Protection of low density lipoprotein oxidation by the antioxidant agent IRFI005, a new synthetic hydrophilic vitamin E analogue

The oxidative modification of low density lipoprotein (LDL) is thought to b e an important factor in the initiation and development of atherosclerosis. Antioxidants have been shown to protect LDL from oxidation and to inhibit atherosclerosis development in animals. Potent synthetic antioxidants are c urrently being tested, but they are not necessarily safe for human use. We here characterize the antioxidant activity of IRFI005, the active metabolit e of Raxofelast (IRFI0016) that is a novel synthetic analog of vitamin E un der clinical development, and demonstrate that it prevents oxidative modifi cation of LDL. IFI005 inhibited the oxidative modification of LDL, measured through the generation of MDA, electrophoretic mobility and apo B100 fluor escence. During the oxidation process IRFI005 was consumed with the formati on of the benzoquinone oxidation product. The powerful antioxidant activity of IRFI005 is at least in part mediated by a chain breaking mechanism as i t is an efficient peroxyl radical scavenger with a rate constant k((IRFI005 + LOO degrees)) of 1.8 x 10(6) M(-1)s(-1). 4. IRFI005 substantially preser ved LDL-associated antioxidants, alpha-tocopherol and carotenoids, and when co-incubated with physiologic levels of ascorbate provoked a synergistic i nhibition of LDL oxidation. Also the co-incubation of IRFI005 with Trolox c aused a synergistic effect, and a lag phase in the formation of the trolox- benzoquinone oxidation product. A synergistic inhibition of lipid peroxidat ion was also demonstrated by co-incubating IRFI005 and alpha-tocopherol inc orporated in linoleic acid micelles. These data strongly suggest that IRFI0 05 can operate by a recycling mechanism similar to the vitamin E/ascorbate system. (C) 1999 Elsevier Science Inc.