Title: How Antioxidants Can Act as Pro-oxidants

Key words: Lipoprotein, coronary artery disease (CAD), selenium, flavonoids, homocysteine, iron, free radicals, Vitamin E, lipid peroxidases, zinc, cancer risk

Date: Oct 1999

Category: 15. Materia Medica

Type: Article

Author: Dr M Draper


How Antioxidants Can Act as Pro-oxidants

IntroductionA number of primary and secondary prevention trials , including angiographic studies, have indicated that a decrease in dietary saturated fat and cholesterol produces a decrease in the blood levels of cholesterol and low density lipoprotein (LDL) cholesterol, leading to a decrease in coronary artery disease (CAD) (1). Increasing evidence indicates that the oxidation of LDL in human beings is atherogenic. Of the three major antioxidants , Vitamin E, beta carotene and vitamin C, the evidence for a strong and independent inverse association with CAD is strongest with vitamin E.

Selenium and flavinoids also have antioxidant properties, but their association with CAD is equivocal. Various studies on cancer have shown an association between low levels of antioxidants and cancer, in a large Finnish study (2) the increased risk of cancer if vitamin E was low was 1.6 and for low selenium 5.8, with a combined risk of 11.4. The Finnish government put selenium back into the soil and elevated the average daily intake from 25 micrograms in 1984 to around 100 micrograms per day (3) and reported a decrease in coronary heart and cancer deaths and an increase in male sperm count. This type of data will make nutritional supplementation an issue for debate.

There are currently two pro-oxidants , homocysteine and iron, which have been associated with CAD.Could antioxidants act as pro-oxidants in intervention studies?The answer, theoretically, is "Yes".

The mechanism is as follows: free radicals (highly reactive molecular species with an unpaired electron) generate other free radicals, unless two free radicals react together. This is unlikely because of the low concentration of radicals and their extremely short half life, hence, most free radical reactions are chain reactions.

The major radicals causing tissue damage are oxygen radicals: superoxide (' 02), perhydoxyl (' 02H) and hydroxyl ('0H). The cell has various mechanisms to protect against radical damage and these include removal of superoxide by superoxide dismutase , protein binding

of metal ions such as iron by transferrin, haemosiderin and ferritin, copper by ceruloplasmin and binding of other metal ions by metallothioein. The cell membrane-situated glutathione peroxidase contains selenium and relies on its presence for its full antioxidant activity.

Reduction of lipid peroxidases by vitamin E forms the relatively stable tocopheroxyl radical, which is reduced back to tocopherol by reaction with vitamin C, forming a relatively stable monodehydroascorbate radical (4). The ascorbate can, however, also react as a pro-oxidant by reacting with oxygen to form a superoxide and monohydroascorbate or by reacting with copper to produce a hydroxyl radical and monohydroascorbate.

The importance of decreasing dietary saturated fat and cholesterol to reduce the incidence of CAD is well established and the possible association between the pro-oxidant activity of homocysteine and iron will make intervention studies using antioxidants come under close scrutiny. The apparent association between low selenium , zinc and other antioxidants causing increased risk of cancer will also mean intervention studies being performed to establish benefit from dietary changes or supplementation.



1. Strain, J.J. Putative Role of Dietary Trace-Elements in Coronary Heart Disease and Cancer. J.Bio Med Sci 1991; 2 p.19 - Royal Society Medicine Services Ltd.

2. Salonen, J. T., Alfthan,G., Puska, P., Maenpaa, P.P. et al. Risk of cancer in re. to serum conc. of prospective data: British Medical Journal 1985; 290:p.417-420

3. Tolonen, M. Finnish studies on antioxidants with special reference to cancer, cardiovascular diseases and aging. Int Clin Nutr Rev 1989; 9:68-75.

4. Bender, D. A. Introduction to Nutrition and Metabolism 1997; Taylor & Francis.