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 HDL-lowering action of probucol. The aim of this study 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 cholesterol efflux process trough the different pathways. To this aim cells were labeled with [3H]-cholesterol. Cells were then equilibrated in 0.2% BSA-containing medium and subsequently treated with probucol or its analogues. Cholesterol efflux to the different acceptors, was measured by the release of [3H]-cholesterol into the medium. None of the tested compounds had effect on either passive diffusion of cholesterol in MPM or on SRBI-mediated cholesterol efflux in Fu5AH rat hepatoma cells. The ABCA1-mediated efflux was measured in MPM stimulated with LXR-RXR agonists. The results showed AGI-1067 to be a stronger inhibitor of ABCA1-mediated efflux compared to probucol and DTBPs. The analogue DTBP had not any effect on efflux via ABCA1. 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 the 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.
MODULATION OF CELLULAR CHOLESTEROL EFFLUX PATHWAYS BY DIFFERENT PROBUCOL-LIKE ANALOGUES / Adorni, Maria Pia; Stocker, R.; Bernini, Franco; Favari, Elda. - (2010), pp. 78-78. (Intervento presentato al convegno 6th IAS-Sponsored Workshop on High Density Lipoproteins tenutosi a Westin Wistler, Whistler, British Columbia, Canada nel 17-20 Maggio 2010).
MODULATION OF CELLULAR CHOLESTEROL EFFLUX PATHWAYS BY DIFFERENT PROBUCOL-LIKE ANALOGUES
ADORNI, Maria Pia;BERNINI, Franco;FAVARI, Elda
2010-01-01
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 HDL-lowering action of probucol. The aim of this study 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 cholesterol efflux process trough the different pathways. To this aim cells were labeled with [3H]-cholesterol. Cells were then equilibrated in 0.2% BSA-containing medium and subsequently treated with probucol or its analogues. Cholesterol efflux to the different acceptors, was measured by the release of [3H]-cholesterol into the medium. None of the tested compounds had effect on either passive diffusion of cholesterol in MPM or on SRBI-mediated cholesterol efflux in Fu5AH rat hepatoma cells. The ABCA1-mediated efflux was measured in MPM stimulated with LXR-RXR agonists. The results showed AGI-1067 to be a stronger inhibitor of ABCA1-mediated efflux compared to probucol and DTBPs. The analogue DTBP had not any effect on efflux via ABCA1. 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 the 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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
