Protective effects of fluvastatin against reactive oxygen species induced DNA damage and mutagenesis.
Oxidative stress may be an important factor in the development of diabetic complications. Advanced glycation end-products have drown attention as potential sources of oxidative stress in diabetes. We investigated the protective effects of fluvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, on oxidative DNA damage from reactive oxygen species or advanced glycation end-products in vitro, as well as effects of main fluvastatin metabolites and other inhibitors of the same enzyme, pravastatin and simvastatin. Protective effects were assessed in terms of the DNA breakage rate in a single-stranded phage DNA system in vitro. DNA was exposed to either reactive oxygen species or advanced glycation end-products. Fluvastatin and its metabolites showed a strong protective effect comparable to those seen with thiourea and mannitol, though pravastatin and simvastatin did not exert clear protective effects. Furthermore, fluvastatin reduced the mutagenesis by reactive oxygen species or advanced glycation end-products in Salmonella typhimurium test strains. Both pravastatin and simvastatin still lacked protective activity. Fluvastatin and its metabolites protect against oxidative DNA damage and may reduce risk of consequent diabetic complications.
Safety Research Laboratory, Tanabe Seiyaku Co., Ltd., Osaka, Japan.
A
A
Imaeda
T
T
Aoki
Y
Y
Kondo
M
M
Hori
M
M
Ogata
H
H
Obayashi
G
G
Hasegawa
N
N
Nakamura
K
K
Tokuda
H
H
Nishino
T
T
Yoshikawa
M
M
Kondo
D001435:Bacteriophages / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects*; D004277:DNA, Single-Stranded / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism / Q000494:pharmacology*; D000077340:Fluvastatin; D016166:Free Radical Scavengers / Q000378:metabolism / Q000494:pharmacology*; D005947:Glucose / Q000737:chemistry / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology*; D016296:Mutagenesis / Q000187:drug effects*; D009152:Mutagenicity Tests / Q000379:methods; D018384:Oxidative Stress / Q000187:drug effects; D017035:Pravastatin / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D019821:Simvastatin / Q000494:pharmacology
D004277:DNA, Single-Stranded; D005229:Fatty Acids, Monounsaturated; D016166:Free Radical Scavengers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D017382:Reactive Oxygen Species; D000077340:Fluvastatin; D019821:Simvastatin; D005947:Glucose; D017035:Pravastatin