Protective effect of fluvastatin sodium (XU-62-320), a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on oxidative modification of human low-density lipoprotein in vitro.
We investigated the protective effect of fluvastatin sodium on the oxidation of low-density lipoprotein (LDL) induced in vitro by copper ions. The extent of lipid peroxidation was assessed by monitoring the increase of UV absorbance at 234 nm, which is the peak absorbance of a conjugated diene. Fluvastatin sodium (1-30 microM) not only prolonged the lag time of oxidation in the initiation step, but also decreased the rate of oxidation in the propagation step, both concentration dependently. Fluvastatin sodium and alpha-tocopherol showed an additive effect when both compounds were added before oxidation. However, when the lag time was prolonged initially by alpha-tocopherol, and fluvastatin sodium and alpha-tocopherol, were further added into the reaction mixture at the end point of the lag phase, fluvastatin sodium still showed an antioxidative effect, whereas alpha-tocopherol showed a pro-oxidative effect. Therefore, the antioxidative property of fluvastatin sodium differs from that of alpha-tocopherol. In this experiment, as neither the double bond-reduced derivative of fluvastatin sodium nor pravastatin sodium showed any protective effect, we concluded that the antioxidative effect of fluvastatin sodium is not a common property of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, but may be derived from its unique chemical structure. Since the oxidative modification of LDL plays an important role in the genesis of atherosclerosis, fluvastatin sodium may help reduce the risk of atherosclerosis, not only by reducing plasma LDL levels but also by protecting LDL from oxidative modification.
Pharmaceutical Development Research Laboratory, Tanabe Seiyaku Co., Ltd., Toda, Saitama, Japan.
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K
Suzumura
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M
Yasuhara
K
K
Tanaka
T
T
Suzuki
D000328:Adult; D000578:Amidines; D000975:Antioxidants / Q000494:pharmacology*; D003300:Copper; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000494:pharmacology*; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000302:isolation & purification / Q000378:metabolism*; D008297:Male; D016877:Oxidants; D010084:Oxidation-Reduction / Q000187:drug effects; D013329:Structure-Activity Relationship; D014810:Vitamin E / Q000494:pharmacology
D000578:Amidines; D000975:Antioxidants; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008077:Lipoproteins, LDL; D016877:Oxidants; D014810:Vitamin E; D000077340:Fluvastatin; C046728:2,2'-azobis(2-amidinopropane); D003300:Copper