Antioxidant activity of amiodarone on human lipoprotein oxidation

Abstract

1 Lipoprotein oxidation is crucial in atherogenic processes. Amiodarone is a lipophilic antiarrhythmic/antianginal drug which is able to in¯uence the physicochemical status of biological lipid components. Since oxidation of lipids is a ected by their physicochemical state and amiodarone binds to lipoproteins, we hypothesized that the drug may exert an antioxidant activity on human lipoprotein oxidation. 2 Dose-dependent e ects of therapeutically achievable amiodarone concentrations (1.5, 3, 5, 7 and 10 mM) were studied on copper-catalysed oxidation of the non-HDL fraction in vitro. Amiodarone inhibited oxidation as judged by generation of thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides (LOOH) and¯uorescent products of lipoperoxidation (FPL) as well as from the kinetics of conjugated diene formation. This antioxidant activity was signi®cant at 1.5 mM with total inhibition at 10 mM and an IC 50 of 4 mM. The primary in vivo metabolite of amiodarone, namely desethylamiodarone, also exhibited speci®c antioxidant properties although it was less e ective than amiodarone with an IC 50 of 7 mM. 3 In further in vivo experiments, susceptibility to copper-mediated oxidation of the non-HDL fraction was investigated before and 4 weeks after oral amiodarone administration to humans. Following treatment, signi®cant inhibition of TBARS, LOOH and FPL generation was observed in comparison with baseline levels and a placebo-treated control group, highlighting an e ective antioxidant capacity of amiodarone in vivo. 4 Amiodarone did not change lipoprotein vitamin E and phospholipid content in vivo and did not show scavenging e ects on oxidizing species involved in lipoprotein oxidation, such as peroxyl radicals, nor metal-binding/inactivating properties, suggesting that physicochemical modi®cations of lipoprotein lipids induced by the lipophilic drug may be involved in its antioxidant activity. 5 In conclusion, amiodarone, and its primary metabolite desethylamiodarone, show previously unrecognized antioxidant activity on human lipoprotein oxidation. This e ect is also evident in vivo and at therapeutically achievable drug concentrations. Thus, amiodarone may act as an antioxidant/ antiatherosclerotic agent in humans, although this issue warrants further clinical study.

The effect of vitamin C supplementation in healthy dogs on antioxidative capacity and immune parameters

“…Thiobarbituric acid reactive substances were analysed spectrophotometrically by the method of Jentzsch et al (1996) and Lapenna et al (2001). Vitamin C was analysed by the method of Vuilleumier and Keck (1989).…”

Antioxidant Activity and Sex Differences of Acute Vascular Effects of Amiodarone in Advanced Atherosclerosis

“…45 Based on their findings, these authors proposed therapeutic consequences for female patients requiring antiarrhythmic therapy. 45 Our findings showing that amiodarone improved endothelium-dependent relaxation in atherosclerotic arteries of males as well as the effect on vascular rhythmic activity may involve scavenging of ROS by amiodarone, 10,11,46 which would increase NO bioactivity. It is important to note that ROS has been implicated in arrhythmogenesis and thus part of the antiarrhythmic effects of amiodarone could be due to its antioxidant property.…”

“…8 Interestingly, amiodarone was initially developed during a systematic search for a potent coronary dilator for the therapy of angina pectoris. 9 Amiodarone inhibits lipoprotein oxidation 10 and may protect myocytes against oxidative stress-mediated injury by scavenging oxygen-derived free radicals under certain conditions. 11 Thus, it is possible that, due to its antioxidant properties, amiodarone could increase bioactivity of nitric oxide (NO) 12 and exhibit beneficial antiarrhythmic effects in patients with cardiovascular disease extending beyond its electrophysiological properties.…”

Copper, zinc superoxide dismutase plus hydrogen peroxide: a catalytic system for human lipoprotein oxidation

“…It is indeed remarkable that the replacement of CuZnSOD by such an adequate amount of free copper ions (1 lM in the specific experiments performed) can induce an extent of non-HDL oxidation similar to that catalyzed by the CuZnSOD/H 2 O 2 system, whose oxidative activity appears therefore copper-dependent. In fact, like the lipoprotein oxidation induced by free copper ions, also that catalyzed by CuZnSOD plus H 2 O 2 is inhibited by the copper chelators EDTA and DPCH, which prevent the binding of the metal to apo B-100 [4,5,12], and by the lipophilic chain breaking antioxidant BHT, which scavenges the oxidant species, such as peroxyl (and equivalent) radicals, implicated in the propagation of lipid peroxidation [4,12,13]. Notably, the OH scavengers formate and azide, but not ethanol or benzoate, afford significant antioxidant protection against CuZnSOD/H 2 O 2 -mediated lipoprotein oxidation.…”