Q J Med 1999; 92: 527-530
© 1999 Association of Physicians
Commentary papers |
Interaction of dietary antioxidants in vivo: how fruit and vegetables prevent disease?
From the Gastrointestinal Unit, Department of Medicine, University of Edinburgh, Western General Hospital Trust, Edinburgh, UK
Dr M.A. Eastwood, Hill House, North Queensferry, Fife KY11 1JJ
Summary
Epidemiological studies indicate that fruit and vegetables are health-promoting and protective against disease, particularly cardiovascular disease and cancer. Possible plant nutrients providing this protection include antioxidants and dietary fibre. Clinical trials with antioxidant supplements give inconsistent results for protection against lung cancer in smokers, invasive cervical cancer, oesophageal and gastric cancers, colorectal polyps and coronary heart disease. The antioxidants used in trials may be contributing to a more complex system. Antioxidants have differing solubilities which partition across the phases of tissues, cells and macromolecular structures: water-soluble ascorbate, glutathione and urate; lipid-soluble tocopherols and carotenoids, and intermediatory-soluble flavonoids and hydroxycinnamic acids. The health protection provided by fruit and vegetables could arise through an integrated reductive environment delivered by plant antioxidants of differing solubility in each of the tissue, cellular and macromolecular phases.
Introduction
Diets which contain an abundance of fruit and vegetables are protective against a variety of diseases, particularly cardiovascular disease and epithelial (but not hormone-related) cancers. The principle nutrients thought to provide the protection afforded by fruit and vegetables are the antioxidants1 and dietary fibre (non-starch polysaccharides2).
In trying to unravel the underlying mechanisms of this protection, various approaches have been taken. Epidemiological studies usually start with a measurement of dietary intake or serum concentrations of the studied antioxidant. Human supplementation trials are critical to testing any hypothetical merit for antioxidant supplementation. The subsequent disease incidence or pattern is followed in that identified population. Susceptible groups are often chosen for the study: e.g. smokers, who have a distinct chance of developing cancer of the lung, individuals with colonic polyps (a precursor of colonic cancer) and women with cervical dysplastic change which can progress to cancer of the cervix. Coronary heart disease and the complications of hypertension and strokes are more difficult to predict, and form multifactorial risk groups.
Potter3 reviewed 200 epidemiological studies, the majority of which showed a protective effect of increased fruit and vegetable intake. When the role of individual antioxidants or dietary fibre is examined by epidemiological studies or supplementation trials, the results are not as clear-cut as those obtained for fruit and vegetables, and are often disappointing.
The conclusion drawn by Potter3 was that fruit and vegetables provide the best polypharmacy against the development of malignancy in tissues. Van Poppel and van den Berg4 and Rexrode and Manson5 echo this sentiment, and recommend a diet rich in fruit and vegetables, seeing no merit in recommending vitamin supplements for disease prevention. This is a safe principle but avoids the issue of which fruit and vegetables to eat, whether the unknown beneficial nutrients are affected by conditions of growing, time of year and maturity of the plant when harvested, time of day of harvesting, method of cooking and freezing, etc.6–9
The absorption and delivery of nutrients from fruit and vegetables may not be the same when given as individual sources. For example, increasing the daily intake of dark-green leafy vegetables did not improve vitamin A status, whereas an equivalent dose supplementation of beta-carotene produced a marked increase.10 In another study, fruit and vegetable consumption was increased and the plasma concentrations of vitamin C, 
- and ß-carotene, but not retinol and -tocopherol nor lipoproteins, increased.11 This variation may be due to the physical inaccessibility of the ß-carotene, held within cells with consequent reduced bioavailability. On the other hand, the reduced bioavailability of antioxidants in foods compared with that of a supplement may be important in minimizing any potential metabolic disturbance arising from taking too much of the pure compound.
In large supplementation trials, individuals are treated as belonging to a homogeneous population. Within such study groups there may be susceptible genetically-defined at-risk subgroups for cardiovascular disease or carcinoma who would benefit from the supplement. Hyperhomocysteinaemia is a possible risk factor for premature cardiovascular death. Supplementation of the diet in hyperhomocysteinaemic individuals with the B group of vitamins (but not antioxidant vitamins) reduces homocysteine concentrations.12
Another important component of fruit and vegetables which has been proposed to have protective effects against disease is dietary fibre. Dietary fibre dilutes gastrointestinal contents, or may be fermented in the colon with release of low-molecular-mass chemicals of nutritional and biochemical significance, e.g. short chain fatty acids13 and hydroxycinnamic acids.14 The protective action of fibre against coronary heart disease could result from a reduction in serum cholesterol. The mechanism may be through the binding of bile acids to fibre resistant to colonic bacterial fermentation15 or more certainly through adsorption to bacteria, which proliferate during colonic fibre fermentation.16
The action of fibre in reducing cancer is confined to colonic cancer, and is essentially a local or direct mucosal effect. The action of fibre may be secondary to the dilution of potential carcinogens in the colon through the water-binding capacity of fibre, e.g. moderately-fermented cereal fibre.17 Alternatively, following fermentation in the colon, short-chain fatty acids, especially butyric acid, may act on cell turnover and growth in the colonic mucosa.
Despite all these contradictory results, there is a strong body of opinion that diseases may be caused by, or their development accelerated by, an imbalance between the overproduction of free radicals and antioxidant activity, the so called oxidative stress concept.
Oxidative stress
During oxidative metabolism, there is a continuous production of free radicals which are scavenged by antioxidants, thereby limiting damage.
A number of low-molecular-mass compounds with a range of solubility properties can act as chain-breaking antioxidants. Amongst these are ascorbate, glutathione and urate, acting as hydrophilic scavengers. Major lipophilic scavengers include carotenoids and sterically-hindered phenols e.g. -tocopherol and flavonoids. The link between dietary fibre and these antioxidants, all constituents of fruit and vegetables, is provided by the hydroxycinnamic acids, p-coumaric acid and ferulic acid. These C6–C3 phenols form cross-linkage dimers in plant cell-wall structural polysaccharides of fruit and vegetables. Hydroxycinnamic acids, e.g. feruloyl ß-glucoside, are also found as soluble conjugates in the vacuoles of plant cells.18
When fruit and vegetables are eaten, the hydroxycinnamic acids contained within vacuoles will be absorbed from the small intestine. After bacterial dissimilation of the plant cell wall in the colon, hydroxycinnamic acids will be released and absorbed from the colon.
Antioxidant activity: an integrated reaction?
The body, its structures, cells and macromolecules, consist of phases with a range of physical variables, anatomical divisions and water-soluble and lipid-soluble fluid phases. Within these phases, and at interphases, there will be variations in pH, ionic strength, osmolality, electrical charge, chemical concentration and redox potential. These variables will influence the ability of the phases to act as solvents for lipid- and water-soluble antioxidants, e.g. vitamin C in an aqueous phase, carotene in a lipid phase. Some water-soluble antioxidants, including transferrin, caeruloplasmin and albumin, have low partition coefficients. Entry into a lipid phase or retention in a water-soluble phase of these weak acid antioxidants will be dependent upon their pKa and the pH gradient across the membrane.
The lipophilicity of a chemical can be estimated by the pKa or by the octanol-water partition coefficient (kow) expressed in log units (log10Pc). This is a useful measurement for determining biological function.19 The partition coefficients for a number of antioxidants are given in Table 1
.20 Of the range of phytochemicals described: among the carotenoids, 95% have a log10Pc value of >9; among the flavonoids, 22% have a log10Pc <1.0, 75% a log10Pc between 1.1 and 5.0, and 2% have a log10Pc between 5.1 and 7.5.
|
Chemicals with both hydrophobic and hydrophilic substitutions, and hence mixed solubility properties will be distributed between aqueous and non-aqueous systems, e.g. hydroxycinnamic acid and lipoic acid,21 a partitioning dependent upon the relative contribution and stereochemistry of hydrophobic and hydrophilic substitutions. Solubility is further modified when the partition coefficient of a chemical is altered by conjugation, chemical combination or binding into more complex substances, e.g. proteins which facilitate miscibility into a phase.
This means that antioxidants of differing solubility will nestle next to each other in cellular structures and tissues. Adjacent antioxidants will recharge neighbouring antioxidants in an integrated manner which will also depend upon reaction stoichiometry and kinetics. The relative importance or significance of a given antioxidant may rely not only on its reaction rate and concentration in a given compartment or solving space, but also on its capability to interact with regenerating systems of varying types. This raises the prospect that a variety of antioxidants are necessary to maintain the antioxidant environment in a non-homogeneous biological state, that there is a continuum of antioxidants. There would thus be synergism between antioxidants dispersed in a non-uniform manner between different phases in the body cells and compartments. Water-soluble antioxidants would have an indirect role in membrane and lipoprotein protection. This can be achieved in a chain reaction through the activity of antioxidants of intermediary partition coefficient, polyphenols, tannins and hydroxycinnamic acids and lipoic acid.21 A precedent for this idea is the concept of osmolality, a summation of a mixture of osmotically active chemicals.
Acknowledgments
This paper is based on work which received financial support from BBSRC. I am grateful for discussions with Stephen Fry, Michael Spencer and Callum Buchanan during the writing of this paper.
References
1. Cadenas E, Packer L. Handbook of Antioxidants. New York, Marcel Dekker, 1996:545–91.
2. Kritchevsky D, Bonfield C. Dietary fiber in health and disease. St Pauls, Eagan Press, 1995.
3. Potter JD. Cancer prevention: epidemiology and experiment. Cancer Lett 1997; 114:7–9.[Web of Science][Medline]
4. van Poppel G, van den Berg H. Vitamins and cancer. Cancer Lett 1997; 114:195–202.[Web of Science][Medline]
5. Rexrode KM, Manson JE. Antioxidants and coronary heart disease: observational studies. J Cardiovasc Risk 1996; 3:363–7.[Medline]
6. Haldimann P. Effects of changes in growth temperature on photosynthesis and carotenoid composition in Zea mays leaves. Physiologia Planatarum 1996; 97:554–62.
7. Islam MS. Variability in different physical and biochemical characteristics of six tomato genotypes according to stages of ripeness. Bangl J Bot 1997; 26:137–47.
8. Torres JM, Laidman CL, Gaunt JK. Diurnal changes in the incorporation of uniformly labelled carbon-14 tyrosine into tocopherols and plastoquinones in leaves of xanthium-strumarium. Phytochemistry (Oxford) 1991; 30:1107–8.
9. Warman PR, Havard KA. Yield, vitamin and mineral contents of organically and conventionally grown carrots and cabbage. Agric Ecosys Environ 1997; 61:155–62.
10. de Pees S, West CE, Darvin Karyadi M, Hautvast JG. Lack of improvement in vitamin A status with increased consumption of dark-green leafy vegetables. Lancet 1995; 346:75–81.[Web of Science][Medline]
11.
Zino S, Skeaff M, Williams S, Mann J. Randomised controlled trial of effect of fruit and vegetable consumption on plasma concentrations of lipids and antioxidants. Br Med J 1997; 314:1787–91.
12. Woodside JV, Yarnell JW, McMaster D, et al. Effect of B group vitamins and antioxidant vitamins on hypercysteinaemia—a double blind randomized factorial design controlled trial. Am J Clin Nutr 1998; 67:858–66.[Abstract]
13.
Cummings JH, Macfarlane GT. Role of intestinal bacteria in nutrient metabolism. J Parent Enteral Nutr 1997; 21:357–65.
14. Buchanan CJ, Wallace G, Fry SC, Eastwood MA. In vivo release of 14C-labelled phenolic groups from intact dietary spinach cell walls during passage through the rat intestine. J Sci Food Agric 1996; 71:459–69.
15. Eastwood MA, Hamilton D. Studies on the absorption of bile salts to non-absorbed components of diet. Biochimica Biophysica Acta 1968; 152:159–66.[Medline]
16. Gelissen IC, Eastwood M. Taurocholic acid adsorption during non-starch polysaccharide fermentation: An in vitro study. Br J Nutrition 1995; 74:221–8.[Web of Science][Medline]
17. Eastwood MA. Dietary Fiber and the Risk of Cancer. Nutrition Rev 1987; 45:193–8.[Web of Science][Medline]
18. Wallace G, Fry SC. Phenolic components of the plant cell wall. Int Rev Cytol 1994; 151:229–67.[Web of Science][Medline]
19. Hansch C, Dunn WJ III. Linear relationship between lipophilic character and biological activity of drugs. J Pharmaceut Sci 1972; 61:1–19.[Web of Science][Medline]
20.
Cooper DA, Webb DR, Peters JC. Evaluation of the potential for olestra to affect the availability of dietary phytochemicals. J Nutr 1997; 127:1699–709S.
21. Packer L, Witt EH, Tritschler HJ. Antioxidant properties and clinical applications of alpha-lipoic acid and dehydrolipoic acid. In: Cadenas E, Packer L. Handbook of Antioxidants. New York, Marcel Dekker, 1996:545–91.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  H. Kan, J. Stevens, G. Heiss, K. M. Rose, and S. J. London Dietary Fiber, Lung Function, and Chronic Obstructive Pulmonary Disease in the Atherosclerosis Risk in Communities Study Am. J. Epidemiol., March 1, 2008; 167(5): 570 - 578. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. J. ATKINSON, P. A. A. DODDS, Y. Y. FORD, J. LE MIERE, J. M. TAYLOR, P. S. BLAKE, and N. PAUL Effects of Cultivar, Fruit Number and Reflected Photosynthetically Active Radiation on Fragaria x ananassa Productivity and Fruit Ellagic Acid and Ascorbic Acid Concentrations Ann. Bot., March 1, 2006; 97(3): 429 - 441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D.-H. Lee, A. R Folsom, L. Harnack, B. Halliwell, and D. R Jacobs Jr Does supplemental vitamin C increase cardiovascular disease risk in women with diabetes? Am. J. Clinical Nutrition, November 1, 2004; 80(5): 1194 - 1200. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. T. Mayne, M. E. Wright, and B. Cartmel Assessment of Antioxidant Nutrient Intake and Status for Epidemiologic Research J. Nutr., November 1, 2004; 134(11): 3199S - 3200S. [Full Text] [PDF]
|
|
|
|
 |
|
 L. M. Butler, W.-P. Koh, H.-P. Lee, M. C. Yu, and S. J. London Dietary Fiber and Reduced Cough with Phlegm: A Cohort Study in Singapore Am. J. Respir. Crit. Care Med., August 1, 2004; 170(3): 279 - 287. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. E. Wright, S. T. Mayne, R. Z. Stolzenberg-Solomon, Z. Li, P. Pietinen, P. R. Taylor, J. Virtamo, and D. Albanes Development of a Comprehensive Dietary Antioxidant Index and Application to Lung Cancer Risk in a Cohort of Male Smokers Am. J. Epidemiol., July 1, 2004; 160(1): 68 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D.-H. Lee, L. M Steffen, and D. R Jacobs Jr Association between serum {gamma}-glutamyltransferase and dietary factors: the Coronary Artery Risk Development in Young Adults (CARDIA) Study Am. J. Clinical Nutrition, April 1, 2004; 79(4): 600 - 605. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. S. Ritchie, K. Joshipura, H.-C. Hung, and C. W. Douglass NUTRITION AS A MEDIATOR IN THE RELATION BETWEEN ORAL AND SYSTEMIC DISEASE: ASSOCIATIONS BETWEEN SPECIFIC MEASURES OF ADULT ORAL HEALTH AND NUTRITION OUTCOMES Critical Reviews in Oral Biology & Medicine, May 1, 2002; 13(3): 291 - 300. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Brown, T. Byers, K. Thompson, B. Eldridge, C. Doyle, A. M. Williams, and American Cancer Society Workgroup on Nutrition and Nutrition During and After Cancer Treatment: A Guide for Informed Choices by Cancer Survivors CA Cancer J Clin, May 1, 2001; 51(3): 153 - 181. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M.A. Eastwood A molecular biological basis for the nutritional and pharmacological benefits of dietary plants QJM, January 1, 2001; 94(1): 45 - 48. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||