Chapter 9
What are Antioxidants?

An antioxidant is any substance that retards or prevents deterioration, damage or destruction by oxidation. As we have seen in Chapter 1, free radicals act by oxidation. Oxidation is always damaging to whatever is oxidized, although often it is very useful—indeed, it is the source of all our energy, and our bodies could not work without it. But in other cases, as when free radicals bring about cell damage in disease processes, it is far from useful and we naturally want to try to do something to stop it. This is where antioxidants come in. In a medical context, they are comparatively new, but in other branches of science they have been around for a long time.

Antioxidants

For many years, chemists have known that free radical oxidation action can be controlled or even prevented by a range of antioxidant substances. It is, for instance, vital that lubricating oils should remain stable and liquid and should not dry up like paints. For this reason, such oils usually have small quantities of antioxidants, such as phenol or amine derivatives, added to them. Although plastics are often formed by free radical action, they can also be broken down by the same process. So they, too, require protection by antioxidants like phenols or naphthols. Low-density polythene is also often protected by carbon black which absorbs the ultraviolet light which causes free radical production (see p.54).

Food in storage also deteriorates by oxidation. When, for instance, fat goes rancid it does so by a free radical oxidation reaction. Oxidized fats are new compounds that taste and smell horrible and anything that can prevent this happening is of great economic importance. So chemists have for some time been actively looking for antioxidants for this purpose. To date, the most popular antioxidant food additives have been BHA (butylated hydroxyanisole), BHT (butylated hydroxytoluene), propyl gallate and tocopherol (vitamin E). These antioxidants act by donating hydrogen atoms to the hydroxyl radical so that water is formed. The equation is simple: H + OH = H2O.In other words, two dangerously active radicals combine to form a harmless molecule: water.

Ironically, the irradiation of food—which is an excellent way of killing bacteria that can cause spoilage and may be dangerous—can, in itself, cause free radical production that can lead to unacceptable chemical changes in the food. So it may sometimes be necessary to counteract the undesirable effects of irradiation of food by using antioxidants.

Natural Body Antioxidants

Fortunately, the body has its own antioxidants for damage limitation. One of the most effective of these is the substance tocopherol (vitamin E). This vitamin dissolves in fat and that is especially important because by far the most significant free radical damage in the body is damage to the membranes of cells and to low-density lipoproteins, and these are made of fat molecules. Vitamin C is also a powerful antioxidant, but is soluble in water, not in fat. This means that it gets distributed to all parts of the body. The two vitamins are both highly efficient at mopping up free radicals, and sometimes even co-operate in so doing.

Other natural body antioxidants include compounds such as cysteine, glutathione and D-penicillamine, and blood constituents such as the iron-containing molecule transferrin and the protein ceruloplasmin. These act either by preventing free radicals from being produced or by mopping them up.

As mentioned in Chapter 1, the body also contains a number of important antioxidant enzymes. An enzyme is a highly active protein that accelerates a chemical reaction. Most of what goes on in the body is promoted by thousands of different enzymes. The most interesting antioxidant enzyme is super-oxide dismutase. This excited enormous interest when it was discovered, as it has no other function than to change the dangerous superoxide free radical to the safer hydrogen peroxide. This made the scientists think and really got the doctors interested in free radicals. Hydrogen peroxide (H 2 0 2 ), although not a free radical, is not particularly pleasant stuff to have around. The extra oxygen atom is readily available to cause oxidation, making it an active compound useful for producing blonde hair. So the body has two other enzymes, catalase and glutathione peroxidase that break down hydrogen peroxide to water and oxygen.

Vitamins

The greatest popular interest, however, is currently focused on the vitamins. Most current medical textbooks still treat vitamins, including vitamin C and vitamin E, in the conventional manner, by giving small recommended daily allowances (RDAs). This is appropriate for the large B group of vitamins (B1, B2, B6 and B12, niacin, pantothenic acid, folic acid and lipoic acid) and for vitamins D and K. All these, plus vitamin C, are substances necessary in very small quantities for the maintenance of health. If these small quantities are not available, various deficiency diseases occur. Vitamin C deficiency causes scurvy, a bleeding disorder; vitamin A deficiency causes serious eye and other problems; vitamin D deficiency causes bone softening, rickets or osteomalacia; and so on.

Danger of Over-dosage

Because many vitamins act in association with enzymes and only tiny quantities are required, it has become conventional to teach that people who take more than the small daily requirement—which is nearly always present in a reasonably balanced diet—are wasting their money. In addition, there have been regular, and well justified, medical warnings about the dangers of vitamin over-dosage, specifically of vitamins A and D. Excessive intake of these vitamins can certainly cause trouble. Too much vitamin D causes calcium to be deposited in the kidneys, arteries and other tissues—a serious matter that can lead to all sorts of problems, including kidney failure. The dangers of vitamin A over-dosage are described below, as are those of vitamin E.

Although few textbooks have yet got around to the role of certain vitamins as biological antioxidants, there is plenty about this in current medical and general scientific literature. Text books take a long time to write, edit and publish and they invariably lag behind current advances, especially in new and rapidly developing fields of research. This is why medical and scientific journals are so important. In the free radical literature most of the emphasis has been on vitamins E and C, so it will be worth looking more closely at these interesting substances.

Vitamin E (Tocopherol)

Until recently, pharmacology textbooks have dismissed the fat-soluble vitamin E as unimportant; some have even said that it is of no medical relevance in humans.

Tocopherol was first discovered in 1922 when it was found that female rats required an unknown substance in their diets to sustain normal pregnancies. Without it, they could ovulate and conceive satisfactorily, but within about 10 days the fetus invariably died and was absorbed. Male rats deficient in this substances were also found to have abnormalities in their testes. For these reasons, vitamin E enjoyed a brief reputation as the 'anti-sterility vitamin' and was, illogically, recommended as a treatment for infertility, although there was no reason to suppose that the people concerned were deficient in the vitamin. It has also been used to try to treat various menstrual disorders, inflammation of the vagina and menopausal symptoms, but there is no reason to suppose that it is specifically useful in these conditions.

Vitamin E was first isolated in 1936 from wheat germ oil. It was found to be any one of a range of eight very complicated but similar molecules known as tocopherols. It is almost insoluble in water but dissolves in oils, fats, alcohol, acetone, ether and other fat solvents. Unlike vitamin C it is stable to heat and alkalis in the absence of oxygen and is unaffected by acids at temperatures up to 10(~° C. If exposed to atmospheric oxygen it is slowly oxidized. This occurs more rapidly in the presence of iron or silver salts. It gradually darkens on exposure to light. Among the richest natural sources are seed germ oils, alfalfa and lettuce. It is widely distributed in plant materials. The international unit is equal to 1 mg of alpha-tocopherol acetate. For practical purposes of dosage, consider 1 international unit to be equivalent to 1 ma.

All the tocopherols are antioxidants and this appears to be the basis for all the biological effects of the vitamin. It is now becoming increasingly clear that vitamin E operates as a natural antioxidant helping to protect important cell structures, especially the cell membranes, from the damaging effects of free radicals. Interestingly, it has been found, for instance, that the vitamin can protect against the effects of over-dosage of vitamin A described below. It is involved in many body processes.

In carrying out its function as an antioxidant in the body, vitamin E is, itself, converted to a radical. It is, however, soon regenerated to the active vitamin by a biochemical process that probably involves both vitamin C and glutathione.

Deficiency of vitamin E is very rare because it occurs widely in food, especially in vegetable oils, but when it does occur the effects can be devastating. The need for vitamin E increases if the diet is high in polyunsaturated fats. Deficiency sometimes occurs in premature babies, especially if malnourished, and in people with disorders that interfere with fat absorption. People who are severely deficient in vitamin E for these reasons may suffer, to vary-in" degrees, degenerative changes in the brain and nervous system, impairment of vision, double vision, walking disturbances, anaemia, an increased rate of destruction of red blood cells, fluid retention (oedema) and skin disorders. Some reports have shown that large doses of vitamin E can prevent the progression of the neurological abnormalities or even lead to improvement.

Human vitamin E deficiency occurs only after many months on a severely deficient diet. A daily intake of 10 to 30 mg of the vitamin is said to be sufficient to keep the blood levels within normal limits and this will always be provided by a normal diet. Diets that contain other antioxidants decrease the requirement. Human milk contains plenty to meet the baby's needs.

Dangers of over-dosage

Vitamin E is generally regarded as being a fairly innocuous substance and few if any warnings are heard of the dangers of over-dosage. For adults, this is probably reasonable, but there are undoubtedly limits to the amounts that can be safely taken. Dangers have arisen from over-dosage of vitamin E in premature babies from probable interference with the action of cells of the immune system against infection (see p.56). Since free radical oxidant action is a necessary part of the body's functioning, both for the destruction of bacteria and for other important purposes, it is only reasonable to suppose that undue interference with it, by excessive dosage of an antioxidant like vitamin E, is likely to be harmful. To do so may be, for instance, to increase the risk of infection.

There is no substance of major medical benefit that does not also carry the risk of undesirable side effects. This is a fact of medical life that should never be forgotten. Like many other substances, vitamin E is necessary for life and health. But, like many other substances, the amount in the body must, for safety, be kept within fairly strict limits.

Vitamin C (Ascorbic Acid)

Vitamin C is a simpler compound than vitamin E and is water-soluble. It was the first vitamin to be discovered, and the disease caused by its deficiency—scurvy—has been known for centuries. Sailors on long sea voyages, who subsisted on salt pork and biscuits, with no fresh fruit or vegetables, used commonly to die of scurvy. But in 1747, the British -naval doctor James Lind (1716 - 84) proved by careful experiments, with controls, that a teaspoonful of lemon juice, taken from time to time, would prevent the disease. Unfortunately, it was 50 years before Their Lordships of the Admiralty—who were not readily impressed by science—could be persuaded to issue appropriate orders to their ships' captains, and in the meantime many more sailors died.

The vitamin was isolated in 1928 and chemically identified in 1932. It is readily destroyed by exposure to air and by cooking, especially in the presence of copper and alkalis. The main structural material of the body is a protein called collagen. This forms the main basis of the bones and of most other tissues. Vitamin C is necessary for the proper synthesis of collagen, and deficiency leads to the failure of wounds to heal, to weakness of small blood vessels with bleeding from the gums and into the joints and skin, to anaemia and looseness of the teeth. Scurvy still occurs in people who live on tea and buns and the first signs— usually swollen and bleeding gums and loose teeth, but in some cases spontaneous bruising on the lower thighs— appear three or four months after the last intake of the vitamin. In babies and small children scurvy also causes bleeding under the bone membranes, causing very tender swellings so that infants resent being touched.

To prevent scurvy, humans need amounts of vitamin C varying from about 60 mg a day to as much as 250 mg a day. Blood levels of the vitamin are reduced by smoking and by the contraceptive pill. People need more while suffering from infectious diseases, injuries, burns, rheumatic disorders and after surgical operations. A normal, well balanced diet will usually supply enough vitamin C to prevent scurvy. The vitamin is plentiful in fruit juices, green peppers, cabbages, greens, potatoes, citrus fruits, tomatoes and strawberries. Orange and lemon juices contain about 0.5 mg in each cc (mI). When large doses are taken, there is a correspondingly large loss of the vitamin in the urine.

Vitamin C is a powerful antioxidant and for this reason is commonly used to preserve the natural flavour and colour of processed fruit, vegetables and dairy products.

The Value of Vitamin C in Medicine

No one disputes that vitamin C is of great value in the treatment of scurvy. As soon as the vitamin is given in adequate dosage, improvement occurs and, within a few weeks, all the symptoms and signs have gone. The real dispute has been whether the vitamin has any value in people who are clot suffering from scurvy. Until recently, the orthodox medical view has been that the vitamin does no good to such people. Oddly enough, in spite of this view, there have been, over the years, repeater! enthusiasms for trials of the vitamin in all sorts of conditions. Even before the current interest in free radlicals and in the use of antioxidants, vitamin C had many respectable supporters. One reason for the medical scepticism is clear: most of the trials of vitamin C in the management of conditions like the common cold failed because the closes given were very little more than the minimum daily requirement to prevent scurvy. It is becoming clear that, used as an antioxidant, much larger doses than the minimum daily requirement are

How Much is Safe?

On this question' Linus Pauling made an interesting point while considering vitamin C in an evolutionary context.

Assuming that early peoples must have eaten whatever they could get their hands on, he decided to work out how much vitamin C they would have taken in if, as must often have happened, the total daily calorie requirement (2,500 calories) was met from a single foodstuff The results were surprising.

If they had eaten enough peas and beans to get 2,500 calories, they would have taken in 1,000 mg of vitamin C. Vegetables with a low vitamin C content would have provided 1,200 mg, vegetables and fruits with an intermediate content would have provided 3,400 mg; high C foods like cabbage, cauliflower, chives and mustard greens would have provided 6,000 mg per day; and very high C foods like black currants, kale, parsley, peppers and broccoli would have provided no less than 12,000 mg per day.

Since humans evolved in an environment providing quantities of vitamin C of this order, Pauling inferred that the ideal daily intake for most adults should be somewhere in the range of 2,300 to 9,000 ma. The very large vitamin C intake throughout a large part of the evolutionary period implied that big doses of this vitamin should be regarded as 'natural'.

Possible Dangers

Vitamin C has an excellent safety record and has been taken in -1,000 mg plus doses by millions of people with no apparent disadvantage. To balance this, there has been a handful of reports of ill effects thought to be due to very large doses of the vitamin.

One of these was published in the British Medical Journal in March 1993. This paper reports the case of a 32-year-old HIV-positive man who developed generalized lymph node enlargement. He was advised by his doctors to start AZT treatment but refused and sought the advice of a medically qualified nutritionist. Investigation showed that he had a lower than normal blood level of the antioxidant glutathione and he was prescribed, among other things, glutathione supplements and a course of vitamin C to be given in a dosage of 40,000 mg, by intravenous injection, three times a week, plus 20,000 to 40,000 mg every day, by mouth. This huge dosage was continued for a month with no obvious change in his condition. The intravenous dose was then doubled to 80,000 mg. The next day he became breathless and feverish and his urine turned to a black colour, indicating that many red blood cells had broken down, releasing haemoglobin which was passing out in the urine, much in the manner of malarial 'Blackwater fever'.

Investigation showed that this man had sickle cell trait and a comparatively rare genetic blood disorder known as glucose-6-phosphate dehydrogenase deficiency. This enzyme deficiency disorder makes red blood cells much more fragile than normal because of a shortage of the antioxidant glutathione which protects the red cells against free radical damage. Many drugs in common use can cause the red cells to break down in this condition. The patient was given lots of fluid to drink so as to flush through his kidneys and on the third day the urine was clear. He made a complete recovery from the red blood cell breakdown.

Vitamin C dosages of this order are exceptional and there are few remedies that can, with perfect safety, be taken in quantities of 20 or 30 times the customary dosage. The report does, however, indicate that there are some people who ought to be particularly cautious about taking any drug, even one as apparently safe as vitamin C.

Beta-Carotene

The antioxidant plant pigment beta-carotene is also known as pro-vitamin A because it is converted into vitamin A (retinal and other forms) in the liver. It is found in whole milk, butter, cheese, egg yolk, liver, yellow and green vegetables and fish, especially in the liver. The same foods also contain a number of different carotene-like substances (carotenoids) that cannot be converted to vitamin A and so are wasted.

Retinol and its related substances have many important functions in the body. They are necessary for the growth and health of the surface and lining tissues and the bones; for the health of the immune system and for protection against cancer; for normal vision and for the health of the corneas; for protection against various skin diseases; and for protection of the skin against sunlight radiation and ageing changes. People deficient in retinoids suffer night blindness and dryness of the eyes (xerophthalmia). Babies may suffer devastating melting of the corneas of the eyes with permanent blindness. Severe deficiency is a common cause of death in small children after severe damage has been sustained by most systems of the body.

A normal, well-balanced diet will provide quite enough retinol to prevent any such effects. If taken as a dietary supplement, 1 mg per day is equivalent to the recommended daily allowance and this dose will probably double the amount needed to prevent deficiency.

Dangers of Over-dosage

Very large doses of vitamin A cause chronic poisoning with skin dryness, itching and peeling; drowsiness, irritability and an irresistible desire to sleep; headache; loss of appetite; enlargement of the liver and spleen; and painful and tender swellings over the bones. The vitamin accumulates in the body and the effects take weeks to wear off. Eskimos and their husky dogs never eat polar bear liver (which contains huge quantities of vitamin A) because they know of these effects. A single gram of polar bear liver contains up to 12 mg of retinal—12 times the minimum daily requirement. Vitamin A is also dangerous to the fetus if taken by the mother in doses of 7 to 12 mg a day during the first three months of pregnancy. This can cause congenital abnormalities.

Once again, here is a warning about the fallacy of believing that if something is good for you, a lot of it will be even better. This is often true, but you shouldn't count on it. In some cases, a lot is very much worse.

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