Rosuvastatin protects against oxidative stress and DNA damage in vitro via upregulation of glutathione synthesis

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, exert various beneficial effects independent of serum cholesterol reduction; among others is antioxixdative action. Human promyelocytic cells (HL-60) were used to examine the effect of the statin resuvastatin on reactive oxygen species-induced DNA damage, formation of oxidative stress and expression of glutathione metabolising enzymes. Rosuvastatin from 10 nM 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-glutamyleysteine synthetase. In conclusion, resuvastatin 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. (C) 2007 Elsevier Ireland Ltd. All rights reserved.