Effect of probucol on antioxidant properties of HDL in patients with heterozygous familial hypercholesterolemia.
OBJECTIVE
High density lipoprotein (HDL) has multi-antiatherogenic effects such as antioxidation and anti-inflammation, in addition to being a key mediator of reverse cholesterol transport. Probucol, known as a lipid lowering drug, is also a potent antioxidant, but it decreases serum HDL cholesterol (HDL-C) levels. To elucidate the effect of probucol on antioxidant properties of HDL, we investigated the function of HDL derived from patients with heterozygous familial hypercholesterolemia (FH) who have been treated with probucol.


RESULTS
Probucol-treated FH patients (n=21) showed a 47% reduction of serum HDL-C levels compared to probucol-untreated FH patients (n=15). High performance liquid chromatography (HPLC) analysis revealed that probucol diminished HDL particle size compared to the non-treated group. Antioxidant capacity of HDL was evaluated by its effect to protect reference LDL from oxidation induced in the presence of an oxidizing agent, AAPH. The HDL derived from the probucol-treated group demonstrated a significantly prolonged time to start oxidation by 112%, decreased the maximum oxidation rate by 14%, and lowered the maximum concentration of conjugated dienes formation by 15%. Furthermore, HDL-associated paraoxonase 1 (PON1) activity, but not platelet-activating factor acetyl-hydrolase (PAF-AH) correlated with these measurements of HDL anti-oxidative activity. Treatment with probucol in vitro and inhibition of PON1 activity demonstrated that probucol in HDL particles and increase of PON1 activity might largely contribute to the increase of HDL anti-oxidative activity.


CONCLUSIONS
Probucol reduced HDL-C levels and HDL particle size in patients with heterozygous FH, while it concomitantly enhanced HDL anti-oxidative properties, possibly through increasing PON1 activity.
Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
Miwako
M
Inagaki
Yumiko
Y
Nakagawa-Toyama
Makoto
M
Nishida
Kazuhiro
K
Nakatani
Hajime
H
Nakaoka
Miyako
M
Kawase
Ryota
R
Kawase
Kazumi
K
Tsubakio-Yamamoto
Daisaku
D
Masuda
Tohru
T
Ohama
Akifumi
A
Matsuyama
Masato
M
Ishigami
Issei
I
Komuro
Shizuya
S
Yamashita
D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology*; D043303:Aryldialkylphosphatase / Q000378:metabolism*; D005260:Female; D006579:Heterozygote; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D010084:Oxidation-Reduction; D011341:Probucol / Q000627:therapeutic use*
D000924:Anticholesteremic Agents; D000975:Antioxidants; D008075:Lipoproteins, HDL; D043303:Aryldialkylphosphatase; C468406:PON1 protein, human; D011341:Probucol