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Mechanisms and Biomarkers (WG 4) page 5
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control, cohort and epidemiological studies. Also analytical and epidemiological studies
contribute evidence of potential causal relationships. It is important to note, however, that
some of these studies provide evidence more for dietary and lifestyle trends rather than the
function of a particular constituent, in disease prevention. It has been shown that the
frequency of fruit and vegetable intake increased with increasing physical activity.
Conversely, consumption of similar protective diets was lower in subjects who were
sedentary, heavy smokers, or heavy drinkers (Serdula et al., 1996). Many studies with animal
models and cell tissue culture systems have provided valuable insight into the potential
protective role of fruit and vegetables against chronic disease risk in humans, but the
relationships are not always clear. The rat model, for example, is difficult to apply where the
stomach pH is high and supports an abundant microflora as compared with the human
stomach which is very acidic and has a very sparse microflora. Notwithstanding the
limitations of animal test systems, well-controlled in vitro and animal experiments provide the
most rapid and cost-effective means of generating data to design future human intervention
trials. For example, experiments spanning some 50 years have demonstrated the value of
caloric restriction in preventing cancer and prolonging life in animal feeding trials. If any
phytochemical or dietary regime produces similar results in an animal model, then this would
provide powerful evidence to study the same regime in human subjects.
Little is known of how many phytochemicals are processed in vivo, how they are absorbed,
metabolised and distributed in the body and whether they even reach the tissues of interest.
Moreover, little account is taken of the wide-ranging metabolic capabilities of the human gut
microflora which can transform a variety of ingested phytochemicals (Borriello et al., 1984).
In the past too much reliance has been placed on the plasma concentrations of dietary
components as biomarkers of uptake and effect and the potential of gut-derived
biotransformation products has rarely been assessed. Cell culture presents considerable
problems, particularly with respect to the study of the role of diet in carcinogenesis. Cell lines,
by definition are not representative of cells in healthy tissues which have a finite lifespan,
have attained the transformed genotype which confers immortality, and many biochemical
features that differ markedly from normal cells. Moreover, traditional cell-culture is carried
out under non-physiological conditions at atmospheric pressure (160 ppm O2) when normally
protective antioxidant compounds may exhibit prooxidant activity eg. β-carotene. The ideal
test of causality would be to carry out human intervention studies with a disease as an
endpoint, but ethical considerations preclude the design of placebo-controlled, randomised
trials with multiple doses of different phytochemicals and dietary factors to evaluate disease