion of prothrombin to thrombin. In healthy individuals it is possible that the intestinal flora provides an adequate supply of the vitamin. Deficiency symptoms are prolonged bleeding and excessive bruising.