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Recent Advances in Oxidative Stress and Antioxidants in Medicine

Posted Sep 11 2009 4:57pm

BY John Smythies, M.D., F.R.C.P.


Until quite recently most physicians adhered to the belief that the only function of vitamins was to prevent deficiency diseases such as scurvy and pellagra. When Linus Pauling founded orthomolecular medicine twenty-five years ago by suggesting that vitamins might have other functions than this, he was greeted with scorn, derision and outright hostility by the orthodoxy. Today the situation is entirely transformed. There is now an enormous literature on the role of vitamins in the body other than their prevention of deficiency diseases. This is based largely on the discovery of the wide role that oxidative stress plays in many diseases and of the role of antioxidant vitamins in preventing and combating these diseases. The only point of disagreement in main stream medicine today is whether the right amount of protective antioxidant vitamins can be obtained by improving one’s diet alone – i.e. by eating more fruits and vegetables – or whether supplements are needed.

Oxidative Stress and Antioxidant Defenses

Oxidative stress arises because the life-giving oxygen molecule is easily converted into toxic reactive oxygen species or ROS (also called free oxygen radicals). The pre-dominant ROS are the superoxide radical ion, hydrogen peroxide and the hydroxyl radical ion. The latter is the most toxic and will attack and damage proteins, lipids and DNA. ROS are made by a variety of different enzymes such as the enzymes of the electron chain in the mitochondria (that generate energy by synthesizing ATP), prostaglandin H synthase (the rate limiting

1. Brain and Behavior Laboratory, Center for Human Information Processing U.C.S.D. La Jolla. CA. 92093-0109 e-mail

enzyme on the prostaglandin synthesis pathway), nitric oxide synthase, and other oxidases. Life would be impossible unless the cell developed powerful antioxidant defenses against ROS. ROS have normal roles in the body as intracellular signals and in controlling gene expression. Trouble only results if there are excess ROS or defective antioxidant mechanisms.

Antioxidant defenses are of two kinds

– small molecules that bind or scavenge the ROS and enzymes that turn them into harmless products. The small molecules are again of two types – water-soluble and lipid-soluble. The principle water soluble antioxidant molecules in the body are ascorbate (vitamin C) and glutathione (GSH). The principle lipid soluble antioxidants are vitamin E and a variety of carotenes, which are relatives of vitamin A. Plants also contain a large number of other important antioxidants called phytochemicals that are not vitamins. The body cannot make them but lack of them does not lead to deficiency diseases. These include the flavonoids and polyphenols. Other important antioxidants are vitamin B3 and coenzyme Q10. The antioxidant enzymes are catalase, superoxide dismutase and glutathione peroxidase.

It is important to note here that these antioxidants act in synergism. When vitamin E, for example, neutralizes a toxic ROS it itself is oxidized. This oxidized form has to be converted back to vitamin E to deal with more ROS. This conversion is carried out by vitamin C or by glutathione, which in turn become oxidized. The oxidized vitamin C is converted back to the protective form by NADH, a complex that contains vitamin B3. The antioxidants coenzyme Q10 and lipoic acid also play a role in this process. Vitamin C and glutathione have other protective actions, e.g. by scavenging ROS themselves, that do not depend on this recharging of vitamin E.

Oxidative stress occurs whenever the production of damaging ROS exceeds the capacity of the antioxidant defenses to cope with them. Oxidative stress is involved in a large number of diseases some of which I will describe briefly. More details on all this information may be found in my new book Every Person’s Guide to Antioxidants shortly to be published by Rutgers University Press.

Systemic Sclerosis

This is a connective tissue disease (also called scleroderma) due to overproduction of collagen that leads to vascular damage and Raynaud’s syndrome (repeated attacks of vascular spasm leading to gangrene of the extremities). It is marked by repeated ischaemia and reperfusion in the tissues with resulting oxidative tissue damage. Many organs are involved including the heart, lung, gut and kidneys. These patients have low plasma levels of vitamin C but normal levels of vitamin E. The low level of vitamin C is not due to dietary deficiencies nor maladsorption. It is not clear if the low plasma levels of vitamin C is a cause or result of the oxidative stress. Clearly antioxidants might be effective in this disease.

Safety of Antioxidants

In general, antioxidants are very safe but there are a few things to watch out for. Vitamin C is contraindicated in patients with iron overload as in the presence of free iron vitamin C turns into a pro-oxidant. In practice this means that patients with hemachromatosis, thalassemia and similar conditions should not be given large doses of vitamin C. There have also been some theoretical worries that vitamin C might increase the chance of getting an oxalate kidney stone as oxalate is a metabolite of vitamin C. However, as far as I know, there has never been a clinical report of such an event. Nevertheless the physician should bear this possibility in mind in dealing with patients with this condition. In a recent report13 Dr. Anthony Diplock of Guy’s Hospital states that the ‘stone story’ has proven on critical examination to be “without foundation”. If excess vitamin C is ingested it is excreted as such not as oxalate. He criticizes earlier studies that seemed to show that increasing vitamin C intake led to increased oxalate output to technical errors in the estimation. In fact he concludes that vitamin C in the doses normally used in supplements is entirely free from side effects. Some other reports suggest that vitamin C should be used with caution in elderly patients with cataract.

Vitamin E is quite safe except in patients with vitamin K deficiency. As we have seen betacarotene should not be given by itself or with vitamin E or vitamin A to heavy smokers. As far as I know there have been no reports of toxicity in the case of coenzyme Q10 and alpha lipoic acid. However, it is always important to give a full range of antioxidants, and not just one or two, since they work together in a very complex system. Giving large amounts of just one or two antioxidants will upset this delicate mechanism and may have undesirable effects. The only circumstance when this rule may be broken is if a blood level profile shows a deficiency of one or more particular antioxidants (see further below).

Effective Therapy with Antioxidants

It is no longer an effective strategy in disease prevention, nor is it rational therapy, to advise that all people should do nothing more than increase their intake of fruit and vegetables to recommended levels. Nor is it advisable simply to take an antioxidant supplement mixture from the shelf at the supermarket without any kind of medical supervision. This is because there are great differences between individuals as to their need for particular anti-oxidants. We now have accurate ways of measuring the blood levels of all important antioxidants and so it should be a part of the routine medical checkup for everyone to have their antioxidant profile taken just as no doctor would neglect to take blood sugar levels. Furthermore, in the case of all diseases in which oxidative stress is involved, it is obviously important to keep track of the state of the patient’s antioxidant defenses by doing this profile. In this manner, both people who wish to minimize their risk of being damaged by oxidative stress, and people who wish to have the optimum treatment for any disease that they be suffering from in which oxidative stress plays a role, will be more likely to have their antioxidant deficiencies put right.


Linus Pauling would be very pleased to see his brain child rapidly becoming part of mainstream medicine. There have been over 4,000 papers published available on Medline on oxidative stress and antioxidants since 1993. On an average twenty new papers are published every week on this topic. The drug industry is busy looking for new natural and synthetic antioxidants. Interestingly many herbs used in traditional medicine contain potent antioxidants that may be responsible for their effectiveness. As I said earlier the only dispute today is between those who say that all we need to do is to eat more fruits and vegetables and those who say that this good advice is simply not going to work. The reason for this is that at present only 10% of the population of the USA follow these guide lines about three helpings of vegetables and two of fruit a day and all attempts to increase this percentage have failed, so hard to shift are ingrained nutritional habits.

So the opposition claim that it is better to take a well balanced and inclusive antioxidant supplement than do nothing other than subsist on the usual junk food diet. The purists claim that this will mean that supplement takers will miss out on the many important flavonoids, polyphenols, isoprenes and similar ingredients of fruits and vegetables that are not usually found in supplements. Therefore, it is encouraging that some supplement manufacturers have started adding flavonoids and polyphenols to their formulas. It is also encouraging that the National Cancer Institute has started a joint venture with the agricultural industry to try to alert the public to the vital need to eat more fruits and vegetables.

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