Probucol decreases apolipoprotein A-I transport rate and increases high density lipoprotein cholesteryl ester fractional catabolic rate in control and human apolipoprotein A-I transgenic mice.
Probucol effects on lipoprotein metabolism were determined in control and human apolipoprotein A-I transgenic (HuAITg) mice. In control mice, probucol reduced total cholesterol from 67 +/- 2 to 25 +/- 2 mg/dl by reducing high density lipoprotein (HDL) cholesterol from 46 +/- 20 to 14 +/- 1 mg/dl and low density lipoprotein (LDL) cholesterol from 11 +/- 1 to 5 +/- 1 mg/dl. Apolipoprotein (apo) A-I levels were reduced from 122 +/- 8 to 56 +/- 5 mg/dl. In HuAITg mice, probucol reduced total cholesterol from 121 +/- 5 to 77 +/- 3 mg/dl by reducing HDL cholesterol from 84 +/- 4 to 56 +/- 3 mg/dl and LDL cholesterol from 19 +/- 2 to 11 +/- 2 mg/dl. Human apo A-I levels were reduced from 267 +/- 13 to 144 +/- 12 mg/dl and mouse apo A-I levels from 18 +/- 2 to 9 +/- 2 mg/dl. Control animals have primarily a monodisperse HDL with a particle diameter of 10 nm. Probucol did not appear to change the particle size distribution in the control animals. The HuAITg mice have a polydisperse HDL with particle diameters of 10.1 and 8.5 nm. Probucol treatment of these animals resulted in HDL with particle diameters of 9.4 and 8.5 nm, apparently reducing the size of the larger particles. In vivo turnover studies revealed that the reduction in apo A-I was primarily due to a decrease in transport rate, whereas the reduction in HDL cholesterol was primarily due to an increase in HDL cholesteryl ester fractional catabolic rate.(ABSTRACT TRUNCATED AT 250 WORDS)
Hayek
T
T
Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, New York, NY 10021-6399.
Chajek-Shaul
T
T
Walsh
A
A
Azrolan
N
N
Breslow
J L
JL
D000818:Animals; D016632:Apolipoprotein A-I / Q000493:pharmacokinetics*; D001692:Biological Transport / Q000187:drug effects; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008970:Molecular Weight; D010316:Particle Size; D011341:Probucol / Q000494:pharmacology*
D016632:Apolipoprotein A-I; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D002784:Cholesterol; D011341:Probucol