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

Abstract

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...

A combined natural supplement lowers LDL cholesterol in subjects with moderate untreated hypercholesterolemia: a randomized placebo-controlled trial

“…One study conducted in mice demonstrated that low and high doses of RYR (monacolin K, respectively, 15 and 75 mg/kg body weight) induced a dramatic decline in CoQ10 levels in the heart and liver (Yang, 2005). Clinical trials conducted with lovastatin or atorvastatin at respectively 60 and 10 mg daily showed a decrease of plasma CoQ10 levels (Palomaki, 1998;Liu, 2010). In our study, a downward trend was observed in the NCLS group for CoQ10 levels (p = 0.0682).…”

Statin-Induced Liver Injury Involves Cross-Talk between Cholesterol and Selenoprotein Biosynthetic Pathways

“…For instance, lovastatin administration to rats has been described to result in a significantly increased liver membrane peroxidizability (Lankin et al, 2007), as would be indicative of a loss of GPx4. Moreover, LDL from patients treated with statins has been shown in several studies to possess decreased antioxidative capacity if properly isolated (Palomä ki et al, 1999;Lankin et al, 2003). Still, it is important to note that the latter parameters reflect specific aspects of intracellular antioxidative capacity (the LDL precursor is assembled intracellularly); hence, their prooxidative response to statin treatment is not contradictory to reports describing antioxidative effects of statins regarding certain plasma/endothelial markers of oxidative stress (Rosenson, 2004).…”

Statins and Modulation of Oxidative Stress

“…Ubiquinol is a first-line antioxidant of plasma LDL and also protects α-tocopherol contained in this fraction from oxidation (de Rijke et al 1997). Treatment with statins reduces UQ content expressed per unit of plasma LDL cholesterol, which may increase the oxidizability of these lipoproteins (Human et al 1997;Oranje et al 2001;Palomaki et al 1997Palomaki et al , 1999. Coadministration of 180 mg/day UQ corrected enhanced LDL oxidizability in lovastatin-treated patients (Palomaki et al 1998).…”