3.6.1 P-Carotene as an antioxidant
The ability of carotenoids to act as antioxidants can be measured in vitro, ex vivo, or in vivo. LDL isolated from an individual who has been supplemented with carotenoids and then evaluated for its antioxidant activity is an extension of an in vivo study, i.e. ex vivo. However, when carotenoids are added to plasma and then the oxidisable value of the LDL is measured it is more like an in vitro model (Krinsky, 2001). Many studies report using the ex vivo method of measuring the oxidisability of the LDL particles after feeding increased amounts of carotene-containing foods. However, when using fruits and vegetables the outcome is variable and difficult to interpret because they also contain vitamin C, polyphenols and flavonoids, which are also potential antioxidants. One study which gave additional dietary fruits and vegetables to subjects reported an increase in the resistance of LDL to oxidation (Hininger et al, 1997) while two other studies found no effect (Chopra et al, 1996; van het Hof et al, 1999). The differing results obtained may be due to different time periods on the diets, different degrees of change in the plasma carotenoids or to different study populations (Krinsky, 2001).
The strongest epidemiological evidence suggesting high intake of fruits and vegetables might give protection against lung cancer came from prospective studies in which low plasma p-carotene was associated with a higher incidence of lung cancer. Carotenoid intake was associated with reduced cancer risk in 8 prospective studies and 18 out of 20 retrospective studies (Zeigler et al, 1996). Based on the results of these studies, three major intervention studies investigated the protective effect of p-carotene in the prevention of lung cancer:
(a) The alpha-tocopherol, beta-carotene (ATBC) Cancer Prevention study, was a randomised-controlled trial that tested the effects of daily doses of 50mg (50 IU) vitamin E (all-racemic a-tocopherol acetate), 20 mg of p-carotene, both or placebo in a population of more than 29 000 male smokers for 5-8 years. No reduction in lung cancer or major coronary events was observed with any of the treatments. What was more startling was the unexpected increases in risk of death from lung cancer and ischemic heart disease with p-carotene supplementation (ATBC Cancer Prevention Study Group, 1994).
(b) Increases in risk of both lung cancer and cardiovascular disease mortality were also observed in the beta-Carotene and Retinol Efficacy Trial (CARET), which tested the effects of combined treatment with 30mg/d p-carotene and retinyl palmitate (25000IU/d) in 18000 men and women with a history of cigarette smoking or occupational exposure to asbestos (Hennekens et al, 1996).
(c) The third study was the Physicians Health Study, in which 22071 US male physicians were randomised to get 50 mg ß-carotene or aspirin (325mg), or both or neither every other day for 12 years. There was no evidence of a significant beneficial or harmful effect on cancer or cardiovascular disease, but the number of smokers in the study was too small to be certain whether ß-carotene was harmful in the group or not (Hennekens et al, 1996).
One other study should also be mentioned. The Cancer Prevention Study II, a prospective study on more than one million US adults investigated the effect of commercially available multivitamins and/or vitamins A, C, and/or E on mortality during a 7 year follow-up. The use of multivitamins plus A, C and/or E significantly reduced the risk of lung cancer in former smokers and in those who never smoked, but increased the risk in men who smoked and used vitamins A, C and/or E compared with men who reported no supplement use. Thus the 'antioxidant' vitamins A, C and E only appear to benefit male non-smokers. No association with smoking was seen in women (Watkins et al, 2000).
3.6.3 Reasons for increased cancer risk associated with P-carotene supplementation
The mechanism for the increased risk associated with p-carotene supplementation in smokers is unclear. One suggestion is that the subjects of the studies already had a 'high risk' of developing lung cancer and many might have had undetected tumours at the start. The stage of carcinogenesis that p-carotene might affect is not known but if mediated by the immune system the effect might be at the promotional stages preceding the formation of a malignant tumour (Hughes, 2001). The immune system appears to be particularly sensitive to oxidative stress. Immune cells rely heavily on cell-to-cell communication, particularly via membrane bound receptors, to work effectively. Cell membranes are rich in polyun-saturated fatty acids and if peroxidised, can lead to a loss of membrane integrity, altered membrane fluidity and result in alterations in intracellular signalling and cell function. It has been shown that exposure to reactive oxygen species (ROS) can lead to a reduction in cell-membrane expression (Hughes, 2001). In addition, the production of ROS by phagocytic immune cells can damage the cells themselves if not adequately protected by antioxidants such as p-carotene, lycopene and lutein.
One of the major unresolved dilemmas of p-carotene research is the intake required to optimise immune function and provide other health benefits (Hughes, 2001). Most studies have been done using pharmacological doses of p-carotene and it is not clear whether different intakes are associated with different outcomes. It is also possible that supplemental p-carotene might be interfering with intestinal absorption of other possible chemopreventive nutrients e.g. p-carotene can inhibit absorption of lutein, a-carotene and canthaxanthin, all of which show good antioxidant properties (Olson, 1999). Another explanation might be that p-carotene is acting as a pro-oxidant in the presence of high oxygen tension in the lung.
The apparent protection of a diet high in fruit and vegetables is likely to be the result of a multifactorial effect from a number of components in those foods. Two recent prospective studies found that subjects entering the studies with higher plasma b-carotene concentrations from dietary intake had a lower risk of lung cancer (McDermott, 2000). This finding perhaps suggests more studies using dietary enrichment with carotenoids rather than pharmacological supplements should be carried out.
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