In vitro inhibitory effects of the optical isomers and metabolites of fluvastatin on copper ion-induced LDL oxidation.
Fluvastatin is a synthetic hypolipidemic drug which inhibits 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. We compared in vitro the antioxidative effects of two enantiomers (3R, 5S and 3S, 5R) of fluvastatin, which is clinically used as a racemic mixture, on copper ion-induced oxidation of human low-density lipoprotein (LDL). Although 3R,5S-enantiomer of fluvastatin has 30-fold stronger inhibitory activity on HMG-CoA reductase than its optical counterpart, the antioxidative effects of these enantiomers on copper ion-induced LDL oxidation were similar. The antioxidative effects of the metabolites of fluvastatin (M2, M3, M4 and M7) on the copper ion-induced LDL oxidation were also investigated. All the metabolites tested showed an inhibitory effect on this system. Among them, the effects of M2 and M3, which have a phenolic hydroxyl group in each indole moiety, were strong and their potencies were 30-50 times greater than that of fluvastatin. We conclude that not only 3R,5S-enantiomer of fluvastatin but also its optical counterpart and the metabolites also have a potential to show the anti-atherosclerotic effect through their antioxidative activities on lipid peroxidation.
Suzumura
K
K
Discovery Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan.
Odawara
A
A
Yasuhara
M
M
Tanaka
K
K
Narita
H
H
Suzuki
T
T
D000704:Analysis of Variance; D003300:Copper / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D013237:Stereoisomerism
D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008077:Lipoproteins, LDL; D000077340:Fluvastatin; D003300:Copper