. "2 Vitamin C, Vitamin E, Selenium, and •-Carotene and Other Carotenoids: Overview, Antioxidant Definition, and Relationship to Chronic Disease." Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington, DC: The National Academies Press, 2000.
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DRI DIETARY REFERENCE INTAKES FOR Vitamin C, Vitamin E, Selenium, and Carotenoids
be carcinogenic. However, a causal relationship between oxidative stress to DNA and cancer in humans has not yet been established (Poulsen et al., 1998).
A great deal of evidence based on epidemiological studies indicates that consuming diets rich in fruits and vegetables is associated with both a decrease in oxidative damage to DNA (Halliwell, 1998) and a lower risk of a number of common cancers. There are several mechanisms that could account for these observations, in addition to antioxidant components that scavenge radical intermediates. Other mechanisms include the modification of carcinogen activation by the inhibition of phase 1 enzymes, modification of carcinogen detoxification by phase 2 enzymes, and suppression of the abnormal proliferation associated with preneoplastic lesions (Wargovich, 1997).
Of all the chronic diseases in which excess oxidative stress has been implicated, cardiovascular disease has the strongest supporting evidence. A coherent pathogenetic mechanism has been developed to account for the earliest stage in atherogenesis, namely, the development of the fatty streak lesion. Hypercholesterolemia and, particularly, increased concentrations of low-density lipoproteins (LDLs) cause the accumulation of cholesterol-loaded “foam cells” beneath the endothelial lining of major arteries, which in turn develop into a fatty streak. This lesion is clinically benign but is the precursor of later lesions (the fibrous plaque and the complex lesion) that ultimately give rise to clinical manifestations (angina pectoris and myocardial infarction) (Steinberg and Witztum, 1990).
An elevated LDL cholesterol level sufficiently increases the risk of cardiovascular disease. Brown and Goldstein (1986) demonstrated that the molecular defect in individuals with familial hypercholesterolemia was the absence of functional LDL receptors. The histological lesions in these patients cannot be differentiated from that of lesions in individuals who have normal LDL receptors. The implication therefore is that normal LDL taken up by way of the normal LDL receptor cannot be the basis for the formation of foam cells. In other words, the LDL must first be modified somehow and the modified form must be taken up into the monocytes or macrophages via one or more alternative receptors ultimately and develop into foam cells. One such modification, and the most extensively studied, is LDL oxidation, and several macrophage receptors have been shown to take up oxidatively modified LDL (oxLDL) and