Title

 

Authors

M.P.Adorni ¹, E.Favari ¹, R.Stocker ², F.Bernini^1
1Dept. of Pharmacol. and Biol. Sciences and Appl. Chem., University of Parma, Parma, Italy; ²Centre for Vascular Research, School of Medical Sciences (Pathology) and Bosch Institute, University of Sydney, Sydney, Australia

 

Abstract

Probucol is a phenolic lipid lowering agent, able to reduce atherosclerosis and restenosis following percutaneous coronary angioplasty in vivo model. In vitro probucol is an effective inhibitor of ABCA1-mediated cholesterol efflux. This effect may in part explain the reported in vivo high-density lipoprotein-lowering action of probucol. The aim of this stady was to compare the activity of probucol and its analogues, the monosuccinate ester (AGI-1067), the probucol dithio-bisphenol (DTBP) and its monosuccinate (DTBPs), in modulating the cholesterol efflux process trough the different specific pathways. To this aim cells monolayers were labeled with [3H]cholesterol for 24h. Cells were then equilibrated in 0.2% BSA-containing medium and treated for 2h with probucol or its analogues. Cells were then exposed to the different cholesterol acceptors. Cholesterol efflux was measured by the release of [3H]-cholesterol into the medium. Like probucol, none of the tested compounds had effect on either passive diffusion of cholesterol in mouse peritoneal macrophages (MPM) or on SRBI-mediated cholesterol efflux in Fu5AH rat hepatoma cells. The ABCA1-mediated efflux of cholesterol was measured in MPM stimulated with the association of the LXR-RXR agonists. The results showed AGI-1067 to be a stronger inhibitor of ABCA1-mediated efflux compared to probucol and DTBPs. On the contrary the analogue DTBP had not any effect on efflux via ABCA1. In addition AGI-1067 and DTBPs but not probucol and DTBP, were able to inhibit efflux of cholesterol in CHO cells over expressing hABCG1 by about 50%. In conclusion he presence of a dithio ketal group on both probucol and probucol-like analogues may be required for the inhibition of ABCA1 cholesterol efflux. The esterification of one of the phenolic group of probucol may enhance the inhibitory effect of the ABCA1 pathway. In addition the presence of the esterified ossydrylic group may be required for the interaction of the molecule with the ABCG1 transporter. Identifying probucol-like analogues may help to explore the mechanism and function of ABCA1-, ABCG1- and SR-BI-mediated cholesterol efflux and their potential therapeutic role.