Inverse deuterium kinetic isotope effect for peroxidation in human low‐density lipoprotein (LDL): a simple test for tocopherol‐mediated peroxidation of LDL lipids

Witting, Paul K.; Bowry, Vincent W.; Stocker, Roland

doi:10.1016/0014-5793(95)01172-b

Cited by 69 publications

(37 citation statements)

References 31 publications

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“…In in vitro studies on copper-induced oxidation of LDL, in which the Cu 2ϩ to LDL particle ratio is at least 3, ␣-tocopherol acts as an antioxidant. 8 Our finding accords with earlier studies, in which doses of not less than 400 IU/d have lengthened the lag time. 7,37 The lag time during LT was statistically significantly shorter than that during PT.…”

Section: Discussionsupporting

confidence: 92%

Effects of Lovastatin Therapy on Susceptibility of LDL to Oxidation During α-Tocopherol Supplementation

Palomäki

Malminiemi

et al. 1999

ATVB

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Abstract-A randomized, double-masked, crossover clinical trial was carried out to evaluate whether lovastatin therapy (60 mg daily) affects the initiation of oxidation of low density lipoprotein (LDL) in cardiac patients on ␣-tocopherol supplementation therapy (450 IU daily). Twenty-eight men with verified coronary heart disease and hypercholesterolemia received ␣-tocopherol with lovastatin or with dummy tablets in random order. The two 6-week, active-treatment periods were preceded by a washout period of at least 8 weeks. The oxidizability of LDL was determined by 2 methods ex vivo. The depletion times for LDL ubiquinol and LDL ␣-tocopherol were determined in timed samples taken during oxidation induced by 2,2-azobis(2,4-dimethylvaleronitrile). Copper-mediated oxidation of LDL isolated by rapid density-gradient ultracentrifugation was used to measure the lag time to the propagation phase of conjugated-diene formation. ␣-Tocopherol supplementation led to a 1.9-fold concentration of reduced ␣-tocopherol in LDL (PϽ0.0001) and to a 2.0-fold longer depletion time (PϽ0.0001) of ␣-tocopherol compared with determinations after the washout period. A 43% prolongation (PϽ0.0001) was seen in the lag time of conjugated-diene formation. Lovastatin decreased the depletion time of reduced ␣-tocopherol in metal ion-independent oxidation by 44% and shortened the lag time of conjugated-diene formation in metal ion-dependent oxidation by 7%. In conclusion, ␣-tocopherol supplementation significantly increased the antioxidative capacity of LDL when measured ex vivo, which was partially abolished by concomitant lovastatin therapy. Key Words: ␣-tocopherol Ⅲ clinical trials Ⅲ lipid oxidation Ⅲ lovastatin Ⅲ ubiquinol H igh serum cholesterol concentrations and oxidation of LDL seem to play key roles in the pathogenesis of an atherosclerotic lesion. An effective means to treat hypercholesterolemic patients is through the use of statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA ) reductase inhibitors. They effectively decrease serum LDL cholesterol, increase HDL cholesterol levels slightly, and improve the prognosis of coronary heart disease (CHD) patients. 1,2 The prominent antioxidant in LDL is ␣-tocopherol, because in every LDL particle there are Ϸ6 to 8 molecules of ␣-tocopherol. 3-5 ␣-Tocopherol acts as a powerful antioxidant after the very early stage of LDL oxidation and especially during intense oxidative stress. 6 -8 However, under mild oxidation, ␣-tocopherol may act as a prooxidant, thus shifting the peroxidative insult from the surface to the inner part of the LDL particle. 8 -10 This event could be prevented by ubiquinol. 11 ␣-Tocopherol supplementation may have a significant role in the prevention of CHD. Retrospective data indicate an inverse relation between plasma concentrations of vitamin E and the risk of angina pectoris. 12 According to 1 prospective study, the serum ␣-tocopherol concentration may affect cardiac risk (ie, nonfatal myocardial infarction or cardiovascular death) in patients with coronary disease...

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Section: Discussionsupporting

confidence: 92%

Effects of Lovastatin Therapy on Susceptibility of LDL to Oxidation During α-Tocopherol Supplementation

Palomäki

Malminiemi

et al. 1999

ATVB

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“…Essentially, ␣-TO⅐ replaces LOO⅐ as the peroxidation chain-carrying species and unless the former radical is eliminated, a large proportion of lipid in LDL can oxidize without significant loss of vitamin E. The ␣-TO⅐ is less reactive than the LOO⅐ and as such tocopherol-mediated peroxidation represents a model of retarded lipid peroxidation relative to that caused by LOO⅐ in the absence of vitamin E. However, as ␣-TOH is highly reactive towards various oxidants, the mere presence of vitamin E in LDL renders the lipoprotein susceptible to oxidation (78,81,497,1051). This property is referred to as the phase-transfer activity of ␣-TOH.…”

Section: Role Of Vitamin E In Ldl Oxidationmentioning

confidence: 99%

Role of Oxidative Modifications in Atherosclerosis

Stocker¹,

Keaney²

2004

Physiological Reviews

Self Cite

2,244

1,756

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This review focuses on the role of oxidative processes in atherosclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. An emerging consensus also underscores the importance in vascular disease of oxidative events in addition to LDL oxidation. These include the production of reactive oxygen and nitrogen species by vascular cells, as well as oxidative modifications contributing to important clinical manifestations of coronary artery disease such as endothelial dysfunction and plaque disruption. Despite these abundant data however, fundamental problems remain with implicating oxidative modification as a (requisite) pathophysiologically important cause for atherosclerosis. These include the poor performance of antioxidant strategies in limiting either atherosclerosis or cardiovascular events from atherosclerosis, and observations in animals that suggest dissociation between atherosclerosis and lipoprotein oxidation. Indeed, it remains to be established that oxidative events are a cause rather than an injurious response to atherogenesis. In this context, inflammation needs to be considered as a primary process of atherosclerosis, and oxidative stress as a secondary event. To address this issue, we have proposed an “oxidative response to inflammation” model as a means of reconciling the response-to-injury and oxidative modification hypotheses of atherosclerosis.

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“…In a number of very elegant studies Stocker and co-workers [14][15][16] have demonstrated that the antioxidant α-tocopherol may behave, under appropriate conditions, as pro-oxidant, thus paradoxically stimulating LDL oxidation promoted by a constant radical flow originating from the thermal decomposition of the azo-compound 2,2h-azobis-(2-amidino propane) hydrochloride (AAPH) or by low concentrations of copper. The pro-oxidant activity of α-tocopherol is mediated through the one-electron oxidation catalysed by peroxyl radicals or by the reductive activation of Cu(II) to Cu(I) with the concomitant formation of the α-tocopheroxyl radical which, in turn, may abstract a hydrogen atom from a polyunsaturated fatty acid in LDL, thus initiating a radical chain ultimately leading to extensive lipid peroxidation.…”

Section: Introductionmentioning

confidence: 99%

When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: a study using uric acid

Bagnati

Perugini

Cau

et al. 1999

Biochemical Journal

135

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The inclusion of uric acid in the incubation medium during copper-induced low-density lipoprotein (LDL) oxidation exerted either an antioxidant or pro-oxidant effect. The pro-oxidant effect, as mirrored by an enhanced formation of conjugated dienes, lipid peroxides, thiobarbituric acid-reactive substances and increase in negative charge, occurred when uric acid was added late during the inhibitory or lag phase and during the subsequent extensive propagation phase of copper-stimulated LDL oxidation. The pro-oxidant effect of uric acid was specific for copper-induced LDL oxidation and required the presence of copper as either Cu(I) or Cu(II). In addition, it became much more evident when the copper to LDL molar ratio was below a threshold value of approx. 50. In native LDL, the shift between the antioxidant and the pro-oxidant activities was related to the availability of lipid hydroperoxides formed during the early phases of copper-promoted LDL oxidation. The artificial enrichment of isolated LDL with α-tocopherol delayed the onset of the pro-oxidant activity of uric acid and also decreased the rate of stimulated lipid peroxidation. However, previous depletion of α-tocopherol was not a prerequisite for unmasking the pro-oxidant activity of uric acid, since this became apparent even when α-tocopherol was still present in significant amounts (more than 50% of the original values) in LDL. These results suggest, irrespective of the levels of endogenous α-tocopherol, that uric acid may enhance LDL oxidation by reducing Cu(II) to Cu(I), thus making more Cu(I) available for subsequent radical decomposition of lipid peroxides and propagation reactions.

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Inverse deuterium kinetic isotope effect for peroxidation in human low‐density lipoprotein (LDL): a simple test for tocopherol‐mediated peroxidation of LDL lipids

Cited by 69 publications

References 31 publications

Effects of Lovastatin Therapy on Susceptibility of LDL to Oxidation During α-Tocopherol Supplementation

Effects of Lovastatin Therapy on Susceptibility of LDL to Oxidation During α-Tocopherol Supplementation

Role of Oxidative Modifications in Atherosclerosis

When and why a water-soluble antioxidant becomes pro-oxidant during copper-induced low-density lipoprotein oxidation: a study using uric acid

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