Putative mechanisms of action of probucol on high-density lipoprotein apolipoprotein A-I and its isoproteins kinetics in rabbits.
Probucol is a widely prescribed lipid-lowering agent, the major effects of which are to lower cholesterol in both low- and high-density lipoproteins (LDL and HDL, respectively). The mechanism of action of probucol on HDL apolipoprotein (apo) A-I kinetics was investigated in rabbits, with or without cholesterol feeding. 125I-labeled HDL was injected intravenously, and blood samples were taken periodically for 6 days. Kinetic parameters were calculated from the apo A-I-specific radioactivity decay curves. Fractional catabolic rate (FCR) and synthetic rate (SR) of apo A-I in rabbits fed a normal chow and normal chow with 1% probucol were similar. Apo A-I FCR of the rabbits fed 0.5% cholesterol was significantly increased but there were no changes in SR, compared to findings in the normal chow-fed group. Apo A-I FCR of the rabbits fed 1% probucol with 0.5% cholesterol (both 1 month and 2 months) was significantly increased compared to findings in rabbits fed the normal chow as well as 0.5% cholesterol diet group, while SR of apo A-I was significantly reduced in the former groups. Kinetics at 1 month after discontinuation of 1% probucol (under cholesterol feeding) showed a similar FCR of HDL-apo A-I to that of the rabbits fed 0.5% cholesterol, but the SR of apo A-I remained lower. Apo A-I isoproteins kinetics assessed by autoradiography of isoelectric focusing slab gels showed that the synthesis of proapo A-I was significantly reduced in the 1% probucol with 0.5% cholesterol administered, compared to the 0.5% cholesterol group. Thus, the action of probucol on HDL apo A-I kinetics was only prominent in case of higher serum cholesterol levels. The decreased HDL or apo A-I seen with probucol was apparently the result of an increase in FCR and a decrease in SR of HDL-apo A-I. A decreased synthesis of apo A-I remained evident even 1 month after discontinuing probucol. The action of probucol on the intracellular synthetic processes of apo A-I was revealed by the reduced synthesis of proapo A-I.
Ying
H
H
Department of Internal Medicine, Fukuoka University School of Medicine, Japan.
Saku
K
K
Harada
R
R
Takami
N
N
Sasaki
N
N
Saito
Y
Y
Arakawa
K
K
D000818:Animals; D016632:Apolipoprotein A-I; D001054:Apolipoproteins A / Q000097:blood* / Q000302:isolation & purification; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000494:pharmacology*; D004591:Electrophoresis, Polyacrylamide Gel; D006168:Guinea Pigs; D007525:Isoelectric Focusing; D007700:Kinetics; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D011341:Probucol / Q000097:blood / Q000494:pharmacology*; D012016:Reference Values; D014280:Triglycerides / Q000097:blood
D016632:Apolipoprotein A-I; D001054:Apolipoproteins A; D002791:Cholesterol, Dietary; D008075:Lipoproteins, HDL; D014280:Triglycerides; D002784:Cholesterol; D011341:Probucol