Combined effects of probucol and benzafibrate on lipoprotein metabolism and liver cholesteryl ester transfer protein mRNA in cholesterol-fed rabbits

Abstract

Probucol decreases and bezafibrate increases plasma high density lipoprotein-cholesterol (HDL-C) levels in humans. This study was performed to determine whether the HDL-C-lowering effects of probucol could be reversed by treatment with bezafibrate in hypercholesterolemic rabbits. Forty-nine normolipidemic Japanese White rabbits were divided into 5 groups [group 1: normal chow; group 2: 0.2% cholesterol (Ch) diet; group 3: 0.2% Ch and 1% probucol diet; group 4: 0.2% Ch and 1% bezafibrate diet; group 5: 0.2% Ch and 1% probucol plus 1% bezafibrate diet] and treated for 8 weeks. Plasma lipids, cholesteryl ester transfer protein (CETP) activity in the lipoprotein-deficient plasma fraction, CETP mRNA in liver tissue and plasma drug concentrations were investigated. Serum total cholesterol (TC) increased after the rabbits in groups 2, 3, 4 and 5 were fed Ch, but overall, no significant differences were observed in serum TC and triglyceride (TG) among these groups. Serum HDL-C levels increased (p<0.01) in the bezafibrate-treated group, but a significant (p<0.05) reduction in HDL-C was observed in both the Ch + probucol (group 3) and Ch + probucol plus bezafibrate (group 5) groups; no significant difference was observed between groups 3 and 5. Significant correlation (p<0.01) was found between serum low density lipoprotein cholesterol (LDL-C) levels and plasma probucol concentrations in groups 3 and 5, but no correlation was found between plasma concentrations of probucol/bezafibrate and serum HDL-C levels. CETP activity in the lipoprotein-deficient plasma fraction increased in the Ch-, Ch + probucol-, and Ch + probucol and bezafibrate-fed groups (groups 2, 3 and 5, respectively), whereas a significant reduction in this activity was observed in the Ch + bezafibrate-fed group (group 4). An analysis of covariance showed that the CETP activity responded more sensitively to drug treatment than did the serum HDL-C level. CETP mRNA in liver tissue was assessed by Northern blotting at 8 weeks, but no changes were observed among the 5 groups. Probucol decreased and bezafibrate increased serum HDL-C levels, through CETP activity without affecting liver CETP mRNA levels, and the decrease in HDL-C levels produced by probucol could not be reversed by bezafibrate.