THE EFFECTS OF PROBUCOL AND CLOFIBRATE ALONE AND IN COMBINATION ON HEPATIC CHOLESTEROL-METABOLISM IN THE MALE-RAT

Male rats were fed for 10 days on a diet supplemented with either probucol or clofibrate, alone or in combination, and the effects of the drugs on hepatic cholesterol metabolism studied. Plasma triacylglycerols were significantly lowered (15.6%, P < 0.05) by the drugs in combination but not individually whereas plasma cholesterol levels were reduced by probucol alone (22.4%, P < 0.05) and the combined treatment effected a further decrease leading to a total reduction of 50.6% (P < 0.001). Probucol reduced hepatic cellular triacylglycerols (20.0%, P < 0.05) and cholesterol (15.3%, P < 0.05) but cholesteryl esters were unaffected. In combination with clofibrate, probucol accentuated the reductions in both cellular cholesterol and cholesteryl esters produced by clofibrate alone and lowered their levels by 22.8%, P < 0.01 and 38.5%, P < 0.001, respectively. Although probucol, on its own, did not affect the activity of acyl-coenzyme A:cholesterol acyltransferase (ACAT), its combination with clofibrate caused less inhibition (43.5%, P < 0.01) of this enzyme activity than clofibrate alone (65.7%, P < 0.001). Probucol had a similarly moderating effect on the clofibrate-induced reductions in microsomal cholesterol and cholesteryl esters. Neither the microsomal nor the cytosolic neutral cholesteryl ester hydrolase was affected by probucol alone although both enzymes were dramatically increased (between 350% and 550%) by clofibrate and the combined treatment. The activity of the hepatic cytosolic inhibitor of cholesteryl ester hydrolase was unaffected by clofibrate or probucol individually but the two drugs in combination increased the total activity of the inhibitor by 52.1%, P < 0.01. When allowance was made for this increased inhibitor activity, it was clear that probucol accentuated the stimulatory effect of clofibrate on the cytosolic nCEH.