Long-term vitamin E supplementation fails to reduce lipid peroxidation in people at cardiovascular risk: analysis of underlying factors

BACKGROUND: Antioxidant supplementation with vitamin E had no effect in the prevention of cardiovascular diseases (CVD) in three recent large, randomized clinical trials. In order to reassess critically the role of vitamin E in CVD prevention, it is important to establish whether these results are related to a lack of antioxidant action. METHODS: We examined the in vivo antioxidant effect of vitamin E (300 mg/day for about three years) in 144 participants in the Primary Prevention Project (females and males, aged ≥ 50 y, with at least one major CV risk factor, but no history of CVD). Urinary 8-epi-PGF(2α) (isoprostane F(2α)-III or 15-F(2t)-isoP), a validated biomarker of lipid peroxidation, was measured by mass spectrometry. RESULTS: Urinary excretion of 8-epi-PGF(2α) [pg/mg creatinine, median (range)] was 141 (67–498) in treated and 148 (76–561) in untreated subjects (p = 0.10). Taking into account possible confounding variables, multiple regression analysis confirmed that vitamin E had no significant effect on this biomarker. Levels of 8-epi-PGF(2α) were in the normal range for most subjects, except smokers and those with uncontrolled blood pressure or hyperglycemia. CONCLUSIONS: Prolonged vitamin E supplementation did not reduce lipid peroxidation in subjects with major cardiovascular risk factors. The observation that the rate of lipid peroxidation was near normal in a large proportion of subjects may help explain why vitamin E was not effective as an antioxidant in the PPP study and was ineffective for CVD prevention in large scale trials

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference