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

Probucol decreases and bezafibrate increases plasma high density lipoprotei n-cholesterol (HDL-C) levels in humans. This study was performed to determi ne whether the HDL-C-lowering effects of probucol could be reversed by trea tment with bezafibrate in hypercholesterolemic rabbits. Forty-nine normolip idemic Japanese White rabbits were divided into 5 groups [group 1: normal c how; 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% pro bucol plus 1% bezafibrate diet] and treated for 8 weeks. Plasma lipids, cho lesteryl ester transfer protein (CETP) activity in the lipoprotein-deficien t plasma fraction, CETP mRNA in liver tissue and plasma drug concentrations were investigated. Serum total cholesterol (TC) increased after the rabbit s in groups 2, 3, 4 and 5 were fed Ch, but overall, no significant differen ces were observed in serum TC and triglyceride (TG) among these groups. Ser um 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 + probu col (group 3) and Ch + probucol plus bezafibrate (group 5) groups; no signi ficant difference was observed between groups 3 and 5. Significant correlat ion (p<0.01) was found between serum low density lipoprotein cholesterol (L DL-C) levels and plasma probucol concentrations in groups 3 and 5, but no c orrelation was found between plasma concentrations of probucol/bezafibrate and serum HDL-C levels. CETP activity in the lipoprotein-deficient plasma f raction increased in the Ch-, Ch + probucol-, and Ch + probucol and bezafib rate-fed groups (groups 2, 3 and 5, respectively), whereas a significant re duction in this activity was observed in the Ch + bezafibrate-fed group (gr oup 4). An analysis of covariance showed that the CETP activity responded m ore 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 chang es were observed among the 5 groups. Probucol decreased and bezafibrate inc reased serum HDL-C levels, through CETP activity without affecting liver CE TP mRNA levels, and the decrease in HDL-C levels produced by probucol could not be reversed by bezafibrate.