ANTIOXIDANT ACTIVITY OF PROBUCOL AND ITS ANALOGS IN HYPERCHOLESTEROLEMIC WATANABE RABBITS

被引:90
作者
MAO, SJT
YATES, MT
RECHTIN, AE
JACKSON, RL
VANSICKLE, WA
机构
[1] Merrell Dow Research Institute, Cincinnati
关键词
D O I
10.1021/jm00105a046
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Probucol (1) and probucol analogues with the substitutions at the disulfide-linked carbon (2, 3) and an additional substitution at a tert-butyl of each phenolic ring (4) were tested for their ability to lower total serum cholesterol and prevent aortic atherosclerosis in modified Watanabe heritable hyperlipidemic (WHHL) rabbits and to inhibit Cu2+-induced lipid peroxidation of isolated plasma low-density lipoproteins (LDL). After 84 days of feeding 1 % of each compound in rabbit chow, probucol was effective in lowering serum cholesterol, whereas 2-4 were not. The concentration of drug in serum and LDL was 2 > 1 > 3 > 4. Probucol and analogues prevented Cu2+-induced oxidation of LDL in vitro to an extent that directly related to their concentrations in LDL. The decrease in lipid oxidation was directly correlated with the inhibition of both oxidized-LDL-induced cholesteryl ester synthesis in cultured macrophages and to the inhibition of aortic atherosclerosis in vivo. These results show that the antioxidant activity of probucol and analogues is directly related to their concentration in LDL, which may explain their pharmacological activity in reducing atherosclerosis.
引用
收藏
页码:298 / 302
页数:5
相关论文
共 40 条
[11]   BIOCHEMICAL AND PATHOLOGICAL FEATURES OF A MODIFIED STRAIN OF WATANABE HERITABLE HYPERLIPEMIC RABBITS [J].
GALLAGHER, PJ ;
NANJEE, MN ;
RICHARDS, T ;
ROCHE, WR ;
MILLER, NE .
ATHEROSCLEROSIS, 1988, 71 (2-3) :173-183
[12]  
GERRITY RG, 1981, AM J PATHOL, V103, P191
[13]  
GERRITY RG, 1981, AM J PATHOL, V103, P181
[14]   PLASMA-LEVELS OF ANTIOXIDANT VITAMINS IN RELATION TO ISCHEMIC-HEART-DISEASE AND CANCER [J].
GEY, KF ;
BRUBACHER, GB ;
STAHELIN, HB .
AMERICAN JOURNAL OF CLINICAL NUTRITION, 1987, 45 (05) :1368-1377
[15]   MALONDIALDEHYDE-ALTERED PROTEIN OCCURS IN ATHEROMA OF WATANABE HERITABLE HYPERLIPIDEMIC RABBITS [J].
HABERLAND, ME ;
FONG, D ;
CHENG, L .
SCIENCE, 1988, 241 (4862) :215-218
[16]  
HALLIWELL B, 1989, BRIT J EXP PATHOL, V70, P737
[17]   OXIDANTS AND HUMAN-DISEASE - SOME NEW CONCEPTS [J].
HALLIWELL, B .
FASEB JOURNAL, 1987, 1 (05) :358-364
[18]   ATHEROSCLEROSIS - EFFECT OF RATE OF GROWTH [J].
HARMAN, D .
CIRCULATION RESEARCH, 1962, 10 (06) :851-&
[19]   ATHEROSCLEROSIS - INHIBITING EFFECT OF AN ANTIHISTAMINIC DRUG, CHLORPHENIRAMINE [J].
HARMAN, D .
CIRCULATION RESEARCH, 1962, 11 (02) :277-&