Modulation of HDL metabolism by probucol in complete cholesteryl ester transfer protein deficiency.
Probucol, an antioxidative and hypolipidemic agent, has been postulated to increase reverse cholesterol transport by enhancing cholesteryl ester transfer protein (CETP) activity. However, its clinical implication in CETP deficient patients has not been fully defined. To characterize the effects of probucol in the absence of CETP, we evaluated the changes in lipid profile, lipid peroxidation, and paraoxonase 1 (PON1) activity in two complete CETP deficient patients, caused by treatment with probucol. When the patients were not receiving probucol, low-density lipoprotein (LDL) particles were smaller and high-density lipoprotein (HDL) particles were larger in these patients than in controls. Treatment with probucol (500 mg/day) resulted in the decrease in the levels of HDL-C and apolipoprotein (apo) A-I up to 22%. The size of HDL particles became smaller. LDL cholesterol concentration did not change in one patient, while it decreased by 47% in the other. PON1 activity/HDL-C, which was about 40% lower in the patients before treatment than in controls with the matching PON1 genotype, increased by 30% during the treatment. Lag time for LDL and HDL in both cases became prolonged more than 1.8 times after administration of probucol. This study demonstrated for the first time that probucol reduces HDL-C even in humans with complete CETP deficiency. Probucol treatment in these patients was also associated with protection of lipoproteins against oxidative stress, suggesting a clinical benefit of this drug even in such a state.
Noto
Hiroshi
H
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Kawamura
Mitsunobu
M
Hashimoto
Yoshiaki
Y
Satoh
Hiroaki
H
Hara
Masumi
M
Iso-o
Naoyuki
N
Togo
Masako
M
Kimura
Satoshi
S
Tsukamoto
Kazuhisa
K
D000368:Aged; D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D001053:Apolipoproteins / Q000097:blood; D043303:Aryldialkylphosphatase / Q000235:genetics / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D002352:Carrier Proteins / Q000187:drug effects / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000187:drug effects / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000187:drug effects / Q000378:metabolism; D005838:Genotype; D006023:Glycoproteins; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000187:drug effects; D011341:Probucol / Q000627:therapeutic use*; D011488:Protein Deficiency / Q000378:metabolism*; D016896:Treatment Outcome; D014280:Triglycerides / Q000097:blood
D000924:Anticholesteremic Agents; D000975:Antioxidants; D001053:Apolipoproteins; D015415:Biomarkers; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D006023:Glycoproteins; D014280:Triglycerides; D043303:Aryldialkylphosphatase; D011341:Probucol