Pharmacological Research 59 (2009) 242–247 Contents lists available at ScienceDirect Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs Effects of atorvastatin therapy on protein oxidation and oxidative DNA damage in hypercholesterolemic rabbits S. Aydin a,∗ , H. Uzun a , V. Sozer b , T. Altug c a Department of Biochemistry, Istanbul University, Cerrahpasa Medical Faculty, Istanbul, Turkey b Department of Biochemistry, Yildiz Technical University, Istanbul, Turkey c Experimental Animal-Research and Breeding Laboratory, Istanbul University, Cerrahpasa Medical Faculty, 34096 Cerrahpasa, Istanbul, Turkey article info Article history: Received 2 September 2008 Received in revised form 13 January 2009 Accepted 14 January 2009 Keywords: Hypercholesterolemia Atorvastatin Protein oxidation Oxidative DNA damage Lipid peroxidation Rat abstract Objective: Our aim was to clarify the effects of hypercholesterolemic diet and administeration of atorvastatin on lipid peroxidation, protein oxidation and oxidative DNA damage in male New Zealand white rabbits. Methods: We determined malondialdehyde (MDA), protein carbonyl (PCO) and total thiol (T-SH) levels in plasma and liver tissue, glutathione (GSH) levels in erythrocyte and liver tissue, and 8-hydroxy-2- deoxyguanosine (8-OHdG) levels in plasma. Twenty rabbits were randomly divided into two groups and fed with a high-cholesterol diet (fortified with 1% cholesterol) for 4 weeks. Such rabbits were subjected to either (Group 1) a high-cholesterol diet non-supplemented with atorvastatin (n =10) or (Group 2) a high-cholesterol diet supplemented with atorvastatin (0.3 mg atorvastatin per day/kg body weight) for 4 weeks (n = 10). A control group (n =5) (Group 3) was fed a cholesterol free diet for 4 weeks. Colorimetric methods were used to determine the level of the oxidative stress markers, except 8-OHdG, which was measured by ELISA. Results: Rabbits were fed with the high-cholesterol diet alone (Group 1) showed higher levels of lipid profile and oxidative protein and DNA damage than compared with dose of the control group (Group 3). Atorvastatin therapy has substantially beneficial effects on oxidative protein and DNA damage in hypercholesterolemic rabbits. Conclusions: The current findings will, we hope, lead to a new insight into the pathogenesis of atheroscle- rosis. On the other hand inhibition of protein oxidation and DNA oxidation in the plasma by atorvastatin may be one of the pleiotropic effects of statins, and thus the underlying mechanism needs to be further clarifications. © 2009 Elsevier Ltd. All rights reserved. 1. Introduction The incidence of cardiovascular disease increases with aging and atherosclerosis being a major underlying histopathological process. One of the most widely recognised initiating factors is hypercholesterolaemia, which is associated with an increased susceptibility to oxidation of low-density lipoproteins (LDL) [1]. On the other hand, statins, a group of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are widely used hypolipidemic drugs in clinical practice. Their hypolipidemic actions mainly related to the decrease in plasma LDL cholesterol levels and statins have also strong antioxidant, anti-inflammatory and antiatherosclerotic properties [2]. Cellular proteins are believed to be primary target for oxida- tive damage in cells. Oxidative damage of the cellular proteins may ∗ Corresponding author. Tel.: +90 212 414 30 56; fax: +90 212 633 29 87. E-mail address: aydinseval@yahoo.com (S. Aydin). be result of increased non-specific oxidation of amino acids and/or metal catalyzed oxidation of specific amino acid residues. The for- mation and accumulation of oxidized proteins could be potentially harmful for various cellular functions [3]. For many years, lipid oxidation was a focus of study, but due to their relatively high abundance in cellular environment it is now recognised that cellu- lar proteins are the main targets for various oxidants. Recently, the number of reports supporting the idea that protein and lipid oxida- tion are coupled processes. However, the interaction between lipids and proteins during oxidation process is still not fully understood. It is now well established that exposure of proteins to reactive oxygen species (ROS) can alter their chemical structures and causing con- sequent oxidation of amino acid side-chain groups. These oxidative modifications mainly consist of peptide backbone fragmentation, cross-linking, unfolding and formation of new reactive groups. The latter include oxidation of hydrophobic amino acyl residues to hydroxy and hydroperoxy (P-OOH) derivatives, protein carbonyl (PCO) formation, oxidation of thiol (T-SH) groups, dityrosine forma- 1043-6618/$ – see front matter © 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2009.01.004