Effects of a novel antihyperlipidemic agent, S-2E, on the blood lipid abnormalities in homozygous WHHL rabbits.
To improve mixed hyperlipidemia in the low-density lipoprotein (LDL) receptor-deficient state, suppression of very-low-density lipoprotein (VLDL) particle production may be an important approach. We previously reported that S-2E, (+)-(S)-p-[1-(p-tert-butylphenyl)-2-oxo-4-pyrrolidinyl] methoxybenzoic acid, suppressed VLDL particle production by inhibiting the biosynthesis of both sterol and fatty acids in the liver. We therefore examined whether S-2E lowered the blood cholesterol and triglyceride (TG) levels simultaneously in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, which correspond to human familial hypercholesterolemia. S-2E given orally at doses of 30 to 300 mg/kg significantly lowered serum total cholesterol (TC) levels at 1 week as well as TG at 2 weeks, and the lowering of TC and TG levels by S-2E reached a maximum at 3 to 4 weeks. In contrast, oral administration of pravastatin at doses of 10 to 100 mg/kg resulted in a significant suppression of TC levels (100 mg/kg) but not TG levels. Further analysis of the TC content in fractionated serum of control and S-2E-treated animals showed that suppression of TC level by S-2E is attributable to a decrease in the proportions of VLDL, intermediate-density lipoprotein (IDL), and LDL. It is, therefore, reasonable to assume that S-2E may be useful to improve the blood lipid abnormalities in the LDL receptor-deficient state.
Ohmori
K
K
Pharmacology Research Laboratory, Taiho Pharmaceutical Co, Ltd, Hanno, Japan.
Yamada
H
H
Yasuda
A
A
Yamamoto
A
A
Matsuura
N
N
Kiniwa
M
M
D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood*; D006720:Homozygote; D062425:Hydroxybenzoate Ethers; D006949:Hyperlipidemias / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000494:pharmacology*; D008074:Lipoproteins / Q000097:blood; D008297:Male; D017035:Pravastatin / Q000494:pharmacology; D011760:Pyrrolidinones / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D014280:Triglycerides / Q000097:blood*
C482648:4-(1-(4-tert-butylphenyl)-2-oxo-4-pyrrolidinyl)methoxybenzoic acid; D001565:Benzoates; D062425:Hydroxybenzoate Ethers; D000960:Hypolipidemic Agents; D008074:Lipoproteins; D011760:Pyrrolidinones; D014280:Triglycerides; C030104:lipoprotein cholesterol; D002784:Cholesterol; D017035:Pravastatin