Antioxidative effects of fluvastatin and its metabolites against DNA damage in streptozotocin-treated mice.
Fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, and its metabolites have been reported to protect against oxidative DNA damage in vitro. Streptozotocin (STZ) has drawn attention as a potential source of oxidative stress that induces genotoxicity. In order to elucidate the antioxidative effects of fluvastatin in vivo, we investigated the effects of 7-day treatment with fluvastatin on DNA damage in STZ-treated mice, as well as the effects of the main fluvastatin metabolites (M2, M3 and M4) and other inhibitors of the same enzyme, pravastatin and simvastatin. Protective effects against DNA damage in the liver and kidney from STZ-treated mice were assessed by the single-cell gel electrophoresis assay, and by detecting 8-hydroxy-2'-deoxyguanosine. A single intraperitoneal injection of STZ (150 mg/kg) increased serum levels of glucose, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and blood urea nitrogen (BUN), and also caused DNA damage in the liver and kidney. Fluvastatin and its metabolites prevented the STZ-induced elevation of DNA damage and inhibited the increase in serum levels of AST, ALT and BUN. Fluvastatin and its metabolites showed protective effects against DNA damage as potent as that of the reference antioxidants (ascorbic acid, trolox and probucol) though pravastatin and simvastatin still lacked protective activity. Fluvastatin protected the mice against STZ-induced DNA damage, and may reduce the risk of oxidative stress in vivo.
Imaeda
A
A
Safety Research Laboratory, Tanabe Seiyaku Co., Ltd, Osaka, Japan. a-ima@tanabe.co.jp
Kaneko
T
T
Aoki
T
T
Kondo
Y
Y
Nakamura
N
N
Nagase
H
H
Yoshikawa
T
T
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D001786:Blood Glucose / Q000032:analysis; D001806:Blood Urea Nitrogen; D003404:Creatinine / Q000097:blood; D004247:DNA / Q000032:analysis; D004249:DNA Damage / Q000187:drug effects*; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000235:genetics*; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism* / Q000494:pharmacology*; D000077340:Fluvastatin; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000378:metabolism* / Q000494:pharmacology*; D007668:Kidney / Q000737:chemistry; D008099:Liver / Q000737:chemistry; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D018384:Oxidative Stress; D017035:Pravastatin / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects
D000975:Antioxidants; D001786:Blood Glucose; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D019821:Simvastatin; D003404:Creatinine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D003849:Deoxyguanosine; D017035:Pravastatin