Dietary Antioxidants and Human Health

Plants produce a very impressive array of antioxi-dant compounds, including carotenoids, flavonoids, cinnamic acids, benzoic acids, folic acid, ascorbic acid, tocopherols, and tocotrienols, and plant-based foods are our major source of dietary antioxidants. Antioxidant compounds are concentrated in the oxidation-prone sites of the plant, such as the oxygen-producing chloroplast and the PUFA-rich seeds and oils. Plants make antioxidants to protect their own structures from oxidant stress, and plants increase antioxidant synthesis at times of additional need and when environmental conditions are particularly harsh.

Humans also can upregulate the synthesis of endogenous antioxidants, but this facility is very limited. For example, production of the antioxidant enzyme SOD is increased with regular exercise, presumably as an adaptation to the increased ROS load resulting from higher oxygen use. However, an increase in other endogenous antioxidants, such as bilirubin and uric acid, is associated with disease, not with improved health. Increasing the antioxi-dant status of the body by purposefully increasing the production of these antioxidants, therefore, is not a realistic strategy. However, the concept that increased antioxidant intake leads to increased anti-oxidant defense, conferring increased protection against oxidant stress and, thereby, decreasing the risk of disease, is a simple and attractive one. Anti-oxidant defense can be modulated by varying the dietary intake of foods rich in natural antioxidants. It has been shown that following ingestion of an antioxidant-rich food, drink, or herb the antioxidant

Figure 7 Dietary antioxidants are absorbed and distributed to various sites within the human body.

status of the plasma does indeed increase. The question remains, however, as to whether increasing the antioxidant defense of the body by dietary means, while achievable, is a desirable strategy to promote human health and well-being.

There are many age-related disorders that, in theory at least, may be prevented or delayed by increased antioxidant defense. These disorders include arthritis, cancer, coronary heart disease, cataract, dementia, hypertension, macular degeneration, the metabolic complications of diabetes mellitus, and stroke. The rationale for prevention of disease by antioxidants is based on the following facts.

1. Epidemiological evidence shows that a high intake of antioxidant-rich foods, and in some cases antioxidant supplements, is associated with a lower risk of these diseases.

2. Experimental evidence shows that oxidation of cells and structures (such as low-density lipoprotein, DNA, membranes, proteins, and mitochondria) is increased in individuals suffering from these disorders.

3. Experimental evidence shows that antioxidants protect protein, lipid, and DNA from oxidative damage.

4. Experimental evidence shows that biomarkers of oxidative damage to key structures are ameliorated by an increased intake of dietary antioxidants.

However, the following cautionary statements must be noted.

1. While there is a large body of observational evidence supporting a protective effect of dietary antioxidants, it has been suggested that the importance of this has been overstated, and recent studies are less supportive.

2. While phenomenological evidence is strong that oxidative damage does occur in aging and in chronic degenerative diseases, cause-and-effect relationships have not been confirmed.

3. While experimental evidence is quite strong, studies have generally been performed in vitro using very high concentrations of antioxidants, making their physiological relevance unclear.

4. Evidence from intervention trials is of variable quality and conflicting; animal studies have shown positive results but have often used very high does of antioxidants, and the relevance to human health is unclear; large human intervention trials completed to date, such as the a-Tocopherol ^-Carotene Cancer Prevention Study, Gruppo Italiano per Io Studio Delia Sopravivenza nell'Infarto Miocardico, the Heart Protection Study, the Heart Outcomes Prevention Evaluation, and the Primary Prevention Project, have been largely disappointing in that they have not shown the expected benefits. These studies are summarized in Table 4.

Overall, observational data are supportive of beneficial effects of diets rich in antioxidants (Figure 8), and intervention trials have often used high-risk groups or individuals with established disease (Table 4). In addition, intervention trials have generally used antioxidant supplements (usually vitamin C or vitamin E) rather than antioxidant mixtures or antioxidant-rich foods. Therefore, while observational data support a role for antioxidant-rich food in health promotion, whether or not it is the antioxidants in the food that are responsible for the benefit remains to be confirmed.

Table 4 Summary of completed large antioxidant intervention trials

Name and aim of study

The a-tocopherol ¡3-carotene cancer prevention study (ATBC); primary prevention

Subjects

29133 high-risk subjects (male smokers, 50-69 years old; average of 20 cigarettes day-1 smoked for 36 years)

Supplementation

50mgday~1 of a-tocopherol (synthetic) or 20mgday~1 of ¡3-carotene, or both, or placebo, for 5-8 years (median follow-up 6.1 years)

The Cambridge Heart Antioxidant Study (CHAOS); secondary prevention

2002 high-risk subjects (angiographically proven cardiovascular disease)

d-a-tocopherol 400IU or 800IU per day (median follow-up 510 days; results on different doses combined into one treatment group)

Gruppo Italiano per lo Studio Delia Sopravivenza nell'lnfarto Miocardico (GISSI); secondary prevention

11 324 survivors of Ml within previous 3 months of enrollment a-tocopherol (synthetic) 300 mg day-1 or omega 3 fatty acids (0.9 g day~1) or both or neither for 3.5 years; subjects continued on normal medication (50% on statins)

Results/comments

Reference

Supplementation with a-tocopherol had no effect on lung-cancer incidence; no evidence of interaction between a-tocopherol and ¡3-carotene; significant increase in fatal coronary events in men with history of heart disease, and 18% increase in lung-cancer incidence in ¡3-carotene supplemented men; follow-up showed significant (32%) decrease in risk of prostate cancer and nonsignificant (8%) decrease in fatal coronary heart disease in a-tocopherol supplemented subjects Significant decrease (77%) in non-fatal Ml in treatment group; slight nonsignificant (18%) increase in fatal cardiovascular events in treatment group, but most (21/27) in noncompliant subjects Nonsignificant decrease (11%) in primary endpoints (death, nonfatal Ml, and stroke) with vitamin E; high dropout rate (25%); open label study

The Alpha-tocopherol, Beta-carotene Cancer Prevention Study Group (1994) Journal of the National Cancer Institute 88: 1560-1570 Pryor WA (2000) Free Radical Biology and Medicine 28: 141-164

Stephens NG et al. (1996) Lancet 347: 781-786

Marchioli R (1999) Lancet 354: 447-455

Table 4 Continued

Name and aim of study

Subjects

Supplementation

Results/comments

Reference

Primary Prevention Project

4495 subjects with >1 major

«-tocopherol (synthetic)

Vitamin E had no significant

Primary Prevention Project

(PPP)

cardiovascular risk factor

300mgday~1 or aspirin

effect on any primary

(2001) Lancet 357: 89-95

100mgday~1 or both or

endpoint (cardiovascular

neither, follow-up average of

death, Ml, or stroke)

3.6 years

The Heart Outcomes

9541 subjects (2545 women,

400IUday~1 vitamin E (from

No significant effect of vitamin E

The Heart Outcomes

Prevention Evaluation

6996 men) aged >55 years,

'natural sources') or Ramipril

on any primary endpoint (Ml,

Prevention Evaluation Study

Study (HOPE); secondary

high-risk (cardiovascular

(angiotensin converting

stroke, or cardiovascular

Investigators (2000) New

prevention

disease or diabetes and >1

enzyme inhibitor) or both or

death)

England Journal of Medicine

other CVD risk factor)

neither; follow-up for

342: 154-160

4-6 years

Heart Protection Study

20536 subjects, high-risk

Daily antioxidant cocktail

No significant differences in

The Heart Protection Study

(diabetes, peripheral vascular

(6001U dl-a-tocopherol,

hemorrhagic stroke or

Collaborative Group (2002)

disease or coronary heart

250 mg vitamin C, 20 mg

all-cause mortality between

Lancet 360: 23-32

disease)

¡3-carotene) or placebo for

treatment and placebo groups

5 years

Ml, myocardial infarction; CVD, cardiovascular disease.

Ml, myocardial infarction; CVD, cardiovascular disease.

ascorbic acid (|M)

Figure 8 Age-adjusted rates of all-cause mortality by sex-specific ascorbic-acid quintiles in 8860 British men (squares) and 10636 British women (diamonds).

ascorbic acid (|M)

Figure 8 Age-adjusted rates of all-cause mortality by sex-specific ascorbic-acid quintiles in 8860 British men (squares) and 10636 British women (diamonds).

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