title: Rosuvastatin protects against oxidative stress and DNA damage in vitro via upregulation of glutathione synthesis.
abstract: Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, exert various beneficial effects independent of serum cholesterol reduction; among others is antioxidative action. Human promyelocytic cells (HL-60) were used to examine the effect of the statin rosuvastatin on reactive oxygen species-induced DNA damage, formation of oxidative stress and expression of glutathione metabolising enzymes. Rosuvastatin from 10nM significantly reduced DNA damage induced by phorbol 12-myristate 13-acetate (PMA) or by hydrogen peroxide, as assessed by the comet assay. PMA-provoked formation of reactive oxygen species, measured by flow cytometric measurement, was also prevented by rosuvastatin. Pre-incubation of cells with rosuvastatin revealed a protective effect of the statin even after its removal from the incubation medium. Total glutathione in cells treated with PMA, with and without co-incubation with rosuvastatin, was increased significantly in cells incubated with rosuvastatin alone. The quantification of the mRNA and activity of glutathione synthesizing enzymes by PCR showed a significant upregulation of gamma-glutamylcysteine synthetase. In conclusion, rosuvastatin exerts antioxidative effects, which are also capable of preventing DNA damage. These effects seem to be independent of HMG-CoA reductase inhibition and involve the induction of the expression of antioxidant defense enzymes.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany. nicole.schupp@toxi.uni-wuerzburg.de
authors.forename: Nicole
authors.initials: N
authors.lastname: Schupp
authors.forename: Ursula
authors.initials: U
authors.lastname: Schmid
authors.forename: August
authors.initials: A
authors.lastname: Heidland
authors.forename: Helga
authors.initials: H
authors.lastname: Stopper
mesh_terms: D000975:Antioxidants / Q000494:pharmacology; D020552:Comet Assay; D004249:DNA Damage; D005434:Flow Cytometry; D005464:Fluorobenzenes / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic; D005978:Glutathione / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D018384:Oxidative Stress; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology*; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate; D015854:Up-Regulation
chemical_list: D000975:Antioxidants; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D006903:Hydroxymethylglutaryl CoA Reductases; D005978:Glutathione; D013755:Tetradecanoylphorbol Acetate