Antioxidant effect of probucol an RO2 center dot/O-2(center dot)-induced peroxidation of human low-density lipoproteins

This study was designed to evaluate the antioxidant effect of probucol on p eroxidation of low-density lipoproteins (LDLs) initiated by oxygenated free radicals (O-2(.-)) and ethanol-derived peroxyl radicals (RO2.) generated b y gamma radiolysis. Initial radiolytic yields related to the markers of lip id peroxidation [i.e. decrease in endogenous alpha-tocopherol, formation of thiobarbituric acid-reactive substances (TBARS) and conjugated dienes] wer e determined as a function of LDL concentration (1.5 and 3 g l(-1), express ed as total LDL) and in the absence or the presence of probucol at differen t concentrations (2.3 x 10(-6), 3.5 x 10(-6), 9 x 10(-6) and 20.5 x 10(-6) mol l(-1)), Our results showed that probucol was able to decrease not only the yields of TEARS and conjugated dienes but also the levels of these pero xidation products obtained at high doses (2500 Gy) compared to LDLs without probucol, Under our conditions, probucol displayed an optimal antioxidant effect for an initial concentration in LDLs equivalent to 15 probucol molec ules per LDL particle, which corresponded to a pharmacologically relevant c oncentration of probucol, Moreover, our data showed that probucol was unabl e to react with RO2. and thus did not protect LDL vitamin E from free radic al attack. In addition, the scavenging capacity of probucol on O-2(.-) appe ared to be very poor, and probucol more likely reacted with LDL intermediat e radical products. Finally, a very significant steady-state level of probu col remained in LDLs at high doses (up to 2500 Gy), equivalent to at least 40% of the initial concentration of probucol, This addressed the question o f a mechanism for regeneration of probucol in LDLs, Our results as a whole suggested that the antioxidant effect of probucol in vivo could not be expl ained hy its scavenging capacity with regard to RO2./O-2(.-) free radicals. (C) 1999 by Radiation Research Society.