Inhibitory effects of fluvastatin and its metabolites on hydrogen peroxide-induced oxidative destruction of hemin and low-density lipoprotein.
Some 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, which are used as hypolipidemic drugs, have been reported to have the potential to reduce the oxidizability of plasma low-density lipoprotein (LDL) when they are administered in vivo. Their in vivo mechanism is believed to be closely related to their hypolipidemic action based on the HMG-CoA reductase inhibitory activity. We hypothesized that some type of HMG-CoA reductase inhibitor has additional mechanism inhibiting LDL oxidation in vivo due not to its hypolipidemic action but to its direct antioxidative effect based on its unique chemical structure. We directly compared in vitro the antioxidative effects of well-known HMG-CoA reductase inhibitors (fluvastatin, pravastatin, simvastatin, cerivastatin and atorvastatin) on the hydrogen peroxide-induced oxidative destruction of hemin and LDL. Fluvastatin but not the others showed the inhibitory effect on this system. Its effect was dose-dependent and almost as strong as the natural antioxidants, alpha-tocopherol and ascorbic acid. Further, M2, which is a hydroxylated metabolite of fluvastatin, showed stronger antioxidative activity than did fluvastatin. We suggest that among these HMG-CoA reductase inhibitors, fluvastatin especially has an ability to retard the LDL oxidation which is based on not only its hypolipidemic action but also its direct antioxidative effect.
Suzumura
K
K
Discovery Research Laboratory, Tanabe Seiyaku Co, Ltd, Toda, Saitama, Japan. suzumura@tanabe.co.jp
Tanaka
K
K
Yasuhara
M
M
Narita
H
H
D000704:Analysis of Variance; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D001205:Ascorbic Acid / Q000494:pharmacology; D004347:Drug Interactions; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism / Q000494:pharmacology*; D000077340:Fluvastatin; D006427:Hemin / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D010084:Oxidation-Reduction; D014810:Vitamin E / Q000494:pharmacology
D000975:Antioxidants; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D007502:Iron Chelating Agents; D008077:Lipoproteins, LDL; D014810:Vitamin E; D000077340:Fluvastatin; D006427:Hemin; D006861:Hydrogen Peroxide; D001205:Ascorbic Acid