Antioxidative effects of fluvastatin and its metabolites against oxidative DNA damage in mammalian cultured cells.
We investigated the effects of fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on reactive oxygen species (ROS) and on oxidative DNA damage in vitro, as well as the effects of the main fluvastatin metabolites (M2, M3, and M4) and other inhibitors of the same enzyme, pravastatin and simvastatin. The hydroxyl radical and the superoxide anion scavenging activities of fluvastatin and its metabolites were evaluated using an electron spin resonance spectrometer. Fluvastatin and its metabolites showed superoxide anion scavenging activity in the hypoxanthine-xanthine oxidase system and a strong scavenging effect on the hydroxyl radical produced from Fenton's reaction. Protective effects of fluvastatin on ROS-induced DNA damage of CHL/IU cells were assessed using the single-cell gel electrophoresis assay. CHL/IU cells were exposed to either hydrogen peroxide or t-butylhydroperoxide. Fluvastatin and its metabolites showed protective effects on DNA damage as potent as the reference antioxidants, ascorbic acid, trolox, and probucol, though pravastatin and simvastatin did not exert clear protective effects. These observations suggest that fluvastatin and its metabolites may have radical scavenging activity and the potential to protect cells against oxidative DNA damage. Furthermore, ROS are thought to play a major role in the etiology of a wide variety of diseases such as cellular aging, inflammation, diabetes, and cancer development, so fluvastatin might reduce these risks.
Imaeda
A
A
Safety Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan. a-ima@tanabe.co.jp
Tanigawa
T
T
Aoki
T
T
Kondo
Y
Y
Nakamura
N
N
Yoshikawa
T
T
D000818:Animals; D000975:Antioxidants / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D002460:Cell Line; D020552:Comet Assay; D006224:Cricetinae; D004249:DNA Damage / Q000187:drug effects*; D004578:Electron Spin Resonance Spectroscopy; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D000077340:Fluvastatin; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007211:Indoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
D000975:Antioxidants; D005229:Fatty Acids, Monounsaturated; D007211:Indoles; D017382:Reactive Oxygen Species; D013481:Superoxides; D000077340:Fluvastatin; D006861:Hydrogen Peroxide